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M Ernst

Publications and source records attributed to M Ernst.

At least 19 recordsLinked to original sources
PubMed1999

Elevated expression of endoglin, a component of the TGF-beta-receptor complex, correlates with proliferation of tumor endothelial cells.

Endoglin/CD105 is a membrane protein involved in the TGF-beta receptor signalling pathway. Endoglin expression has been reported to be selective for a few cell types, in particular endothelial cells, although a number of conflicting reports have been published. In this study, we performed a detailed analysis of endoglin expression in human lung tumors and different tumor and endothelial cell lines, employing reverse-transcriptase-polymerase-chain reaction as well as immunoblotting and immunohistochemistry using verified antibodies to endoglin. Our data show a clearly preferential expression of both endoglin mRNA and protein in endothelial cells. In tumors, endoglin expression was strongly elevated in the angiogenic endothelium at the tumor edges. In agreement with this observation, we find a clear correlation between endoglin expression and markers of proliferation, such as cyclin A and Ki-67, suggesting that endoglin expression is linked to cell-cycle regulation. These findings not only resolve some of the discrepancies in the literature, but also provide the basis for further applications making use of its selective localization and expression in the tumor vasculature.

Antigens, CD↗
PubMed1999

The carboxyl-terminal domains of gp130-related cytokine receptors are necessary for suppressing embryonic stem cell differentiation. Involvement of STAT3.

Cell type-specific responses to the leukemia inhibitory factor (LIF)/interleukin 6 cytokine family are mediated by dimerization of the LIF receptor alpha-chain (LIFRalpha) with the signal transducer gp130 or of two gp130 molecules followed by activation of the JAK/STAT and Ras/mitogen-activated protein kinase cascades. In order to dissect the contribution of gp130 and LIFRalpha individually, chimeric molecules consisting of the extracellular domain of the granulocyte colony stimulating factor receptor (GCSF-R) and various mutant forms of the cytoplasmic domains of gp130 or LIFRalpha were expressed in embryonic stem (ES) cells to test for suppression of differentiation, or in a factor-dependent plasma cytoma cell line to assess for induction of proliferation. Carboxyl-terminal domains downstream of the phosphatase (SHP2)-binding sites were dispensable for mitogen-activated protein kinase activation and the transduction of proliferative signals. Moreover, carboxyl-terminal truncation mutants which lacked intact Box 3 homology domains showed decreased STAT3 activation, failed to induce Hck kinase activity and suppress ES cell differentiation. Moreover, STAT3 antisense oligonucleotides impaired LIF-dependent inhibition of differentiation. Substitution of the tyrosine residue within the Box 3 region of the GSCF-R abolished receptor-mediated suppression of differentiation without affecting the transduction of proliferative signals. Thus, distinct cytoplasmic domains within the LIFRalpha, gp130, and GCSF-R transduce proliferative and differentiation suppressing signals.

Antigens, CD↗
PubMed1999

Retinoic acid effects on an SV-40 large T antigen immortalized adult rat bone cell line.

Clonal cell lines were established from adult rat tibia cells immortalized with SV-40 large T antigen. One clone (TRAB-11), in which retinoic acid (RA) induced alkaline phosphatase (AP) activity, was selected for further study. The TRAB-11 cells express high levels of type I collagen mRNA, type IV collagen, fibronectin, practically no type III collagen, little osteopontin, and no osteocalcin. RA stimulates proliferation of TRAB-11 cells (starting at 10 pM) and survival (starting at 100 pM). TRAB-11 cells synthesize fibroblast growth factor-2 (FGF-2), which has potent autocrine mitogenic effects on these cells and acts synergistically with RA. TRAB-11 cells attach better to type IV collagen than to fibronectin or laminin. Cell attachment to type IV collagen is increased by RA and decreased (65%) by an antibody directed against alpha1beta1 integrin. RA up-regulates steady-state levels of alpha1, mRNA without affecting beta1 mRNA expression. In conclusion, we report the establishment of a clonal cell line from the outgrowth of adult rat tibiae which is highly sensitive to RA in its growth and survival in culture, apparently as a result of integrin-mediated cell interaction with extracellular matrix proteins.

Alkaline Phosphatase↗
PubMed1999

High presynaptic dopaminergic activity in children with Tourette's disorder.

OBJECTIVE: Tourette's disorder is characterized by chronic fluctuating motor and vocal tics. Despite extensive investigation of the neuropathophysiology of the disorder by a wide array of methodologies, its neurobiochemical substrate is still unclear. Converging evidence, however, suggests a primary role of the dopaminergic system, particularly within the basal ganglia. METHOD: This study examined the integrity of presynaptic dopaminergic function in children with Tourette's disorder, using positron emission tomography and the tracer [18F]fluorodopa (FDOPA). Accumulation of FDOPA in synaptic terminals, a measure of DOPA decarboxylase activity, was quantified in caudate nucleus, putamen, frontal cortex, and midbrain (i.e., substantia nigra and ventral tegmentum). RESULTS: Subjects with Tourette's disorder showed higher FDOPA accumulation than controls in the left caudate nucleus (by 25%; p = .03) and right midbrain (by 53%; p = .08). CONCLUSION: These findings provide evidence of dopaminergic dysfunction in children with Tourette's disorder which affects both cell nuclei and nerve terminals. Based on the known regulation of DOPA decarboxylase activity by post- and presynaptic receptors, and by extracellular dopamine concentration, abnormal activity in this enzyme may reflect deficits in a variety of functional elements of the dopamine system. The precise mechanism underlying an up-regulation of DOPA decarboxylase activity needs to be identified in future studies.

Adolescent↗
PubMed1999

Nontricyclic antidepressants: current trends in children and adolescents.

OBJECTIVES: First, to review the extant data on the safety and efficacy of the use of nontricyclic antidepressants in children and adolescents; second, to identify the main limitations of our current knowledge in this area; and third, to point to future research directions. METHOD: A Medline search and a review of previous scientific meetings were conducted; all available reports on the efficacy and safety of nontricyclic antidepressants in children and adolescents were critically reviewed. RESULTS: As in adults, also in children nontricyclic antidepressants are potentially useful in treating a variety of psychiatric disorders. The data supporting their efficacy, however, are quite limited. Obsessive-compulsive disorder is the only psychiatric diagnosis for which pediatric use of selective serotonin reuptake inhibitors has been approved. One placebo-controlled study in children and adolescents with major depression supports the efficacy of fluoxetine. Other clinical trials of nontricyclic antidepressants in depressed adolescents are in progress. Available data indicate that the safety of these medications is good, at least in the short term. CONCLUSIONS: The potential usefulness of nontricyclic antidepressants for children and adolescents suffering from a range of disorders is considerable. While information from adults can suggest potential areas of possible efficacy in pediatric patients suffering from similar psychopathology, further research is essential to provide the necessary information on the efficacy, safety, and pharmacokinetics of these medications in children and adolescents.

Adolescent↗
PubMed1999

The internalization time course of a given lipopolysaccharide chemotype does not correspond to its activation kinetics in monocytes.

The prerequisites for the initiation of pathophysiological effects of endotoxin (lipopolysaccharide [LPS]) include binding to and possibly internalization by target cells. Monocytes/macrophages are prominent target cells which are activated by LPS to release various pro- and anti-inflammatory mediators. The aim of the present study was to establish a new method to determine the binding and internalization rate of different LPS chemotypes by human monocytes and to correlate these phenomena with biological activity. It was found that membrane-bound LPS disappears within hours from the surface being internalized into the cell. Further, a correlation between the kinetics of internalization and the length of the sugar chain as well as an inverse correlation between the time course of internalization and LPS hydrophobicity was revealed. Comparison of the internalization kinetics of different LPS chemotypes with kinetics of tumor necrosis factor alpha release and kinetics of oxidative burst did not reveal any correlation of these parameters. These findings suggest that cellular internalization of and activation by LPS are mechanisms which are independently regulated.

Biological Transport, Active↗
PubMed1998

DOPA decarboxylase activity in attention deficit hyperactivity disorder adults. A [fluorine-18]fluorodopa positron emission tomographic study.

Converging evidence implicates the dopaminergic system and the prefrontal and nigrostriatal regions in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Using positron emission tomography (PET) with [fluorine-18]fluorodopa (F18-DOPA), we compared the integrity of the presynaptic dopaminergic function between 17 ADHD adults and 23 healthy controls. The ratio of the isotope concentration of specific regions to that of nonspecific regions reflects DOPA decarboxylase activity and dopamine storage processes. Of three composite regions (prefrontal cortex, striatum, and midbrain), only the prefrontal cortex showed significantly different F18-DOPA ratios in ADHD as compared with control adults (p < 0.01). The medial and left prefrontal areas were the most altered (lower F18-DOPA ratios by 52 and 51% in ADHD as compared with controls). Similarly, the interaction [sex x diagnosis] was significant only in the prefrontal cortex (p < 0.02): lower ratios in men than in women in ADHD and vice versa in controls. These findings suggest that a prefrontal dopaminergic dysfunction mediates ADHD symptoms in adults and that gender influences this abnormality. On the basis of previous neuroimaging findings in ADHD showing discrepant findings in adults and adolescents and on evidence for midbrain dopaminergic defect in adolescents, we hypothesize that the prefrontal dopaminergic abnormality in ADHD adults is secondary and results from an interaction of the primary subcortical dopaminergic deficit with processes of neural maturation and neural adaptation.

Adult↗
PubMed1998

High-speed magic-angle spinning 13C MAS NMR spectra of adamantane: self-decoupling of the heteronuclear scalar interaction and proton spin diffusion.

We have investigated the carbon line shape of solid adamantane under high-speed magic-angle sample spinning (MAS) acquired without proton decoupling. The CH-group shows a spinning-speed-dependent line broadening while the CH2-group consists of a spinning-speed-independent sharp component and a spinning-speed-dependent broader part. These phenomena can be explained by self-decoupling of the J-interaction due to proton spin diffusion. Such a self-decoupling process can be described by a magnetization exchange process between the multiplet lines. Changing the spin-diffusion rate constant by off-resonance irradiation of the protons allows us to observe the full range from slow exchange to coalescence to fast exchange of the carbon spectra. One of the multiplet components in the CH2-group corresponds to a group spin of the protons of zero and therefore does not couple to the other protons. This gives rise to the sharp central line. The magnetization exchange rate constant between the different multiplet lines can be determined from the spectra and is a measure for the spinning-speed-dependent proton spin-diffusion rate constant. Even at an MAS speed of 30 kHz, proton spin diffusion is still observable despite the relatively weak intermolecular proton dipolar-coupling network in adamantane which results in a static proton line width of only 14 kHz (full width at half height).

Adamantane↗
PubMed1998

Are MAO-A deficiency states in the general population and in putative high-risk populations highly uncommon?

Lack of monoamine oxidase A (MAO-A) due to either Xp chromosomal deletions or alterations in the coding sequence of the gene for this enzyme are associated with marked changes in monoamine metabolism and appear to be associated with variable cognitive deficits and behavioral changes in humans and in transgenic mice. In mice, some of the most marked behavioral changes are ameliorated by pharmacologically-induced reductions in serotonin synthesis during early development, raising the question of possible therapeutic interventions in humans with MAO deficiency states. At the present time, only one multi-generational family and a few other individuals with marked MAO-A deficiency states have been identified and studied in detail. Although MAO deficiency states associated with Xp chromosomal deletions were identified by distinct symptoms (including blindness in infancy) produced by the contiguous Norrie disease gene, the primarily behavioral phenotype of individuals with the MAO mutation is less obvious. This paper reports a sequential research design and preliminary results from screening several hundred volunteers in the general population and from putative high-risk groups for possible MAO deficiency states. These preliminary results suggest that marked MAO deficiency states are very rare.

Adolescent↗
PubMed1998

Gene transfer into rat heart-derived endothelial cells.

OBJECTIVE: Progressive graft arteriosclerosis is responsible for the majority of late deaths in cardiac transplant recipients. Despite many investigations, the pathogenesis of this disease remains undetermined and its control inadequate. A somatic gene transfer during the cold ischemic time and thus before transplantation might be a new therapeutic tool. This approach allows a long incubation time of the DNA and a safe transfer with liposomes and transferrin with less adverse effects for the organ recipient. METHODS: The target cells (microvascular endothelial cells (MVECs)) for this gene transfer were isolated from rat hearts by perfusion with collagenase via an aortic cannulae. The cells were purified by changing the medium 30 min after subcultivation in order to remove fibroblasts and smooth muscle cells. The endothelial cells (ECs) were identified by typical morphology and the uptake of Dil-Ac-LDL. The gene transfer was carried out with a beta-galactosidase reporter plasmid (pCMVbeta), cationic liposomes (Lipofectin), and transferrin. Different transfection solutions were prepared with or without serum, and with different plasmid-liposome ratios and transferrin concentrations. The transfer rate was monitored with a semiquantitative orthonitrophenyl-beta/-D-galactoside (ONPG) assay and histologically by X-Gal staining. The cytotoxicity of this procedure was determined with a colorimetric ELISA with Alamar blue. The cardioplegic property of the transfection solution was tested in a Langendorff perfusion system monitoring the coronary blood flow over time after a cold ischemic time of 4 h. RESULTS: The maximal gene expression could be detected after transfection with 4 microl Lipofectin, 2 microg pCMVbeta, and 16 microg transferrin/200 microl transfection solution. Under these conditions 60% of the cells showed a blue staining with X-Gal. Only 20% of the cells died during transfection. The lowest cytotoxicity during cold ischemic time for ECs was assessed with normal cell culture medium and the Buckberg solution. The best coronary flow rates after 4 h cold ischemia of the heart were measured for cardioplegia with St. Thomas and Buckberg solutions. In summary, the best transfection solution with a good cardioplegic property was the Buckberg solution. CONCLUSIONS: Finally, the results of this study show that an effective DNA delivery with a low toxicity into ECs is possible with a combination of liposomes and transferrin. This method might be useful for a safe and effective gene transfer into solid organs during the cold ischemic time and thus a therapeutic tool for chronic rejection.

Animals↗
PubMed1998

Laboratory and diagnostic testing in child and adolescent psychiatry: a review of the past 10 years.

OBJECTIVE: To review in a critical fashion the literature of the past decade covering diagnostic and laboratory testing in the field of child and adolescent psychiatry. METHOD: A computerized search of articles published during the past decade was made, and selected articles are presented. Because of the paucity of articles specifically relating to minors, selected articles from adult psychiatry are cited. RESULTS: With a few notable exceptions, few controlled studies on the specificity and sensitivity of any laboratory test for any specific disorder of behavior presenting in children have been conducted in children and adolescents. A high index of suspicion will remain the clinician's best ally in utilizing laboratory measures in the assessment of psychopathology. Nonetheless, studies have appeared that will guide the clinician as to what tests are not clinically useful. CONCLUSION: Indications and the lack of indications for specific laboratory studies are an integral part of the knowledge base that child psychiatrists must have. Much more empirical data will need to be collected prospectively to inform the field and to move the judicious use of the laboratory from an art to a science.

Adolescent↗
PubMed1998

Differences in the anti-inflammatory effects of theophylline and pentoxifylline: important for the development of asthma therapy?

Antiasthma drugs are now being re-evaluated for their anti-inflammatory effects. Theophylline is an immunomodulator; however, weak effects and the narrow therapeutic window make it a controversial drug. We compared the immunomodulatory potencies of theophylline with those of the xanthines pentoxifylline (POF) and A802715. Using a whole-blood, cell-culture system, we studied the effects on the release of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin-6 (IL-6) in six healthy subjects, and, in granulocyte suspensions, the effects on the release of reactive oxygen species (ROS). We also studied the influence of a 14-day treatment with theophylline or POF on the release of the cytokines named above in 14 asthmatics. We found that equimolar concentrations of A802715 most effectively inhibit ROS generation, followed by POF; the effects of theophylline were weakest. A802715-inhibited release of TNF-alpha was four times as potent as that of theophylline, and POF two times as potent. Inhibition of IFN-gamma by A802715 was three times as potent, and by POF two times. Neither drug influenced IL-6 release. After a 14-day treatment of asthmatics, POF proved to inhibit TNF-alpha release more effectively (by 44.3%) than theophylline (7.5%). It is concluded that study of xanthine derivatives in asthmatics might help the development of asthma therapy. POF seems to be an especially promising candidate.

Adult↗
PubMed1998

Age-related changes in brain glucose metabolism in adults with attention-deficit/hyperactivity disorder and control subjects.

Using positron emission tomography and [18F]-2-fluoro-2-deoxy-D-glucose, the authors determined cerebral metabolic rates for glucose (CMRglc) in 39 adults (18-51 years old) with attention-deficit/hyperactivity disorder (ADHD) and 56 healthy control adults (19-56 years old) during the performance of a continuous attention task. Increased age was associated with reduced global CMRglc in ADHD women, but not in ADHD men, control men, or control women. Better performance on the attention task was significantly associated with increased age only in the ADHD female group. Determining the role of behavioral, hormonal, and genetic factors is a challenge for future research.

Adolescent↗
PubMed1998

Oral dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression.

Women with adrenal insufficiency suffer from chronic dehydroepiandrosterone (sulfate) [DHEA(S)] deficiency. To define a suitable dose for DHEA replacement, we studied the pharmacokinetics and biotransformation of orally administered DHEA in nine healthy female volunteers (mean age 23.3 +/- 4.1 yr, mean body mass index 22.5 +/- 1.8 kg/m2) with transient suppression of adrenal androgen secretion because of dexamethasone (dex) administration (4 x 0.5 mg/day for 4 days). Diurnal blood sampling was performed during the early follicular phase of four subsequent menstrual cycles (study period 1: baseline; study periods 2-4: dex + placebo, dex + 50 mg DHEA or dex + 100 mg DHEA in a randomized cross-over design). Dex induced not only a significant suppression of serum cortisol (to 8% of baseline) but also of DHEA (18%), DHEA(S) (16%), and androstenedione (26%), as well as of testosterone (28%), dihydrotestosterone (43%), and estrone (54%). Oral administration of 50 mg DHEA led to restoration of DHEA(S) baseline levels, whereas 100 mg induced supraphysiological concentrations [baseline vs. 50 mg DHEA vs. 100 mg DHEA: area under the concentration-time curve (AUC) 0-12 h DHEA: 280 +/- 85 vs. 241 +/- 73 vs. 383 +/- 106 nmol/L x h; AUC 0-12 h DHEA(S): 89.1 +/- 48.4 vs. 139.6 +/- 43.5 vs. 213.3 +/- 21.6 mumol/L x h). Serum concentrations of dihydrotestosterone and estrone were restored to baseline after 50 mg DHEA, whereas baseline testosterone and androstenedione levels were only achieved by administration of 100 mg DHEA. In conclusion, 50 mg DHEA seems to be a suitable replacement dose in females with adrenal insufficiency. Furthermore, the rapid and lasting conversion to potent androgens demonstrates a potential role of DHEA for androgen replacement in females in general.

Administration, Oral↗
PubMed1998

Immune cell functions in industrial workers after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin: dissociation of antigen-specific T-cell responses in cultures of diluted whole blood and of isolated peripheral blood mononuclear cells.

A comparative analysis was performed of the phenotype and function of peripheral blood leukocytes of two age-matched cohorts of industrial workers in chemical plants, one of which was exposed occupationally to high concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Median actual TCDD burdens were 116 ng/kg and 4 ng/kg, respectively. The phenotype analysis of peripheral blood mononuclear cells (PBMC) revealed no significant differences in the proportions of CD3, CD4, or CD8+ T lymphocytes, of CD16+ natural killer cells, and of CD19+ B lymphocytes. However, in PBMC of the TCDD-exposed workers; the proportion of CD8+ memory T cells (CD45R0+) was significantly higher, and that of lymphocytes with naive phenotype (CD45RA+) was significantly lower than in PBMC of the control group. Polyclonal and antigen-specific T-cell activation was assessed in parallel in isolated PBMC as well as in diluted whole blood cultures. In both culture systems the polyclonally stimulated cytokine release did not differ significantly between the two cohorts; however, we found a significantly reduced interferon gamma release in diluted whole blood cultures but not in isolated PBMC cultures of the TCDD-exposed cohort when we performed an antigen-specific T-cell stimulation with tetanus-toxoid. Therefore, we propose that exposure of individuals to high doses of TCDD can partially impair in the "blood milieu" those T-cell/monocyte interactions that are essential for antigen-specific T-cell responses, whereas isolated PBMC of the same donors appear functionally less affected.

Adult↗