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M Ernst

Publications and source records attributed to M Ernst.

At least 55 records · Page 3Linked to original sources
PubMed2000

The CXC-chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages.

Unstimulated monocytes rapidly undergo physiological changes resulting in programmed cell death (apoptosis) while stimuli promoting differentiation of these cells into macrophages were shown to inhibit apoptotic processes. In the present study, we report that the platelet-derived alpha-chemokine platelet factor 4 (PF4) induces the differentiation of monocytes into macrophages, as is evident from morphological changes as well as from the up-regulation of differentiation markers (carboxypeptidase M/MAX1 and CD71). Significant alterations of the phenotype were observed after 72 hours of culture in the presence of the chemokine and required a minimal concentration of 625 nmol/L PF4. PF4-induced macrophages were characterized by a lack of HLA-DR antigen on their surface but showed a strong increase in the expression of the CD28 ligand B7-2. Furthermore, PF4 stimulation prevented monocytes from undergoing spontaneous apoptosis during 72 hours of culture as determined in an annexin-V-binding assay. Although PF4 induced the secretion of relevant amounts of TNF-alpha, neutralizing antibodies directed against TNF-alpha or granulocyte-macrophage colony-stimulating factor (GM-CSF) did not revert PF4-induced rescue from programmed cell death, suggesting that PF4 exerts its antiapoptotic effects in a TNF-alpha- or GM-CSF-independent fashion. On the basis of these results, we propose a novel role for PF4 in the control of monocyte differentiation during an inflammatory process in vivo. (Blood. 2000;95:1158-1166)

Antibodies, Monoclonal↗
PubMed2000

Functional neuroimaging of autistic disorders.

Functional neuroimaging methods hold promise for elucidating the neurobiology of autistic disorders, yet they present difficult practical and scientific challenges when applied to these complex and heterogeneous syndromes. Single-state studies of brain metabolism and blood flow thus far have failed to yield consistent findings, but suggest considerable variability in regional patterns of cerebral synaptic activity. Patients with idiopathic autism are less likely to show abnormalities than are patients with comorbid illness or epilepsy. Activation studies have begun to suggest alterations in brain organization for language and cognition. Neurotransmitter studies using positron emission tomography (PET) suggest abnormalities of serotonergic and dopaminergic function. Studies using magnetic resonance spectroscopy (MRS) have begun to document metabolic deficits in the frontal cortex and cerebellum. A single study using magnetoencephalography suggests a high incidence of epileptiform activity in children with autistic regression. Research needs include well-controlled developmental studies, particularly of young subjects and relatively homogeneous subgroups, which balance scientific rigor with ethical constraints. Investigations of the serotonergic and dopaminergic systems, limbic-based memory and emotional systems, and the role of epileptiform activity in autism represent priorities for future research.

Autistic Disorder↗
PubMed2000

[Diagnosis and therapy of well-differentiated neuroendocrine lung tumors].

INTRODUCTION: Neuroendocrine tumours of the lung are uncommon malignant neoplasms. They represent a heterogeneous spectrum of disease, encompassing the well-differentiated neuroendocrine tumours through to small-cell lung cancer, which has a poor prognosis and only palliative therapeutic options for most patients. Due to the low incidence of well-differentiated lung tumours there is as yet little experience. METHODS: Clinical records of 14 patients with well-differentiated neuroendocrine tumours of the lung were assessed retrospectively for patients' initial symptomatology, diagnostic procedures, therapy and results. RESULTS: Eight lobectomies, 2 bronchoplastic lobectomies, 2 segmental resections, 1 bilobectomy and 1 wedge resection were performed; seven of them without regional lymphadenectomy. All patients were alive after a mean follow-up of 38 (2-96) months. Thirteen of 14 patients were free of complaints, twelve had no recurrences and returned to work. CONCLUSIONS: Well-differentiated NET of the lung have an excellent prognosis after curative resection. Limited resections even without lymphadenectomy can be performed in some cases.

Adult↗
PubMed2000

Functional neuroimaging in child psychiatry.

Functional neuroimaging in child psychiatry presents unique scientific, ethical, and technical challenges. The study of childhood disorders presupposes knowledge of neurodevelopment and brain maturation. However, much of human brain science is based on inferences from animal work and indirect neurochemical measures from body fluids. Neuroimaging can examine brain development directly in humans. The benefits can be enormous for learning how and when to intervene to prevent or treat a disorder. These unprecedented potential gains are countered by complex and difficult ethical issues. Technical advances can reduce ethical concerns by minimizing risks. They also promise to enhance the sensitivity and specificity of the measures (eg, by improving spatial and temporal resolution). Judiciously designed investigations will permit the testing of a priori hypotheses built on rational models of neuropathology. Finally, it is the integration of scientific knowledge across the various fields of neuroscience and clinical research that will push the limits of our understanding of health and disease.

Adolescent↗
PubMed2000

Human MO subsets as defined by expression of CD64 and CD16 differ in phagocytic activity and generation of oxygen intermediates.

Phagocytosis and killing of microorganisms by reactive oxygen radicals are important defence mechanisms of the immune system and it was shown that human monocytes (MO) are heterogeneous in exerting these functions. Previously, we described that human peripheral blood MO consist of a major subset of Fc gamma-receptor-I (CD64)-positive cells exhibiting low accessory cell capacity but high phagocytic activity, and a minor subset of CD64-negative cells with dendritic cell (DC)-like high T cell accessory cell capacity but low phagocytic capacity. Recently, we could show that each subset itself further differs in the expression of the Fc gamma-receptor-III (CD16) and T cell accessory activities resulting in four different subsets: two CD16+ subsets (CD64+ or CD64-) with high T cell stimulation capacity and two CD16- subsets (CD64+ or CD64-) with low accessory activities. In the present study we demonstrate that these subsets also differ in their ability to phagocytose opsonized bacteria (S. aureus and E. coli) and in the generation of reactive oxygen species. Both CD64+ subsets (CD16+ or CD16-) exhibit high phagocytic activity accompanied by intracellular superoxide induction. Luminol-dependent (mainly myeloperoxidase (MPO)-mediated) chemiluminescence (CL) response to latex and FMLP (formylmethionylleucylphenylalanine) was also high in these cell populations. Phagocytic activity and modest CL response was shown in CD64-/CD16+ but not in CD64-/CD16- cells, indicating that each subset except for CD64-/CD16- cells may engulf bacteria and exhibit MPO activity. Taken together, these data demonstrate further heterogeneity of peripheral blood MO in both, phagocytic activity and generation of reactive oxygen species indicating differences between the four subsets in this kind of defence mechanisms against pathogens.

Cell Differentiation↗
PubMed2000

Experimental tissue acidosis leads to increased pain in complex regional pain syndrome (CRPS).

The aim of this study was to investigate the role of local acidosis in the generation of pain in complex regional pain syndrome (CRPS). We investigated ten patients with CRPS of the upper extremity with a mean duration of the disease of 43 weeks (range 4-280 weeks) and ten control subjects for sensitivity to infusion of fluids with low pH (pH 6.1). Another group of five CRPS patients and three healthy controls was investigated using the same protocol but neutral infusion fluid (pH 7.4). A motorized syringe pump was installed for a constant infusion of synthetic interstitial fluid (SIF, either acidified (pH 6.1) or neutral) into the skin at the back of the hands and, thereafter, into the interosseus I muscle on both sides. A flow rate of 30 ml/h was chosen for intradermal and 7.5 ml/h for intramuscular infusion over a period of 10 min. The magnitude of pain was rated on an electronic visual analogue scale. Patients were requested to give their ratings every 10 s during the whole stimulation period. The ratings were normalized as fractions of individual grand mean values. We found significantly increased pain perception during infusion of acidified SIF on the affected side in CRPS patients. Low pH fluid into the skin was significantly more painful between 4 and 6 min (ipsi 1.27 normalized rating (NR) (0. 19-1.94), contra 0.31 NR (0.03-0.51), P<0.02) and between 8 and 10 min (ipsi 1.38 NR (0.19-1.94), contra 0.08 NR (0-0.27), P<0.03) on the affected side, while analysis over the whole stimulation period just failed to reach statistical significance (ipsi 281 area under the curve (AUC) (187-834), contra 87 AUC (28-293), P=0.059). Low pH infusion into the muscle was significantly more painful on the affected side during the whole infusion time (ipsi 861 AUC (308-1377), contra 190 AUC (96-528), P<0.01). The quality of the deep pain during infusion into the muscle was described by the patients as very similar to the CRPS-related pain. In controls we found no side differences of pain intensity during low pH stimulation. Neutral SIF evoked no pain at all, neither in CRPS patients (ipsi 0 AUC, contra 0 AUC) nor in healthy controls. Our results suggest that hyperalgesia to protons is present in patients with CRPS. Further, we could demonstrate that pain is not only restricted to the skin but is also generated in deep somatic tissue of the affected limb.

Acidosis↗
PubMed2000

Adrenergic and noradrenergic plasma levels in Lesch-Nyhan disease.

Noradrenergic dysfunction and abnormality in monoamine oxidase (MAO) enzyme activity have been reported previously in Lesch-Nyhan (LN) disease. This study examines peripheral indices of adrenergic, noradrenergic, and MAO function in children and young adults with LN disease (n = 11), and healthy subjects (n = 9). Blood samples, collected in identical conditions prior to a positron emission tomography (PET) study, were assayed for concentrations of epinephrine (EPI), norepinephrine (NE), and 3-methoxy-4-hydroxyphenylglycol (DHPG) (which results from the degradation of NE by monoamine oxidase type A [MAO-A]). The LN subjects had significantly higher EPI levels by 245% (p < .00) and lower DHPG levels by 42% (p < .00) compared to the control group. No group differences were noted in NE plasma levels. Cognitive function (IQ tested by Stanford Binet Intelligence Scale) was associated with EPI in the LN group (r = 0.77, p = .009), but not in the control group. The abnormally high EPI plasma concentrations may indicate another biochemical dysfunction secondary to the absence of the HPRT enzyme in LN patients. Such a biochemical deficit is likely to originate from the adrenal medulla, which is the primary site of EPI synthesis. The adrenal medulla may be directly affected by the absence of hypoxanthine guanine phosphoribosyl transferase (HPRT) enzyme, or may receive inappropriately high descending activation input from the brain. The abnormally low DHPG levels, in the context of normal NE levels, indicates low MAO activity, either as a primary deficit, or as secondary adaptive changes to spare NE levels that would otherwise be too low for adequate noradrenergic function.

Adolescent↗
PubMed2000

Lipopolysaccharide-like molecules derived from Wolbachia endobacteria of the filaria Onchocerca volvulus are candidate mediators in the sequence of inflammatory and antiinflammatory responses of human monocytes.

The majority of Onchocerca volvulus-infected persons show signs of cellular anergy, and long-time survival of adult and larval parasites in subcutaneous tissue is observed. The mechanisms leading to immunological hyporesponsiveness are poorly understood. Monocytes/macrophages represent a link between the innate and acquired immune system and are candidate cells to promote inflammatory and antiinflammatory processes. In the present study we have shown that products of microfilarial (O. volvulus) and adult (O. volvulus and O. ochengi) parasites affect monocytes in vitro. An early production of TNF-alpha by exposed monocytes was followed by the production of IL-10 and a reduced expression of HLA-DR and the costimulatory molecules B7-1 and B7-2, while other adhesion receptors remained unaffected. Downregulation of the functional membrane receptors failed to occur after treatment of the cells with anti-IL-10 antibodies. The engagement of CD14, a dominant membrane receptor on monocytes and major binding protein for lipopolysaccharides, was indicated by partial blocking of monocyte modulation by neutralizing antibodies to CD14 and by the antagonistic lipid A analog compound 406. Lipopolysaccharide-like molecules were detected in sterile products of O. volvulus stages which could originate from Wolbachia bacteria related to Gram-negative Rickettsiales, known to be abundant in the hypodermis and the female reproductive organs of O. volvulus. The present results indicate that the monocyte/macrophage may be a major target cell for immunomodulatory parasite-derived and intraparasitic, bacteria-derived molecules, thereby contributing to the host's cellular hyporesponsiveness.

Animals↗
PubMed2000

Low in vitro production of interferon-gamma and tumor necrosis factor-alpha in HIV-seronegative patients with pulmonary disease caused by nontuberculous mycobacteria.

We studied 32 HIV-seronegative patients with pulmonary disease caused by nontuberculous mycobacteria (NTM). Immunologic studies included lymphocyte subset analysis by flow cytometry, measurement of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) production following in vitro stimulation of diluted whole blood (DWB) and peripheral blood mononuclear cells (PBMC) by phytohemagglutinin (PHA), anti-CD3 as well as purified protein derivative of tuberculin (PPD), and in four cases with different amounts of the very mycobacterium, which caused disease in these patients. Data were compared to those of 30 HIV-seronegative patients with disease by Mycobacterium tuberculosis (MTb). Following alpha-CD3-stimulation of PBMC, NTM patients showed lower IFN-gamma (P < 0.00005) and lower TNF-alpha (P < 0.02). For a subgroup of tuberculin skin test-positive NTM patients we found significantly lower PPD-induced IFN-gamma releases in cultured DWB (P < 0.0002) and PBMC (P < 0.0004) compared to MTb patients. Data for PPD-induced TNF-alpha release for this subgroup were also significant (P < 0.001 and P < 0.05, respectively). The four NTM patients with poor PPD-induced IFN-gamma response hardly showed increased cytokine production on stimulation with their specific mycobacterium. The lower production capacity of IFN-gamma and TNF-alpha of NTM patients compared to the MTb patients points to an immunologic imbalance forming the basis for their increased susceptibility to pulmonary infections by nontuberculous mycobacteria.

Adult↗
PubMed2000

Anti-neutrophil cytoplasmic antibodies directed against the bactericidal/permeability-increasing protein (BPI) in pediatric cystic fibrosis patients do not recognize N-terminal regions important for the anti-microbial and lipopolysaccharide-binding activity of BPI.

This study was performed to examine the prevalence and clinical correlates of bactericidal/permeability-increasing protein anti-neutrophil cytoplasmic antibodies (BPI-ANCA) in pediatric cystic fibrosis (CF) patients and to elucidate their possible role in CF pulmonary pathology. Sera of 27 CF patients were tested for ANCA by indirect immunofluorescence (IFT) and by enzyme-linked immunosorbent assay (ELISA) for ANCA sub-specificities. BPI-ANCA were examined by using standard ELISA for BPI, lipopolysaccharide-binding protein (LBP), and BPI/LBP fusion proteins to epitope map the main binding sites and look for cross-reactivity with LBP. Pulmonary function and serum concentrations of total immunoglobulin G (IgG) were measured and infections were diagnosed. In addition, release of reactive oxygen species (ROS) by neutrophil granulocytes was measured after stimulation with monoclonal BPI-ANCA. Using IFT, two patients showed atypical ANCA staining, six patients exhibited perinuclear ANCA staining, and no cytoplasmic ANCA staining was detected. Of 27 patients, 13 (48%) were BPI-ANCA (IgG) positive, and three were also immunoglobulin A (IgA) BPI-ANCA positive; one patient had ANCA against lactoferrin; and no proteinase 3 ANCA was detected in any of the patients. All BPI-ANCA bound to the C-terminal region of the molecule; none bound to the N-terminus or to LBP. There was no significant correlation between clinical data and the occurrence of BPI-ANCA in this cross-sectional study. Release of ROS from granulocytes was induced by monoclonal BPI-ANCA. Activation of neutrophils and possible modulation of BPI-mediated opsonophagocytosis and disposal of Gram-negative bacteria and lipopolysaccharides by BPI-ANCA raise the possibility that they contribute to pulmonary pathology in pediatric CF patients but intervention longitudinal studies in large groups of patients are needed to establish a causative association.

Adolescent↗
PubMed2000

Granulocyte-macrophage colony-stimulating factor (GM-CSF) but not granulocyte colony-stimulating factor (G-CSF) induces plasma membrane expression of proteinase 3 (PR3) on neutrophils in vitro.

The theoretical risk of triggering vasculitis resulting from administration of G-CSF and GM-CSF to patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), such as Wegener's granulomatosis (WG), who develop agranulocytosis due to cytotoxic therapy, is unknown. Since there is strong evidence that activation of polymorphonuclear neutrophils (PMN) induced by binding of ANCA to PR3 or myeloperoxidase (MPO) expressed on their plasma membrane is involved in the pathogenesis of systemic vasculitides (SV), we studied the surface expression of PR3 and MPO on PMN from healthy donors in response to G-CSF and GM-CSF in vitro by flow cytometric analysis. Increasing doses of G-CSF did not alter PR3 expression on either untreated or tumour necrosis factor-alpha (TNF-alpha)-primed donor PMN significantly. In contrast, GM-CSF significantly increased PR3 membrane expression on both intact PMN and neutrophils primed with TNF-alpha. MPO expression was not significantly altered by either G-CSF or GM-CSF. In summary, these data demonstrate that GM-CSF, but not G-CSF, induces plasma membrane expression of PR3 on PMN in vitro. Since in AAV accessibility of the antigen (PR3 or MPO) to the antibody (ANCA) on the plasma membrane of PMN is thought to be essential for neutrophil activation by ANCA, the results of the present study suggest that administration of GM-CSF to patients with WG with neutropenia implies a definite theoretical risk of deterioration of vasculitis via this mechanism.

Adult↗
PubMed2000

In vitro generation of bacillus Calmette-Guérin-activated killer cells.

Tumor regression induced in cancer patients by local instillation of bacillus Calmette-Guérin (BCG) into the bladder is considered to be mediated by cellular immune and inflammatory reactions. In an attempt to elucidate which of these effects are relevant to tumoricidal activity, an in vitro system was employed in which the immunostimulatory effects of BCG could be studied. This report describes the induction of BCG-activated killer (BAK) cells, which effectively lyse bladder tumor cells. Human peripheral blood mononuclear cells (PBMC) were stimulated with viable and sonicated BCG (v-BCG and s-BCG, respectively) to generate BAK cells. Cytotoxicity of BAK cells was comparable with the cytotoxicity exerted by lymphokine-activated killer (LAK) cells generated by interferon (IFN)-gamma but did not reach the level of interleukin-2 (IL-2)-generated LAK cells. Induction of BAK cells was possible only with v-BCG and not with s-BCG. By depletion and enrichment of defined cell populations, the cytotoxic potential of BAK cells could be attributed to a population of CD8(+) and CD56(+) double-positive lymphocytes. Macrophages and CD4(+) cells were required for the induction of killing activity but had no such activity by themselves. Furthermore, the presence of IFN-gamma and IL-2 in the supernatants harvested during the generation of BAK cells was demonstrated. Monoclonal antibodies neutralizing these cytokines abolished BCG-mediated cytotoxicity. From these results, it is concluded that the known beneficial effect of local instillation of BCG on maintenance of the relapse-free state in superficial bladder cancer may be due to local generation of BAK cells.

BCG Vaccine↗
PubMed2000

Reduction of side effects of intravesical therapy with bacille Calmette-Guérin by pentoxifylline?--an in vitro approach.

Immunotherapy with intravesical bacille Calmette-Guérin (BCG) is the treatment of choice against superficial bladder cancer recurrences. However, this therapy is associated with side effects that are considered to be the result of inflammatory cytokines. Since pentoxifylline is known to interfere with the production of cytokines, this drug was tested in vitro with regard to a later clinical application in BCG-treated patients. The cytokine release and the cytotoxicity of interleukin-2 or BCG-stimulated mononuclear cells were analyzed, and the growth of BCG under the influence of pentoxifylline was assayed. The results showed an inhibition of cytokine release of stimulated mononuclear cells. The cytotoxicity of BCG-stimulated mononuclear cells but not of lymphokine-stimulated mononuclear cells against bladder carcinoma cells was significantly inhibited. Restimulation with fresh BCG restored cytotoxicity. Direct coincubation of BCG and pentoxifylline resulted in a reduction of mycobacterial metabolism. From these data, we conclude that the use of pentoxifylline to reduce BCG-related side effects should be tested further in a clinical study.

Administration, Intravesical↗
PubMed2000

Generation of monoclonal antibodies directed against the immunogenic glycoprotein K8.1 of human herpesvirus 8.

Human Herpesvirus 8 (HHV-8) is clearly associated with Kaposi's sarcoma (KS), body cavity-based lymphomas (BCBL), and certain forms of multifocal Castleman's disease (MCD). It appears to be the sexually transmissible agent involved in the development of AIDS-associated KS. HHV-8 genomes are invariably present in BCBL-derived cell lines where lytic replication of the virus can be induced by phorbol esters (PE). First-generation HHV-8 serological assays were based on these cell lines. More recently, several genes encoding HHV-8 antigens have been identified. One of the most reactive antigens is encoded by HHV-8 open reading frame K8.1. Although K8.1 does not exhibit overt sequence homology to any other known gene, it is likely to be analogous to gp220/350 of Epstein-Barr or gp150 of murine herpesvirus-68, virion-envelope glycoproteins involved in target cell recognition. Mice were immunized with purified GST-K8.1 fusion protein expressed in E. coli. After fusion of murine plasma cells with the myeloma cell line P3-X63-Ag8. monoclonal antibodies (MAbs) were generated, which are specifically directed against K8.1 protein. The binding site for each MAb was identified by deletion mutant analysis using recombinant GST-K8.1 mutants and K8.1-specific peptides. Without exception, the epitopes recognized by these MAbs were located within the N-terminal part of the protein [amino acids (aa) 29 to 80], thus identifying a highly immunogenic region. These antibodies will not only be useful tools for HHV-8 diagnostics, but will also facilitate the analysis of K8.1 function.

Animals↗
PubMed2000

Orbitofrontal cortex and human drug abuse: functional imaging.

The orbitofrontal cortex (OFC) plays a central role in human behavior. Anatomically connected with association areas of all sensory modalities, limbic structures, prefrontal cortical regions that mediate executive function and subcortical nuclei, this brain region can serve to integrate the physical and emotional attributes of a stimulusobject and establish a motivational value based on estimation of potential reward. To the extent that addictive disorders reflect a dysregulation of the ability to evaluate potential reward against harm from drug self-administration, it would be anticipated that substance abuse disorder might reflect dysfunction of the OFC. With the application of brain imaging techniques to the study of human substance abuse, evidence has been obtained that activity in the OFC and its connections plays a role in several components of the maladaptive behavior of substance abuse, including expectancy, craving and impaired decision making.

Frontal Lobe↗
PubMed2000

Pictorial Instrument for Children and Adolescents (PICA-III-R).

OBJECTIVE: The Pictorial Instrument for Children and Adolescents (PICA-III-R) is presented as part of a comprehensive review of the tools used to diagnose psychiatric disorders in children and adolescents. METHOD: The PICA-III-R's development, content, initial psychometric properties, and directions for use are described. RESULTS: The PICA-III-R assesses all DSM-III-R Axis I psychiatric disorders in children aged 6 to 16 years, categorically (diagnosis present or absent) and dimensionally (range of severity). It comprises 137 pictures organized in modules that cover 5 diagnostic categories, including disorders of anxiety, mood, psychosis, disruptive behavior, and substance abuse. Its initial psychometric properties are promising, with good internal consistency, significant discriminative power for diagnoses, and sensitivity to changes. CONCLUSIONS: Despite great interest expressed by child and adolescent psychiatrists, further testing has not been possible for practical reasons unrelated to the scientific importance of such work. Although it needs to be modified to follow DSM-IV criteria, the PICA-III-R can be of significant help to child and adolescent psychiatrists, for clinical as well as research diagnostic purposes. In addition, it can be used for the assessment of non-English-speaking or hearing/speech-impaired children.

Adolescent↗
PubMed2000

A review of tobacco smoking in adolescents: treatment implications.

OBJECTIVE: To review current data on the tobacco epidemic in adolescents that impact treatment decisions. METHOD: Epidemiological and pharmacological data, risk factors, characteristics of nicotine use in adolescents, and treatment intervention reports from the literature are discussed. RESULTS: Of students in grades 9 to 12, 42.7% have used tobacco; 75% of teenage smokers will smoke as adults. Environmental and biological factors influence adolescent smoking, including sociodevelopmental aspects of adolescence, psychiatric history, genetic background, ethnic and gender characteristics, drug effects, and regulatory factors. Criteria for nicotine dependence are currently based on the experience with adult smokers. Overall, smoking cessation treatment for adolescents has been disappointing because of low participation, high attrition, and low quit rates. CONCLUSION: Characterization of nicotine dependence and further assessment of the safety and efficacy of pharmacological treatment interventions in adolescents are needed given the formidable challenge of the tobacco epidemic in adolescents.

Adolescent↗