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Biomedical subjects

M Ernst

Publications and source records attributed to M Ernst.

At least 91 records · Page 5Linked to original sources
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↗
PubMed1999

The role of cytokines in monocyte apoptosis.

Survival or apoptosis, activation and differentiation, phagocytosis and antigen presentation, migration or participation in granuloma formation are features of freshly recruited blood-borne monocytes in the local environment. In this presentation we describe that human monocytes undergo spontaneous apoptosis in vitro which involves Fas/FasL interactions, and that proinflammatory cytokines such as tumor necrosis factor-alpha (TNFalpha), interleukin-1beta and granulocyte-monocyte-colony-stimulating factor prevent spontaneous apoptosis. In vitro infection of purified monocytes with low numbers of Mycobacterium tuberculosis H37Rv prevents spontaneous apoptosis. The apoptosis-preventing effect is correlated to the release of TNFalpha and not due to phagocytosis per se. Furthermore, the minor subset of CD64-negative monocytes is found to be less susceptible to recall antigen-activated CD4-positive T cell-mediated apoptosis than CD64-positive monocytes. Finally, recent findings of our group indicate that the chemokine platelet factor 4 protects monocytes from spontaneous apoptosis and induces the differentiation of monocytes into macrophages. From these findings we conclude that monocyte recruitment, their survival, their differentiation and their functional activity at the site of inflammation are regulated by a cytokine network which needs to be further analyzed in order to design strategies for immune intervention.

Antibodies, Bacterial↗
PubMed1999

High midbrain [18F]DOPA accumulation in children with attention deficit hyperactivity disorder.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a highly prevalent childhood psychiatric disorder characterized by impaired attention, excessive motor activity, and impulsivity. Despite extensive investigation of the neuropathophysiology of ADHD by a wide array of methodologies, the neurobiochemical substrate of this disorder is still unknown. Converging evidence, however, suggests a primary role of the dopaminergic system. METHOD: This study examined the integrity of presynaptic dopaminergic function in children with ADHD through use of positron emission tomography and the tracer [18F]fluorodopa ([18F]DOPA). Accumulation of [18F]DOPA in synaptic terminals, a measure of dopa decarboxylase activity, was quantified in regions rich in dopaminergic innervation, including caudate nucleus, putamen, frontal cortex, and midbrain (i.e., substantia nigra and ventral tegmentum). RESULTS: Accumulation of [18F]DOPA in the right midbrain was higher by 48% in 10 children with ADHD than in 10 normal children. Despite its magnitude, this difference would not have reached statistical significance if corrected by the Bonferroni test for multiple comparisons. However, [18F]DOPA in the right midbrain was correlated with symptom severity. No other dopamine-rich regions significantly differed between groups. CONCLUSIONS: These findings are suggestive of dopaminergic dysfunction at the level of the dopaminergic nuclei in children with ADHD. Abnormality in dopa decarboxylase activity may be primary or secondary to deficits in other functional units of the dopamine pathway (e.g., receptor, uptake transporter, vesicular transporter, degradation enzymes). Efforts toward defining the origin of this abnormality should help delineate mechanisms of midbrain control of attention and motor behavior important for the understanding of the causes and treatment of ADHD.

Adolescent↗
PubMed1999

Biotransformation of oral dehydroepiandrosterone in elderly men: significant increase in circulating estrogens.

The most abundant human steroids, dehydroepiandrosterone (DHEA) and its sulfate ester DHEAS, may have a multitude of beneficial effects, but decline with age. DHEA possibly prevents immunosenescence, and as a neuroactive steroid it may influence processes of cognition and memory. Epidemiological studies revealed an inverse correlation between DHEAS levels and the incidence of cardiovascular disease in men, but not in women. To define a suitable dose for DHEA substitution in elderly men we studied pharmacokinetics and biotransformation of orally administered DHEA in 14 healthy male volunteers (mean age, 58.8 +/- 5.1 yr; mean body mass index, 25.5 +/- 1.5 kg/m2) with serum DHEAS concentrations below 4.1 micromol/L (1500 ng/mL). Diurnal blood sampling was performed on 3 occasions in a single dose, randomized, cross-over design (oral administration of placebo, 50 mg DHEA, or 100 mg DHEA). The intake of 50 mg DHEA led to an increase in serum DHEAS to mean levels of young adult men, whereas 100 mg DHEA induced supraphysiological concentrations [placebo vs. 50 mg DHEA vs. 100 mg DHEA; area under the curve (AUC) 0-12 h (mean +/- SD) for DHEA, 108 +/- 22 vs. 252 +/- 45 vs. 349 +/- 72 nmol/L x h; AUC 0-12 h for DHEAS, 33 +/- 9 vs. 114 +/- 19 vs. 164 +/- 36 micromol/L x h]. Serum testosterone and dihydrotestosterone remained unchanged after DHEA administration. In contrast, 17beta-estradiol and estrone significantly increased in a dose-dependent manner to concentrations still within the upper normal range for men [placebo vs. 50 mg DHEA vs. 100 mg DHEA; AUC 0-12 h for 17beta-estradiol, 510 +/- 198 vs. 635 +/- 156 vs. 700 +/- 209 pmol/L x h (P < 0.0001); AUC 0-12 h for estrone, 1443 +/- 269 vs. 2537 +/- 434 vs. 3254 +/- 671 pmol/L x h (P < 0.0001)]. In conclusion, 50 mg DHEA seems to be a suitable substitution dose in elderly men, as it leads to serum DHEAS concentrations usually measured in young healthy adults. The DHEA-induced increase in circulating estrogens may contribute to beneficial effects of DHEA in men.

Aged↗
PubMed1999

Brain imaging studies of cocaine abuse: implications for medication development.

Contemporary in vivo brain imaging techniques confer the ability to assess brain function and structure noninvasively, and thereby can yield information to help guide the development of new treatments for substance abuse. The advantages and limitations of the major imaging modalities (positron emission tomography [PET], single photon emission computed tomography [SPECT], structural and functional magnetic resonance imaging [MRI, fMRI, respectively]) are discussed with respect to their applicability to research on cocaine abuse. The effects of acute administration of cocaine have been studied using PET and fMRI, with PET manifesting decreases in cerebral glucose metabolism and blood flow, and fMRI revealing regional effects that are correlated temporally with subjective responses. In addition, studies of drug abusers, abstinent from cocaine for various lengths of time, have revealed persistent differences in brain function and structure, especially in the frontal cortex, when compared with parameters in the brains of subjects who do not use illicit drugs of abuse. PET studies also have revealed abnormalities in markers for dopaminergic and opioid systems during withdrawal from cocaine. Moreover, studies of cue-elicited craving for cocaine demonstrate a connection between the response to drug-related stimuli and neural elements of cognition and emotion. The future directions of in vivo brain imaging to identify functional and structural alterations in the brains of cocaine abusers are discussed in relation to the development of medications to treat cocaine dependence.

Animals↗
PubMed1999

From IgG monoclonals to IgM-like molecules.

One problem in blood group testing is that IgG monoclonal antibodies, in contrast to IgM, do not usually agglutinate erythrocytes. One of the reasons is the high zeta potential induced by the negative charge of the cell surface. During the last few years, we have produced a series of human monoclonal antibodies by the conventional fusion technique directed against antigens of the Rh blood group system. Some of these monoclonals, especially those directed against Rh-subgroups such as the c-antigen, were mainly of the IgG-subtype and unsuitable for agglutination tests. We have therefore tried to establish a molecular biological method to make IgM-like molecules from IgG monoclonals. From the c-antigen specific human hybridoma BS 240 (IgG subtype), we isolated mRNA that was transcribed into cDNA and then amplified by PCR using family specific primers. The heavy and light chain products were cloned into the pHen vector containing a DNA linker fragment, a myc-tag for identification and a His-tag for purification. After transformation in E.coli and phage rescue with helper phage, the culture supernatant was screened for antigen positive recombinant phage antibodies as a first control for specificity using c-antigen positive erythrocytes and anti-M13 antibodies as bridging antibodies (Coombs technique). Erythrocytes being negative for the c-antigen served as a negative control. After changing the culture conditions, soluble single chain fragments (scFv) were obtained from the periplasmatic extract. Specificity was shown using the c-antigen positive and negative erythrocytes and the 9E10 antibody (anti-myc) as a bridging antibody. To obtain IgM-like molecules, DNA coding for the specific scFv was cloned into the vector pSTE containing DNA coding for the monomer of core streptavidin. After expression, purification and refolding of the monomer, the core streptavidin combines to form tetrameric structures, termed scFv::strep, that are able to bind biotin as shown using ELISA plates coated with biotinylated BSA. Binding was detected with 9E10 and a peroxidase conjugated secondary antibody. In the agglutination assay, the construct was able to agglutinate c-antigen positive erythrocytes but not the negative erythrocytes. These experiments show that it is possible to construct IgM-like agglutinating molecules from cells containing secreting IgG antibodies. Experiments employing human antibody libraries instead of hybridoma cell lines are now in progress.

Amino Acid Sequence↗
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↗