Biomedical subjects

E Möller

Publications and source records attributed to E Möller.

At least 19 recordsLinked to original sources

PubMed2005

Transcriptomic and proteomic patterns of systemic inflammation in on-pump and off-pump coronary artery bypass grafting.

BACKGROUND: Coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) provides controlled operative conditions but induces a whole-body inflammatory response capable of initiating devastating morbidity and mortality. Although technically more demanding, deliberate avoidance of CPB in off-pump surgery attenuates the physiological insult associated with CABG. METHODS AND RESULTS: To systematically assess the molecular mechanisms underlying the better-preserved remote organ function, we studied gene expression patterns in leukocytes and plasma proteomic response to on-pump and off-pump CABG. Proteomic analysis confirmed (tumor necrosis factor-alpha, interleukin [IL]-6, IL-10) and expanded (eg, interferon [IFN]-gamma, granulocyte colony-stimulating factor [G-CSF], monocyte chemotactic protein-1, macrophage inflammatory protein-1beta) the mediators released on CPB, whereas blood leukocyte transcriptomics suggested that circulating leukocytes are not primarily responsible for this response. Interestingly, release of some cytokines (eg, IL-6, IFN-gamma, G-CSF) was observed on off-pump surgery to a similar extent but with delayed kinetics. A total of 45 of 4868 transcripts were identified to be significantly altered as a result of initiation of CPB. Systematic analysis of transcriptional activation by CPB revealed primarily genes involved in inflammation-related cell-cell communication (such as L-selectin or intercellular adhesion molecule-2) and signaling (such as IL-1, IL-8, or IL-18 receptors and toll-like receptors 4, 5, and 6), thus confirming a "primed" phenotype of circulating peripheral blood mononuclear cells. CONCLUSIONS: Gene array and multiplex protein analysis, only in concert, can illuminate the molecular mechanisms responsible for systemic sequelae of CPB and indicate that circulating leukocytes overexpress adhesion and signaling factors after contact with CPB, which potentially facilitates their trapping, eg, in the lungs and may promote a subsequent tissue-associated inflammatory response.

Animals↗

PubMed2002

Phase-coupling of theta-gamma EEG rhythms during short-term memory processing.

Because of the importance of oscillations as a general phenomenon of neuronal activity the use of EEG spectral analysis is among the most important approaches for studying human information processing. Usually, oscillations at different frequencies occur simultaneously during information processing. Thus, the question for synchronisation of different frequencies by phase coupling and its possible functional significance is of primary importance. An answer may be given by bispectral analysis. Estimation of the (cross-) bispectrum allows to identify synchronised frequencies and possibly, the existence of non-linear phase coupling of different oscillators. Previous studies have demonstrated the simultaneous occurrence of slow (4-7 Hz) and fast (20-30 Hz) oscillations at frontal and prefrontal electrode positions during memory processing. However, interrelations between these rhythms have not been investigated up to now. In order to test short-term memory, the Sternberg task with random figures and number words was carried out on 10 female subjects. During the task EEG was recorded. Power and bispectral analyses from frontal, prefrontal and frontopolar regions were performed off-line. Increased power was found in both the theta and the gamma bands. Strong phase-coupling between theta at Fz and gamma at F3 and at Fp1, respectively, was shown for memorising number words by means of cross-bicoherence. A possible reason for this is an amplitude modulation of gamma frequencies by slow oscillations. The correspondent coherence analysis between the envelope of gamma frequencies at Fp1 and the raw EEG at Fz supports this presumption. This finding is interpreted as an EEG aspect of the functional linking between the prefrontal areas and the G.cinguli (as part of the limbic system), which are both extremely important for memory functions.

Adult↗

PubMed2002

Human cytomegalovirus (HCMV)-infected endothelial cells and macrophages are less susceptible to natural killer lysis independent of the downregulation of classical HLA class I molecules or expression of the HCMV class I homologue, UL18.

A number of reports have suggested that human cytomegalovirus (HCMV)-infected fibroblasts are resistant to natural killer (NK) lysis, and that the HCMV-encoded human leucocyte antigen (HLA) class I homologue UL18 may be responsible for this effect. While fibroblasts are easy to infect in vitro, their role in HCMV pathogenesis in vivo is unclear. Here, we have established systems to address NK recognition of infected endothelial cells and macrophages, two important HCMV cellular reservoirs in vivo. The HCMV-infected endothelial cells exhibited increased resistance to NK killing, and, in most experiments, infected macrophages demonstrated a decreased susceptibility to NK lysis. Infection with the mutant HCMV strain RV670, lacking the genes US1-9 and US11 that are responsible for downregulation of HLA class I molecules, also led to decreased NK susceptibility. Furthermore, reduced NK susceptibility was independent of the expression of the HLA class I homologue UL18, since cells infected with the UL18Delta HCMV strain were also less susceptible to NK killing. These results suggest that HCMV-induced resistance to NK cytotoxicity in endothelial cells and macrophages is independent of known pathways that interfere with the expression of cellular HLA class I A, B and C surface antigens and the HCMV encoded class I homologue UL18.

Capsid↗

PubMed2002

[Brief causal relations in EEG based on adaptive Granger causality].

Commonly, coherence and correlation are used to describe interrelations between EEG signals. But, on this basis, the investigation of causality or direction of interrelations is not possible. The general idea of causality between two signals may be expressed in terms of upgrading the predictability of one signal bye the knowledge of the past of the other signal. The best established approach in this context is the so-called Granger causality. The study present an adaptive estimation of Granger causality, which allows to detect dynamic causal relations within time intervals of less 100 ms. The time-variant Granger causality is applied to EEG data of the Stroop task. It could be shown, that conflict situation generates a dense web of directed interactions from posterior to anterior cortical areas.

Adult↗

PubMed2001

Instantaneous multivariate EEG coherence analysis by means of adaptive high-dimensional autoregressive models.

This study presents an efficient algorithm for the fitting of multivariate autoregressive models (MVAR) with time-dependent parameters to multidimensional signals. Thereby, the dimension of the model may be chosen to equal the number of signal channels. The autoregressive (AR) parameter matrices are estimated by an extension of the recursive least squares (RLS) algorithm with forgetting factor. The estimation procedure includes a single trial as well as an ensemble mean approach. The latter approach allows the simultaneous fit of one mean MVAR model to a set of single trials, each of them representing the measurement of the same task. A particular advantage of this ensemble mean approach is that it requires only a low computation effort in comparison to well known procedures applied to single trials. Furthermore, the ensemble mean approach is linked with a high adaptation capability. The properties of the estimator are investigated using simulated time series. It can be demonstrated that the adaptation capability of the estimation (measured by its adaptation speed and variance) does not depend on the model dimension. The mean MVAR fit is applied to 19-dimensional EEG data, recorded during an elementary comparison procedure. The calculation of ordinary and multiple coherence is discussed. The sensitivity of the multiple instantaneous EEG coherence will be demonstrated.

Algorithms↗

PubMed2001

Bracing versus nonbracing in rehabilitation after anterior cruciate ligament reconstruction: a randomized prospective study with 2-year follow-up.

This study prospectively randomized 62 patients to rehabilitation programs either with or without postoperative brace for 6 weeks following bone-tendon-bone anterior cruciate ligament reconstruction. The nonbraced group had a smaller knee circumference 2 weeks after surgery. At 6-month follow-up the nonbraced group had a better Tegner score. At 2 years there was no difference between the groups. There was one partial rupture of the graft in the nonbraced group after a new trauma 1 year after surgery. There were no differences between the groups in either subjective or objective knee stability at 2 or 6 weeks or at follow-up 3, 6, and 24 months after surgery. This study found no benefit of using a postoperative knee brace on patients' knee function at any stage up to 24 months after surgery. Furthermore, the braced group was not more stable than the nonbraced group, indicating that the brace does not contribute to a more stable knee during rehabilitation or 2-year follow-up.

Adult↗

PubMed2001

Continued production of xenoimmune antibodies 6-8 years after clinical transplantation of fetal pig islet-like cell-clusters.

We have monitored the humoral immune responses of 10 type I diabetic patients, xenotransplanted with fetal porcine islet-like cell clusters for up to 8 years after xenotransplantation. We investigated the immunoglobulin subclass distribution as well as specificity differences of xenoreactive antibodies. Hemagglutintion tests, using pig erythrocytes, showed that some patients maintained higher titers of xenoreactive IgM antibodies during the entire follow up period, compared with pretransplant levels. In microcytotoxicity tests all but one patient tested showed higher than pretransplant levels of cytotoxic antibodies against pig peripheral blood mononuclear cells (PBMC) 6-8 years after transplantation. Levels of Gal alpha 1,3Gal specific antibodies, were also high. Antibody dependent cellular cytotoxicity (ADCC) activity against a Gal alpha 1,3Gal expressing human B cell line was detected in four patients while ADCC reactivity against adult pig islet cells was detected in only two patients, 6-8 years after transplantation. Immune sera collected 30 days and 1 year after transplantation showed positive staining of adult pig islet cells in fluoromicroscopy whereas sera from later time points did not. Western blot experiments showed that some patients had IgG1 antibodies reactive against epitopes on pig cells other than Gal alpha 1,3Gal, while xenoreactive IgM and IgG2 antibodies mainly reacted with Gal alpha 1,3Gal-containing epitopes as shown by absorption experiments. These results show that patients continue to produce higher than pretransplant levels of IgM and IgG2 xenospecific antibodies against Gal alpha 1,3Gal for extended time periods following xenotransplantation. Some patients also produce xenoreactive IgG1 antibodies directed against non-Gal alpha 1,3Gal epitopes.

Animals↗

PubMed2001

Xylene-free method for histological preparation: a multicentre evaluation.

The backbone of daily pathological diagnostic work is the paraffin section. Paraffin sections are still prepared by methods largely unchanged for over 150 years. A xylene-free method has been developed that excludes xylene, not only as the intermediate step before the paraffin baths, but also for deparaffinizing of the cut sections, which also eliminates the need for rehydration and dehydration for the staining and mounting steps. Elimination of xylene from tissue processing cuts costs, saves time, and improves the laboratory environment. Experience with xylene-free sections since 1995 at the Vrinnevi Hospital is favorable. Our opinion is that the xylene-free sections are equivalent to conventionally processed sections. To test this hypothesis, nine pathologists from three hospitals participated in an evaluation trial. Paired tissue blocks from 10 consecutively submitted samples each of breast, intestine, and skin were processed by either the xylene-free or the conventional method. Sections from each block were deparaffinized and stained with hematoxylin-eosin (H&E), with periodic acid-Schiff (PAS), and with van Gieson's method. A randomized mix of 180 sections (10 samples x 3 tissues x 3 stains x 2) gave 90 matched pairs. Each section was blindly examined and scored by nine pathologists to give 810 paired observations for statistical evaluation. The xylene-free sections were ranked as good as or better than their conventional counterparts in 74% of the comparisons, and poorer in 26%. The major discriminating factor was the staining method. H&E and PAS sections were equivalent. The xylene-free van Gieson sections, cut from the same blocks and randomly assigned to this stain, tended to be downgraded. This could be traced to a faulty stain solution used for this batch. The overall results have demonstrated professional acceptance for the xylene-free method of processing histological sections.

Breast↗

PubMed2001

Immune complex-induced chronic and intense IL-4 independent IgG1-rheumatoid factor production in NZB mice.

Immune complexes from the synovial fluid of rheumatoid arthritis (RA) patients, or artificial rheumatoid factors (RF)-like (antibody--antibody) immune complexes, induce a remarkably intense, sustained and selective immunoglobulin (Ig)G1 response under certain experimental conditions in mice. Because the IgG1 antibody response is extraordinarily strong, the role of interleukin (IL)-4, important for IgG1 synthesis, was investigated. Both C57BL/6 and NZB IL-4-deficient mice produced IgG1--RF antibodies after injection with RF-like immune complexes, although the antibody levels were slightly delayed compared to wild type mice. This shows that IL-4 is not obligatory in RF-like immune complex induced IgG1--RF production. A discrepancy in the decline of serum IgG1--RF was noted between NZB and C57Bl/6 mice. Serum IgG1-RF declined 43 days postinjection (p.i.), in C57BL/6 mice whereas high serum levels of IgG1--RF were maintained more than 100 days in the NZB mice, indicating different regulatory mechanisms in these mice. To study if the affinity for mouse IgG increased with time in NZB mice and thus become more directed against self, the cross-reactivity of the IgG1--RF antibodies with IgG from other species was investigated early and late after injection. It was, however, found that the cross-reactivity with IgG of human, goat and rabbit origin did not change between the two time points.

Animals↗

PubMed2001

EEG frequency and phase coupling during human information processing.

Neuronal activity during information processing is represented by oscillations within local or widespread neuronal networks. These oscillations may be recorded by the EEG (electroencephalogram). The oscillatory interaction between neuronal ensembles may be at one single frequency or at different frequencies due to non-linear coupling. The investigation of momentary coherence and phase enables the examination of synchronized oscillatory network activity during fast-changing cognitive processes. On this basis information transfer from occipital areas towards frontal areas could be described during processing of visual presented words. Non-linear phase coupling between oscillations with different frequencies during memory processing was detected by means of cross-bicoherence.

Adult↗

PubMed2000

Longevity of immune complexes and abnormal germinal centre formation in NZB mice.

Rheumatoid factor (RF)-like (antibody-antibody) immune complexes induce a selective and intensive immunoglobulin (Ig)G1-RF response after a single injection in mice. However, the longevity of the response differs between mouse strains: serum IgG1-RF antibody titres decline 40 days after injection in C57Bl/6 mice whereas levels are maintained for more than 100 days in NZB mice. In order to elucidate whether this difference was owing to a lower ability of NZB mice to clear the injected immune complexes, sections of kidney, spleen, liver and mesenteric lymph nodes were harvested at different time points after injection with RF-like immune complexes. Immunohistochemical staining revealed that NZB mice have a delayed clearance of the injected immune complexes, because the immune complexes are retained for more than 40 days in their spleens and 100 days in their kidneys, compared to only 14 days in C57Bl/6 mice. Germinal centres were also present for a longer period in the spleens of the NZB mice, accompanying the presence of the immune complexes, and were abnormally large compared to C57Bl/6 mice. The clearance of immune complexes from the spleen coincided with the decline in serum levels of IgG1-RF, indicating that prolonged retention of immune complexes is responsible for the sustained IgG1-RF response.

Animals↗

PubMed1999

Adaptive phase estimation and its application in EEG analysis of word processing.

Oscillations are a general phenomenon of neuronal activity during information processing. Mostly, widespread networks are involved in brain functioning. In order to investigate network activity coherence analysis turned out to be a useful tool for examining the functional relationship between different cortical areas. This parameter allows the investigation of synchronisation phenomena with regard to defined frequencies or frequency bands. Coherence and cross phase are closely connected spectral parameters. Coherence may be understood as a measure of phase stability. Whereas coherence describes the amount of information transfer, the corresponding phase, from which time delays can be computed, hints at the direction of information transfer. Mental processes can be very brief and coupling between different areas may be highly dynamic. For this reason a two-dimensional approach of adaptive filtering was developed to estimate coherence and phase continuously in time. Statistical and dynamic properties of instantaneous phase are discussed. In order to demonstrate the value of this method for studying higher cognitive processes the method was applied to EEG recorded during word processing. During visual presentation of abstract nouns an information transfer from visual areas to frontal association areas in the Alpha1 frequency band could be verified within the first 400 ms. The Alpha1 band predominately seems to reflect sensory processing and attentional processes. In addition to conventional coherence analyses during word processing phase estimations may yield valuable new insights into the physiological mechanisms during word processing.

Adult↗

PubMed1999

No evidence for specific in vitro lymphocyte reactivity to HgCl2 in patients with dental amalgam-related contact lesions.

Blood lymphocytes from 20 patients with oral contact lesions to dental amalgam and 10 healthy individuals were analyzed for HgCl2-induced proliferation in vitro, using both a modified assay and a conventional assay. The release of interferon-gamma (IFN-gamma) was measured in cell supernatants. Six patients displayed positive reactions in patch tests to mercuric compounds. No significant differences were recorded in HgCl2-induced proliferation in cells from patients and controls, since only few in the whole material responded to submitogenic concentrations. IFN-gamma was detectable in cell supernatants from some patients but also from controls and is not predictive of mercury allergy. Neither the phenotypes of peripheral lymphocyte subsets, the frequency of circulating cells expressing the interleukin-2 (IL-2) receptor, spontaneous lymphocyte proliferation nor concentrations of serum interleukin-6 differed between patient and control samples. In contrast to what has been claimed before, we did not find any evidence for specific in vitro lymphocyte reactivity in patients with oral contact lesions.

Adult↗

PubMed1999

HgCl(2)-induced human lymphocyte activation in vitro: a superantigenic mechanism?

Mercuric chloride (HgCl(2)) has been proposed to be a mitogen for human blood lymphocytes in vitro. In our previous study, we demonstrated that HgCl(2) preferentially stimulates the CD4+ T cell subset to blast transformation and DNA synthesis and that the reaction is dependent on CD14+ accessory cells. In order to characterise the responding cells further and to elucidate the mechanism of T cell activation, the T cell receptor (TCR) Vbeta chain expression of the blast-transformed cells was analysed by monoclonal antibodies and flow cytometry. The 22 TCR-Vbeta-specific antibodies used were found to react with 55-80% of the naive CD4+ and CD8+ blood T cells from the different donors. Six to 18% of the lymphocytes, mainly CD4+ T cells, were blast transformed after addition of HgCl(2). The distribution of the lymphoblasts carrying certain TCR Vbeta chains were skewed, and 15-40% expressed the TCR Vbeta2 chain. Furthermore, if cells were pretreated for 5 days with HgCl(2), whereafter recombinant interleukin-2 in fresh medium was added, the TCR Vbeta7+ T cell subset was also stimulated to blast transformation. The superantigen staphyloccal enterotoxin B, as a control, induced blast transformation in 10-26% of the lymphocytes, mainly CD4+ T cells, which were, as expected, positive for Vbeta3, Vbeta12, Vbeta14 or Vbeta17. We conclude that HgCl(2) has characteristics of a superantigen, activating the human lymphocytes in a Vbeta-chain-selective manner in vitro.

CD4-Positive T-Lymphocytes↗

PubMed1999

Role of alloimmunity in clinical transplantation.

HLA-specific humoral immunity, as a result of recipient allosensitization, induces hyperacute rejection of allogeneic kidney grafts. Cross-match tests are performed to avoid this complication. However, present techniques do not allow determination of HLA specificity of donor-reactive antibodies in the acute necro-donor situation. New methods are described and discussed in this communication as well as the alloantibody specificities which are of clinical importance. Alloantibodies not only mediate hyperacute rejection, but may also participate in the acute rejection of organ grafts. Clinical associations between early immunological complications, such as acute rejection, in heart, liver and kidney allografted patients and pre-transplantation humoral alloimmunity emphasize the need for proper determination of donor-specific humoral immunity prior to transplantation. Acute rejection episodes are associated with an increased risk of subsequent chronic rejection. Cytomegalovirus (CMV) infection is also an important risk factor for chronic organ graft rejection as well as for chronic graft-versus-host (GvH) disease in bone marrow transplanted patients. CMV infection triggers autoantibody formation against CD13 in transplanted patients which, in turn, has been shown to be associated with the development of chronic GvH disease. Recently, alloactivation of immune reactivity in vitro was found to induce reactivation of latent CMV infection. We present here a hypothesis to explain the series of clinically associated events: acute rejection--CMV infection--chronic rejection.

Antibody Formation↗

PubMed1998

Productive cytomegalovirus (CMV) infection exclusively in CD13-positive peripheral blood mononuclear cells from CMV-infected individuals: implications for prevention of CMV transmission.

BACKGROUND: Monocytes are suggested to harbor latent cytomegalovirus (CMV) in peripheral blood, which concurs with the finding that all CMV-susceptible cells carry the CD13 surface molecule. Here, we investigated whether all latently and productively CMV-infected peripheral blood mononuclear cells (PBMCs) could be eliminated by depletion of CD13-expressing cells. METHODS: Depletion of CD13-positive cells was performed with monoclonal antibodies and magnetic cell separation (MACS) beads followed by MACS. CMV DNA and cDNA were amplified by polymerase chain reaction with specific primers for two CMV genes, major immediate early and phosphoprotein 150. The presence of infectious virus was tested by incubating homogenized in vitro- or in vivo-infected PBMCs with human fibroblasts. CMV infection of fibroblasts was detected by intracellular expression of CMV proteins. RESULTS: Elimination of CD13-positive PBMCs removed productively in vitro- and in vivo-infected cells, as demonstrated by detection of infectious virus only in PBMC fractions containing CD13-positive cells. In support of this finding, CMV RNA was not detected in pure CD13-negative cell fractions. Furthermore, CMV DNA was found exclusively in CD13-positive PBMCs obtained from patients with acute CMV infection. CONCLUSIONS: Our data suggest that CMV replicates exclusively in CD13-positive PBMCs. These findings have important clinical applications, because the elimination of CD13-positive cells may reduce the risk for transmission of latent CMV in blood products and bone marrow grafts and thereby also decrease the risk for CMV-induced complications, such as chronic graft-versus-host disease in bone marrow transplant patients.

Adult↗

PubMed1998

Induction of IgG rheumatoid factor (RF) production by antibody-antibody (RF-like) immune complexes: the role of T cells, complement and Fc gamma receptors.

Rheumatoid factors (RF) are autoantibodies with specificity for the constant regions of IgG molecules. They are found in several immunopathological diseases. The mechanism(s) by which these autoantibodies are produced is largely unknown. We have previously shown that a single injection of RF-like immune complexes (ICs) into mice selectively induced an intense IgG1-antibody production with RF activity. This response was sustained for several months and did not resemble a conventional immune response to an antigen or other immune complexes. In the present study, we sought to elucidate the mechanism for the IgG1 RF response to RF-like ICs. Therefore, the roles of CD4+ T cells, complement and Fc gamma receptors were analysed. In order to characterize the role of CD4+ T cells, RF-like induced IgG1-RF production was analysed in NZB mice treated with a monoclonal antibody (mAb) against the CD4 molecule, which resulted in complete abrogation of IgG1 RF production. To evaluate the importance of Fc gamma Rs, the effect of RF-like ICs was tested in mice deficient for RF gamma RI/III. A significant decrease in the numbers of IgG1 antibody secreting cells, as well as in serum IgG1 RF levels, was found in the deficient mice, as compared with their normal outbred littermates. The role of complement in RF-like ICs mediated IgG1 RF was tested in complement depleted NZB mice, using Cobra venom factor. The IgG1 RF response in complement depleted and intact mice was comparable. Thus, our results demonstrate that RF-like immune complexes selectively induce an Fc gamma R-dependent, complement independent antibody response in mice.

Animals↗

PubMed1998

Synovial fluid cytokines in patients with rheumatoid arthritis or other arthritic lesions.

The synovial fluid (SF) of rheumatoid arthritis (RA) patients contains a mixture of inflammatory mediators. In order to determine whether certain cytokine patterns locally in the joint are specifically related to the chronic inflammation in RA, the concentrations of interleukin (IL)-1alpha, IL-1beta, IL-6, IL-10, transforming growth factor-beta (TGF-beta), tumour necrosis factor-alpha (TNF-alpha) and IgG2b-inducing factor (IgG2bIF) were measured in SF from 22 patients with RA and 22 patients with other types of arthritic lesions. High levels of IL-10, latent and active TGF-beta and the presence of IgG2bIF are significantly correlated with RA when corrected for age. As these factors have the capacity to promote antibody production, they might contribute to the maintenance of local antibody production in RA synovial tissues. All RA-SF samples contained detectable levels of IL-10 and all except one contained IL-1beta, while concentrations in several non-RA-SF samples were below detection limits. IL-6 and TGF-beta were present in all SF samples from both RA and non-RA patients. The presence of IgG2bIF was strongly correlated with high levels of IL-10 and IL-1beta in SF. However, no distinct cytokine profile specific for the chronic inflammation characteristic of RA was found.

Adult↗