[Default mode network of the brain. Neurobiology and clinical significance]. / "Default-mode"-Netzwerk des Gehirns. Neurobiologie und klinische Bedeutung.

The resting state of the human brain is intrinsically organized by the so-called default mode network (DMN) which comprises cortical midline structure as well as lateral parietal and temporal areas. The activity of this system increases during self-oriented thinking, e.g. during a resting state but decreases during externally oriented attention and specific cognitive tasks. This review article provides a historical and methodological outline of the DMN model and describes its functional anatomy and putative functions. Based on the empirical literature the clinical implications of alterations of the DMN architecture and its role in various mental disorders are discussed.

[The medical habilitation at German universities: a comparison of the regulations over 23 years]. / Die medizinische Habilitation an deutschen Hochschulen: ein Vergleich der Ordnungen über 23 Jahre.

BACKGROUND: Due to the further decrease in the number of habilitations in medicine since 2010, the general requirements for habilitation could have increased during the same period. OBJECTIVE: The requirements for a medical habilitation at German universities in a comparison of 23 years are re-evaluated. MATERIAL AND METHODS: An analysis of habilitation regulations for 12 target parameters and evaluation of these by a scoring system (range 0-34 points). RESULTS: Only the criterion of the requirement for a doctorate has remained the same in the 23-year comparison in the evaluation (1998-2021). All results of the other 11 criteria have changed compared to the previous study from 2010. The rating of habilitation achievements has increased from a total score in 1998 of 15.2 ± 5.1 points (95% confidence interval 13.6-16.9 points) to 25.1 ± 3.6 points in 2021 (95% confidence interval 23.9-26.2 points; p < 0.001). The range of assigned scoring values is again more broadly spread in the 11-year comparison with values from 12 to 31 points. A striking new criterion was that 98% of the assessed habilitation regulations now require a didactic continuing education in, however, significantly different requirements from the faculties. CONCLUSION: The requirements for a medical habilitation continued to significantly increase over the 23-year period with, however, a wider dispersion of scores. The more detailed description can be seen as a direct indication of an improvement in transparency. In contrast, the broader dispersion shows that a uniform assessment standard for Germany has again receded into the distance.

Evoked responses to rhythmic visual stimulation vary across sources of intrinsic alpha activity in humans.

Rhythmic flickering visual stimulation produces steady-state visually evoked potentials (SSVEPs) in electroencephalogram (EEG) recordings. Based on electrode-level analyses, two dichotomous models of the underpinning mechanisms leading to SSVEP generation have been proposed: entrainment or superposition, i.e., phase-alignment or independence of endogenous brain oscillations from flicker-induced oscillations, respectively. Electrode-level analyses, however, represent an averaged view of underlying 'source-level' activity, at which variability in SSVEPs may lie, possibly suggesting the co-existence of multiple mechanisms. To probe this idea, we investigated the variability of SSVEPs derived from the sources underpinning scalp EEG responses during presentation of a flickering radial checkerboard. Flicker was presented between 6 and 12 Hz in 1 Hz steps, and at individual alpha frequency (IAF i.e., the dominant frequency of endogenous alpha oscillatory activity). We tested whether sources of endogenous alpha activity could be dissociated according to evoked responses to different flicker frequencies relative to IAF. Occipitoparietal sources were identified by temporal independent component analysis, maximal resting-state alpha power at IAF and source localisation. The pattern of SSVEPs to rhythmic flicker relative to IAF was estimated by correlation coefficients, describing the correlation between the peak-to-peak amplitude of the SSVEP and the absolute distance of the flicker frequency from IAF across flicker conditions. We observed extreme variability in correlation coefficients across sources, ranging from -0.84 to 0.93, with sources showing largely different coefficients co-existing within subjects. This result demonstrates variation in evoked responses to flicker across sources of endogenous alpha oscillatory activity. Data support the idea of multiple SSVEP mechanisms.

[Cognitive reserve and its relevance for the prevention and diagnosis of dementia]. / Kognitive Reservekapazität und ihre Bedeutung für Auftreten und Verlauf der Demenz.

Progressive brain damage is undoubtedly the main cause of clinical symptoms of dementia in neurodegenerative disorders such as Alzheimer's disease. However, the association between brain damage and cognitive symptoms is not linear. Certain interindividual differences such as a good school education or a greater brain volume are associated with a higher resilience against brain damage that is usually referred to as cognitive reserve (CR). Individuals with high CR have a diminished risk for dementia and both active and passive concepts for this phenomenon are discussed. In the concept of passive CR, peculiarities of brain structure such as higher synapse or neuron counts are regarded as buffers against brain damage. Symptoms of dementia do not occur until a certain threshold of damage is passed. In addition to the passive concepts, active mechanisms are also discussed that are associated with the ability to maintain a certain level of cognitive performance in the face of progressive neurodegeneration for a longer period. In subjects with healthy cognitive function, these active mechanisms contribute to the adaptation of brain activity when task difficulty level is increased. Confronted with progressive neurodegeneration, these active mechanisms help to compensate for brain damage. Individuals with higher CR show more efficient activation for solving the same task, which helps them to preserve normal levels of cognitive performance for a longer period.

Products of activated lymphocytes. I. The use of radiolabeling techniques in the characterization and partial purification of the migration inhibition factor of the guinea pig.

General methods were developed and applied to the biosynthesis and purification of products of activated lymphocytes available in minute quantities. The activity studied here was the migration inhibitory factor (MIF) produced by purified protein derivative (PPD)- or concanavalin A (Con A)-stimulated lymphocytes obtained from one guinea pig or less. The methods selected yielded results in terms of two chemical parameters characteristic of the molecules involved, namely K(d) on Sephadex G-75 and isoionic point, pI, on isoelectric focusing. When supernatants were fractionated on G-75 columns, there were several areas even in control supernatants which produced migration inhibition relative to medium controls. However, in PPD- and Con A-stimulated supernatants, at least one peak of MIF activity was found solely in the stimulated cultures, with a K(d) of 0.15. A double-labeling technique was used to characterize the proteins of this peak. Control, unstimulated cultures were labeled with [(14)C]leucine and stimulated cultures were labeled with [(3)H]leucine. After mixing the supernatants and G-75 filtration, a major "ratiolabeled" broad peak. i.e. one with increased (3)H/(14)C ratio, was found. When a narrow portion of this peak about K(d) 0.15, containing most of the MIF activity, was subjected to analytical isoelectric focusing, all of the label was associated with proteins of lower net charge than albumin. A unique ratiolabeled peak was found in PPD- and Con A-stimulated fractions with a pI of approx. 5.3. A micropreparative isoelectric focusing technique was developed and yielded MIF activity in the same region as the major ratiolabeled peak. Further study will be required to ascertain whether the ratiolabeled protein is MIF. By following the K(d), pI, and (3)H/(14)C labeling ratio, at least 14 products of activated lymphocytes, synthesized either de novo or in increased amounts, could be distinguished.

Low zone tolerance to contact allergens in mice: a functional role for CD8+ T helper type 2 cells.

Normal skin is permeable to low molecular hydrophobic substances, including allergenic chemicals. Whereas such foreign matter appears to enter the skin naturally, it rarely induces contact hypersensitivity. This suggests that immunological tolerance would be the normal state of affairs. In search of a suitable model, we painted picryl chloride or oxazolone once or repeatedly on normal skin of BALB/c or C57B1/6 mice and found subsensitizing doses to be tolerogenic. The most effective doses in inducing tolerance were doses between those at the point of inflection from no responses to threshold sensitivity. But even doses three orders of magnitude lower than these suppressed subsequent sensitization if applied repeatedly. C57B1/6 mice (low responders) were consistently easier to make tolerant than BALB/c mice (high responders). The tolerant state established by a single painting was found to be fully developed at 48 h after initiation and long-lasting (>14 d). It could be adoptively transferred by intravenous injection of total spleen cells (SC), lymph node cells (LNC), or purified T cells and shown to be hapten specific. Pretreatment with cyclophosphamide (Cy) prevented tolerization. The T cells capable of transferring suppressive activity were found to be generated irrespective of the dose applied. On day 2 after painting, tolerance could be transferred with LNC from both tolerant and sensitized animals. On day 5, however, only cells from tolerant donors transferred tolerance. But by action of Cy, suppression was shown to be part of every sensitization, although masked. Production of hapten-specific antibodies was suppressed as well. Through depletion by monoclonal antibody in vitro the T suppressor cells were shown to belong to the murine CD8+ subset (Lyt2+). Upon restimulation in vitro by haptenized and irradiated normal SC, LNC from tolerant donors produced predominantly interleukin (IL)-4, IL-5, and IL-10. In contrast, LNC from sensitized donors produced preferentially IL-2 and interferon-gamma. Thus we demonstrate that painting subsensitizing doses of contact sensitizers on normal murine skin generates CD8+ Th2-like cells that give rise to hapten-specific tolerance. The model may have broader significance and apply to other species, including humans.

The association of children's mathematic abilities with both adults' cognitive abilities and intrinsic fronto-parietal networks is altered in preterm-born individuals.

Mathematic abilities in childhood are highly predictive for long-term neurocognitive outcomes. Preterm-born individuals have an increased risk for both persistent cognitive impairments and long-term changes in macroscopic brain organization. We hypothesized that the association of childhood mathematic abilities with both adulthood general cognitive abilities and associated fronto-parietal intrinsic networks is altered after preterm delivery. 72 preterm- and 71 term-born individuals underwent standardized mathematic and IQ testing at 8 years and resting-state fMRI and full-scale IQ testing at 26 years of age. Outcome measure for intrinsic networks was intrinsic functional connectivity (iFC). Controlling for IQ at age eight, mathematic abilities in childhood were significantly stronger positively associated with adults' IQ in preterm compared with term-born individuals. In preterm-born individuals, the association of children's mathematic abilities and adults' fronto-parietal iFC was altered. Likewise, fronto-parietal iFC was distinctively linked with preterm- and term-born adults' IQ. Results provide evidence that preterm birth alters the link of mathematic abilities in childhood and general cognitive abilities and fronto-parietal intrinsic networks in adulthood. Data suggest a distinct functional role of intrinsic fronto-parietal networks for preterm individuals with respect to mathematic abilities and that these networks together with associated children's mathematic abilities may represent potential neurocognitive targets for early intervention.

Level of HLA antigens in locoregional metastases and clinical course of the disease in patients with melanoma.

Immunohistochemical staining with monoclonal antibodies showed marked variations in the percentage of melanoma cells stained by anti-HLA Class I and anti-HLA Class II monoclonal antibodies among 48 locoregional metastases removed from 39 patients with malignant melanoma. On the other hand there was limited variation in the percentage of melanoma cells stained by anti-HLA antibodies in autologous locoregional metastases removed from 8 of 9 patients. In the remaining patient marked differences were found in the percentage of melanoma cells stained by anti-HLA Class I antibodies in the two parts of the lymph node metastasis analyzed. Therefore this patient was not included in additional analyses to correlate the level of expression of HLA antigens with the clinical course of the disease. In all the lesions tested the percentage of melanoma cells stained by anti-HLA Class II antibodies was lower than or equal to but never higher than that stained by anti-HLA Class I antibodies. According to the level of expression of HLA Class I and Class II antigens the 38 patients could be divided into three groups: Pattern A included lesions with more than 50% of tumor cells stained by anti-HLA Class I antibodies (mean, 86.1; median, 85) and 50% or less by anti-HLA Class II antibodies (mean, 10.5; median, 5); Pattern B included lesions with 50% or less tumor cells stained by anti-HLA Class I antibodies (mean, 14.9; median, 5) and by anti-HLA Class II antibodies (mean, 4.1; median, 1); Pattern C included lesions with more than 50% tumor cells stained by anti-HLA Class I antibodies (mean, 88.8; median, 92) and by anti-HLA Class II antibodies (mean, 70.0; median, 70). The survival of 21 patients with Pattern A was significantly longer than those of 13 and 4 patients with Patterns B and C, respectively. No difference in the survival of patients in the latter two groups was found. These results suggest that HLA antigens play a role in the biology of melanoma and that analysis of the level of HLA antigens in locoregional metastases of patients with melanoma may provide clinically useful information.

Transdiagnostic commonalities and differences in resting state functional connectivity of the default mode network in schizophrenia and major depression.

Schizophrenia and depression are prevalent psychiatric disorders, but their underlying neural bases remains poorly understood. Neuroimaging evidence has pointed towards the relevance of functional connectivity aberrations in default mode network (DMN) hubs, dorso-medial prefrontal cortex and precuneus, in both disorders, but commonalities and differences in resting state functional connectivity of those two regions across disorders has not been formally assessed. Here, we took a transdiagnostic approach to investigate resting state functional connectivity of those two regions in 75 patients with schizophrenia and 82 controls from 4 scanning sites and 102 patients with depression and 106 controls from 3 sites. Our results demonstrate common dysconnectivity patterns as indexed by a significant reduction of functional connectivity between precuneus and bilateral superior parietal lobe in schizophrenia and depression. Furthermore, our findings highlight diagnosis-specific connectivity reductions of the parietal operculum in schizophrenia relative to depression. In light of evidence that points towards the importance of the DMN for social cognitive abilities and well documented impairments of social interaction in both patient groups, it is conceivable that the observed transdiagnostic connectivity alterations may contribute to interpersonal difficulties, but this could not be assessed directly in our study as measures of social behavior were not available. Given the operculum's role in somatosensory integration, diagnosis-specific connectivity reductions may indicate a pathophysiological mechanism for basic self-disturbances that is characteristic of schizophrenia, but not depression.

The mouse homologue of the HTLV-I tax responsive element binding protein TAXREB107 is a highly conserved gene which may regulate some basal cellular functions.

We report the cDNA sequence of a mouse gene homologous to the HTLV-I tax responsive element binding protein TAXREB107 (M-TAXREB107). This gene is constitutively and ubiquitously expressed indicating a conserved biological function. We present evidence that its transcription is under strict control of a regulatory factor, which is rapidly metabolized.

Novel insights into structure and function of MRP8 (S100A8) and MRP14 (S100A9).

The two migration inhibitory factor- (MIF)-related protein-8 (MRP8; S100A8) and MRP14 (S100A9) are two calcium-binding proteins of the S100 family. These proteins are expressed during myeloid differentiation, are abundant in granulocytes and monocytes, and form a heterodimeric complex in a Ca2+-dependent manner. Phagocytes expressing MRP8 and MRP14 belong to the early infiltrating cells and dominate acute inflammatory lesions. In addition, elevated serum levels of MRP8 and MRP14 have been found in patients suffering from a number of inflammatory disorders including cystic fibrosis, rheumatoid arthritis, and chronic bronchitis, suggesting conceivable extracellular roles for these proteins. Although a number of possible functions for MRP8/14 have been proposed, the biological function still remains unclear. This review addresses recent developments regarding the MRP14-mediated promotion of leukocyte-endothelial cell-interactions and the characterization of MRP8/14 heterodimers as a fatty acid binding protein complex. In view of the current knowledge, the authors will hypothesize that MRP8 and MRP14 play an important role in leukocyte trafficking, but do not affect neutrophil effector functions.

Molecular characterisation of the genomic locus of the mouse MRP8 gene.

MRP8 is an inflammatory marker protein specifically expressed throughout the myeloid cell lineage in mouse and humans. Here the nucleotide sequence and the genomic structure of the mouse MRP8 gene (MM-MRP8) is presented. A strong homology between the mouse and human MRP8 promoters reflects the highly specific expression pattern of both genes and suggests that a conserved transcriptional machinery regulates these genes.

A homologue of the human MSS1 gene, a positive modulator of HIV-1 gene expression, is massively expressed in Xenopus oocytes.

Here the nucleotide sequence of a Xenopus homologue of the human MSS1 gene, a positive modulator of the HIV-1 Tat mediated transactivation in mammalian cells, is presented. This gene is highly conserved and almost exclusively expressed in Xenopus oocytes. We speculate about a possible role of this gene in the HIV-1 Tat/TAR mediated transactivation in Xenopus oocytes.

Homocysteine inhibits tumor necrosis factor-induced activation of endothelium via modulation of nuclear factor-kappa b activity.

Homocystinuria is a metabolic disorder associated with an increased incidence of vascular disease. Here, we analyzed the effects of homocysteine on endothelial cell activation that is a prerequisite for the recruitment of leukocytes to sites of evolving atherosclerotic plaques. Exposure of human umbilical vein endothelial cells to homocysteine alone did not modulate expression of the adhesion molecules E-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and the chemokines monocyte chemotactic protein-1 and interleukin-8. In contrast, tumor necrosis factor (TNF)-induced upregulation of these molecules was almost completely inhibited by homocysteine, but not by related thiol amino acids. Using electrophoretic mobility shift and reporter gene assays, the inhibitory effect of homocysteine could be attributed to inhibition of DNA binding and transcriptional activity of NF-kappa B. TNF-induced phosphorylation and degradation of I kappa B-alpha, however, were not affected. Neither was NF-kappa B-independent activation of endothelial cells by interferon-gamma influenced by homocysteine. In summary, our data indicate that homocysteine alters the response to injury of endothelial cells which may have fundamental impacts on mechanisms of leukocyte recruitment to sites of inflammation. Our findings might refer to a novel pathway by which homocysteine is involved in vascular disorders associated with homocystinuria.

Macrophage-derived angiogenesis factors.

A majority of angiogenic factors has been shown to be produced by macrophages. This review will give a concise description of their biochemical nature, their isolation from macrophages and their angiogenic activity. Among the factors with mitogenic effects on endothelial cells are basic fibroblast growth factor (bFGF), transforming growth factor-alpha (TGF-alpha) and very probably insulin-like growth factor-1 (IGF-1). Other secretory products such as angiotropin and human angiogenic factor (HAF) are nonmitogenic but promote angiogenesis by inducing migration of endothelial cells. Prostaglandins, platelet-derived growth factor (PDGF), granulocyte-macrophage- and granulocyte-colony stimulating factor (GM-CSF, G-CSF), interleukin 6 (IL-6) and angiotensin converting enzyme (ACE) have also been shown to be angiogenic, but their mode of action is still to be clearly defined. As the extracellular matrix appears to be involved in the control of angiogenesis, macrophage-derived factors that can alter this structure via degradation or via the clotting system will also be discussed. Tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1) and transforming growth factor-beta (TGF-beta) have complex actions on endothelial cells, and can partially inhibit angiogenesis. Among the factors which solely inhibit neovascularization are the interferons. As it is not known whether all of these factors play a role in angiogenesis in vivo attempts to detect them in situ during the course of neovascularization will be described. Finally macrophages will be discussed as cells that may not be mandatory for each phase of the angiogenic process but whose angiogenic capabilities are comprehensive and unsurpassed by any other cell.

Heterodimers of the calcium-binding proteins MRP8 and MRP14 are expressed on the surface of human monocytes upon adherence to fibronectin and collagen. Relation to TNF-alpha, IL-6, and superoxide production.

The 27E10 antigen is a heterodimer of MRP8 and MRP14, two Ca(2+)-binding proteins related to the S-100 protein family. Previous studies have shown that 27E10 epitope-bearing monocyte subsets are prevalent in early acute but absent in chronic inflammatory conditions. These observations further provide an impetus for identifying the cellular mechanisms responsible for the appearance of different monocyte subpopulations during inflammation. Therefore this in vitro study was carried out to investigate the influence of adhesion in inducing 27E10-positive subsets. In adhesion assays the role of 27E10 antigen in spontaneous adherence was obvious, as a monoclonal antibody directed against the 27E10 antigen significantly inhibited the adherence of monocytes to collagen and fibronectin. In contrast, these extracellular matrix (ECM) proteins induce the cell surface expression and association of 27E10 antigen with cytoskeleton (CSK), detected by flow cytometry and confocal laser scan microscopy, respectively. Similar results were obtained on cross-linking with specific antibodies, thus showing involvement of the integrin molecules VLA-2 and VLA-4. In addition, the association with CSK could be confirmed by differential detergent extraction. The observed redistribution of 27E10 antigen guided by collagen compared with fibronectin was also paralleled by an augmented release of inflammatory cytokines interleukin-6, tumor necrosis factor alpha, and superoxide anions. Thus, this study demonstrates that under inflammatory conditions the interactions of extravasating monocytes with the ECM may induce an activated phenotype of monocytes marked by 27E10.

The monoclonal antibody MAC387 detects an epitope on the calcium-binding protein MRP14.

The present study was initiated to identify the antigen recognized by the monoclonal antibody (MAb) MAC387 which is widely used for phenotypical characterization of myelomonocytic cells in situ. MAC387 has been described to show a similar reaction pattern as antisera to a complex formed by the calcium-binding proteins MRP8 and MRP14. However, the exact nature of the molecule recognized by MAC387 has been controversial. Using Western blot analysis, MAC387 was found to detect a single protein band of 14 kDa in lysates of human monocytes and granulocytes. Transfection of embryonic lung fibroblasts L132 with either MRP8 or MRP14 cDNA revealed that MAC387 reacts with MRP14 but not MRP8. This finding was confirmed by dot blot analysis of recombinant MRP8 and MRP14. Our data thus provide unequivocal evidence that MAC387 is a monoclonal antibody directed against the calcium-binding protein MRP14.

Macrophages and angiogenesis.

Macrophages are supposed to play a key role in inflammatory and tumor angiogenesis. Their importance derives from (1) their ubiquitous presence in normal and especially inflamed tissues, (2) their potential to become activated in response to appropriate stimuli, and (3) their repertoire of secretory products. By release of proteases, growth factors (bFGF, GM-CSF, TGF-alpha, IGF-I, PDGF, VEGF/VPF, TGF-beta), and other monokines (IL-1, IL-6, IL-8, TNF-alpha, substance P, prostaglandins, interferons, thrombospondin 1), activated macrophages have the capability to influence each phase of the angiogenic process, such as alterations of the local extracellular matrix, induction of endothelial cells to migrate or proliferate, and inhibition of vascular growth with formation of differentiated capillaries. This review describes macrophage physiology and the influence of macrophage secretory products on the different phases of angiogenesis in vitro and in vivo.

Differences in the onset of the inflammatory response to cutaneous leishmaniasis in resistant and susceptible mice.

Sites of cutaneous infection with Leishmania major in genetically susceptible (BALB/c) and resistant (C57B1/6) mice were investigated for the early inflammatory response (6 h to 12 days) by electron microscopy combined with enzyme-histochemical methods. Susceptible BALB/c mice spontaneously recruited only polymorphonuclear leukocytes (PMNs) at the site of infection. Infiltrating mononuclear phagocytes (and eosinophils) were first observed at day 1 in a ratio equal to the influx of PMNs (about 40%). This pattern persisted during the following 11 days of infection. In the resistant C57/B16 mice, the first cellular infiltrate at the infected site contained mononuclear phagocytes (25%) and eosinophils (15%) besides PMNs (60%). Within 3 days after infection, mononuclear phagocytes became the dominant population of cells in cutaneous lesions (up to 80%). It was found in situ that L. major accumulated and replicated in immature macrophages, that is, intermediate stages between monocytes and resident macrophages, which were found in lesions of both strains. The burden of parasites was, however, degraded more rapidly by the infiltrating cells of the resistant mice than by those of the susceptible ones. Within the first 4 days of infection, the parasites were found in PMNs, mononuclear phagocytes, and extracellular spaces in both strains. In susceptible mice this distribution pattern persisted up to 12 days after infection; in resistant C57B1/6 mice parasites accumulated inside mononuclear phagocytes within this period. It is concluded that the features of acute inflammation during leishmaniasis in BALB/c mice are sustained over a prolonged period that is ineffective in the elimination of L. major.

Expression and complex assembly of calcium-binding proteins MRP8 and MRP14 during differentiation of murine myelomonocytic cells.

In the present study we analyzed expression and biochemical properties of the two recently cloned calcium-binding proteins MRP8 and MRP14, both members of the S-100 family, in murine myelomonocytic cells. Expression of MRPs was found to be restricted to granulocytes and distinct stages of macrophage differentiation when compared to the expression of other markers (Mac-1, F4/80) in transformed macrophage cell lines (M1, RMB.TG, WEHI.TG, J774A, P388D) and resident and exudate peritoneal and tissue macrophages. Similarly, mRNA and protein levels of MRP8/MRP14 in murine bone marrow cells decreased during culture in L cell-conditioned medium. Applying a cross-linking technique, the formation of noncovalently associated heteromeric MRP8/MRP14 complexes of 25, 35, and 48 kd was demonstrated. Our data suggest that MRP8/MRP14 expression and complexation are characteristic for granulocytes and distinct stages of macrophage differentiation in mice. Analysis of the MRP8/MRP14+ phenotype of macrophages may provide further insights into the mechanisms underlying macrophage differentiation.