FKBP51 inhibits GSK3ß and augments the effects of distinct psychotropic medications.

Psychotropic medications target glycogen synthase kinase 3ß (GSK3ß), but the functional integration with other factors relevant for drug efficacy is poorly understood. We discovered that the suggested psychiatric risk factor FK506 binding protein 51 (FKBP51) increases phosphorylation of GSK3ß at serine 9 (pGSK3ß(S9)). FKBP51 associates with GSK3ß mainly through its FK1 domain; furthermore, it also changes GSK3ß's heterocomplex assembly by associating with the phosphatase PP2A and the kinase cyclin-dependent kinase 5. FKBP51 acts through GSK3ß on the downstream targets Tau, ß-catenin and T-cell factor/lymphoid enhancing factor (TCF/LEF). Lithium and the antidepressant (AD) paroxetine (PAR) functionally synergize with FKBP51, as revealed by reporter gene and protein association analyses. Deletion of FKBP51 blunted the PAR- or lithium-induced increase in pGSK3ß(S9) in cells and mice and attenuated the behavioral effects of lithium treatment. Clinical improvement in depressive patients was predicted by baseline GSK3ß pathway activity and by pGSK3ß(S9) reactivity to ex vivo treatment of peripheral blood mononuclear lymphocytes with lithium or PAR. In sum, FKBP51-directed GSK3ß activity contributes to the action of psychotropic medications. Components of the FKBP51-GSK3ß pathway may be useful as biomarkers predicting AD response and as targets for the development of novel ADs.

[Memorandum 'Development of health services research in Bavaria from the perspective of the Bavarian State Working Group 'Health Services Research (LAGeV)': status quo - potential - strategies']. / Memorandum "Weiterentwicklung der Gesundheitsversorgungsforschung in Bayern aus Sicht der Landesarbeitsgemeinschaft Gesundheitsversorgungsforschung: Status quo - Entwicklungspotenziale - Strategien".

The aim of the memorandum on the development of health services research (HSR) in Bavaria is to operationalise the global objectives of the State Working Group "Health Services Research" (LAGeV) and to collectively define future topics, specific implementation steps, methods as well as ways of working for the future course of the LAGeV. The LAGeV is an expert committee that integrates and links the competencies of different actors from science, politics and health care regarding HSR and facilitates their cooperation. The memorandum is based on an explorative survey among the LAGeV members, which identified the status quo of health services research in Bavaria, potential for development, important constraints, promoting factors, specific recommendations as well as future topics for the further development of HSR in Bavaria. From the perspective of the LAGeV members, the 12 most important future topics are: 1) Interface and networking research, 2) Innovative health care concepts, 3) Health care for multimorbid patients, 4)Health care for chronically ill patients, 5) Evaluation of innovations, processes and technologies, 6) Patient orientation and user focus, 7) Social and regional inequalities in health care, 8) Health care for mentally ill patients, 9) Indicators of health care quality, 10) Regional needs planning, 11) Practical effectiveness of HSR and 12) Scientific use of routine data. Potential for development of HSR in Bavaria lies a) in the promotion of networking and sustainable structures, b) the establishment of an HSR information platform that bundles information and results in regard to current topics and aims to facilitate cooperation as well as c) in the initiation of measures and projects. The latter ought to pinpoint health care challenges and make recommendations regarding the improvement of health care and its quality. The cooperation and networking structures that were established with the LAGeV should be continuously expanded and be used to work on priority topics in order to achieve the global objectives of the LAGeV.

[Status quo and potential of health services research: the perspective of Bavarian actors]. / Stand und Potenziale der Versorgungsforschung: Die Perspektive der Akteure in Bayern.

In 2011, the Bavarian Parliament decided to advance health services research (HSR) in Bavaria by bundling scientific competencies in a State Working Group and integrating other actors in it. The establishment of such a State Working Group "Health Services Research" -(LAGeV) together with members from science, health care and politics followed in 2012. The objective of this study is to identify the status quo of HSR in Bavaria including its determinants and potential for development based on the actors' perspective.After the inaugural meeting a semi-structured questionnaire was sent to all 36 members from 28 organisations. Items comprise information on the respondent's background as well as status quo, future topics and potential for development of HSR in Bavaria.27 members took part in the survey, resulting in a response rate of 75.0%. Satisfaction of actors with the status quo of HSR is rather low, especially regarding the effectiveness of policy advice. Researchers and health care providers are also not much satisfied with the HSR environment. For the future of HSR, respondents prioritise the topics interface and networking research, followed by innovative care concepts, care for patients with multiple or chronic conditions as well as evaluation of innovations, processes and technologies. Potential for development and thus improvement of care is primarily seen in the abolishment of existing constraints by an overall HSR concept (including selective research promotion), networking and cooperation, research funding as well as improving the interface between politics and science. Respondents assess the benefit of an increased networking within the LAGeV as high.Status quo of HSR in Bavaria is not very satisfactory. The survey reveals important constraints as well as promoting factors based on the viewpoints of different groups of actors. It also prioritises future HSR topics and identifies potential for development, which are important for the LAGeV. The findings can be used for advancing HSR in Bavaria and beyond.

Disparity in expression of protein kinase C alpha in human glioma versus glioma-derived primary cell lines: therapeutic implications.

Intracellular signal transduction by the protein kinase C (PKC) family of enzymes plays a critical role in carcinogenesis and cellular growth regulation. Recent studies have suggested that the PKC isoform alpha may be a critical target for antiglioma therapy in humans (G. H. Baltuch et al., Can. J. Neurol. Sci., 22: 264-271, 1995). We studied the expression and subcellular distribution of the PKC alpha isoform in human high- and low-grade gliomas and also in glioma-derived cell lines with immunoblot analyses. Cell lines derived from high-grade gliomas expressed higher levels of PKC alpha than did cell lines derived from low-grade gliomas. In glioblastoma-derived cell lines, PKC alpha was mainly expressed in the soluble (cytosolic) fraction, indicating an inactive state of the enzyme. When analyzed in freshly frozen samples from human gliomas, the expression of PKC alpha was at similar levels in high- and low-grade tumors and was also similar to the levels in normal brain tissue controls. The PKC partial antagonist bryostatin 1, currently undergoing Phase II testing in patients with malignant gliomas, was capable of specifically down-regulating PKC alpha in vitro in glioblastoma-derived cell lines. However, this was not associated with significant growth inhibition. We conclude that the observed overexpression of PKC alpha in glioblastoma-derived cell lines may be an artifact of in vitro growth. Furthermore, we conclude that expression of PKC alpha in glioma-derived cell lines is not essential for cellular growth in vitro because down-regulation of PKC alpha following treatment with bryostatin 1 was not associated with growth inhibition.

DNA ploidy and cell-cycle analysis in intracranial meningiomas and hemangiopericytomas: a study with high-resolution DNA flow cytometry.

Although various DNA flow-cytometric studies have been performed on meningiomas, the role of DNA ploidy and the S-phase fraction (SPF) in predicting biological tumor behavior remains unresolved. Discrepant results in earlier studies might be due to different preparing, staining and measuring techniques; different quality standards; and lack of sophisticated computer software. In this study, high-resolution DNA flow cytometry using the DNA-specific dye DAPI (4', 6'-diamidino-2-phenylindol) was performed on stored frozen tissue from 128 microsurgically resected meningiomas and 7 hemangiopericytomas, including 17 recurrent meningiomas and 4 recurrent hemangiopericytomas. The computer software Multicycle 2.5 was used to determine the ploidy level and to perform cell-cycle analysis. DNA aneuploidy and SPF were significantly higher in atypical, anaplastic and recurrent meningiomas and correlated well with histopathological features such as focal necrosis, infiltration of dura mater and mitotic activity. Among 128 meningiomas, 42 had additional DNA aneuploid stem lines. No association between hypo- and hyperploidy and either histological subtype or clinical outcome was found. In 7 hemangiopericytomas, SPF was significantly higher compared to the benign meningioma group, while only 1 tumor was aneuploid. In all 42 DNA aneuploid tumors, cell-cycle analysis was performed separately for the euploid and aneuploid stem lines. The proliferation parameters (SPF, G2/M phase) were significantly higher in the DNA aneuploid stem lines. DNA ploidy and SPF are thus useful indicators of different biological behavior within identical histological subgroups in meningiomas.

Role of ploidy, chromosome 1p, and Schwann cells in the maturation of neuroblastoma.

BACKGROUND: Neuroblastoma is a heterogeneous disease, with manifestations ranging from spontaneous regression to lethal spread. Sometimes the tumor spontaneously differentiates toward a benign ganglioneuroma (maturing neuroblastoma). The prognosis is frequently related to ploidy, deletions in the short arm of chromosome 1, and amplifications of the N-myc oncogene. Maturing neuroblastomas consist of both neuronal cells and Schwann cells. We investigated the genetic composition of both cell types in maturing neuroblastomas, to determine the relation between genetic abnormalities and maturation. METHODS: We studied 20 maturing and mature neuroblastomas by in situ hybridization to count the chromosomes and evaluate possible deletions in the short arm of chromosome 1 in neuronal and Schwann cells. The DNA content of the cells was measured by flow cytometry. RESULTS: Neuroblastic and ganglionic cells showed aberrations in the number of chromosomes. In situ hybridization and flow cytometry demonstrated near-trip-loidy in 18 of 19 tumors and pentaploidy in the remaining tumor. The Schwann cells in all 20 neuroblastomas contained normal numbers of chromosomes. In 18 tumors studied, there were no chromosome 1 deletions in either type of cell. CONCLUSIONS: The Schwann cells in maturing neuroblastomas differ genetically from the neuronal cells. The normal number of chromosomes in Schwann cells and the abnormal number in neuroblastic ganglionic cells suggests that Schwann cells are a reactive population of normal cells that invade the neuroblastoma. Near-trip-loidy of neuroblastoma cells and intact chromosome 1 are presumably genetic prerequisites for spontaneous organoid maturation, because we found no diploidy or chromosome 1 depletions in the neuronal cells of spontaneously maturing neuroblastomas.

Prognostic significance of nuclear DNA content in human meningiomas: a prospective study.

Flow cytometric DNA analyses were performed to study the correlation between alterations of nuclear DNA content and clinical aggressive tumour behaviour in 134 cranial meningiomas. Forty-one meningiomas revealed an aneuploid DNA content with a distribution of n = 24 in benign, n = 12 in atypical and n = 5 in anaplastic tumours. Aneuploid DNA content was correlated with a significantly higher amount of histomorphological criteria like evidence of mitoses, necrosis, infiltration and increased cellularity. There was a significantly higher Ki 67 proliferation index in the aneuploid meningiomas in comparison to the diploid tumour group. The rate of aneuploid cell-lines was increased in recurrent tumours. No tumour recurrence could be found in diploid meningiomas during follow up (mean 37 months, range 22-46 months). However eight of forty-one aneuploid tumours showed meningioma recurrence. Nuclear DNA content has an important significance in predicting risk of recurrence and poor clinical outcome after benign meningioma surgery.

Impingement symptoms caused by a synovial fold in the glenoid fossa projecting into the sublabral hole.

In this case report, an atypical impingement in a 40-year-old male patient with terminal restrictions in the shoulder joint is used to show the development of an atypical synovial fold through the sublabral hole with protrusion into the glenoid fossa.

[MR tomography in autologous plastic repair of the anterior cruciate ligament: a comparison of 2 surgical methods]. / Die Kernspintomographie bei autologer Plastik des vorderen Kreuzbandes: Vergleich zweier Operationsmethoden.

UNLABELLED: The aim of this prospective MRI study was the analysis of the post-operative signals derived from two techniques for cruciate ligament reconstruction. PATIENTS AND METHODS: Group 1 consisted of 15 patients who had undergone conventional plastic repair by patellar tendon transplant and group 2 was made up of 15 patients with arthroscopic reconstruction with semitendinosus grafts. They were examined at 6 weeks and 6 months post-operatively. RESULTS: Typical appearances of normal transplants were found in 19 patients. After 6 months 8 of the patellar tendon transplants and three of the semitendinosus transplants could not be clearly defined. At this time there was a significant increase in signal intensity in the middle third of the transplant in group 1. CONCLUSION: Bearing in mind the different operative techniques, there was a higher impingement rate in group 1. The post-operative MRI findings at 6 months after surgery allowed differentiation between pathological changes (impingement) and revascularisation (remodelling).

Differential diagnosis in variants or abnormalities of the hip on MRI.

In the differential diagnosis of unspecific hip pain MRI becomes increasingly important. In particular it is useful in the diagnosis of avascular necrosis, primary and secondary bone tumors, osteomyelitis and synovial processes. According to the higher frequence of MR examinations of the hip the number of nonpathological incidental findings is rising. 39 'pitfalls' and abnormalities were found on MRI of 152 patients with unspecific hip pain. Soft tissue penetrating cortical lesions of the femoral neck (herniation pit, n = 4), physiological changes of bone marrow, synovial proliferation (n = 6) of the hip joint capsule, epiphyseal scars of the femoral head (n = 12) and the transient osteoporosis (n = 12) are some of the morphological changes of the hip, which may cause difficulties and misinterpretations on MRI of the hip. Knowledge of their radiological characteristics on MRI is important, especially in cases of unspecific hip pain.

Flow cytometric assessment of human MIC2 expression in bone marrow, thymus, and peripheral blood.

The cell-surface expression of the MIC2 antigen defined by the monoclonal antibody 12E7 was investigated on human leukocytes in bone marrow (BM), thymus, and peripheral blood (PB) using multiparameter flow cytometry and cell sorting. In contrast to preceding reports, we found that the MIC2 antigen is not restricted to T cells and monocytes. We show that it is also expressed in the B cell and in the granulocytic lineage, the levels of expression being related to distinct maturational stages. CD34+ cells of BM were found to express the antigen at high levels. Along the granulocytic maturation pathway from CD34+CD33+ blasts to mature granulocytes, MIC2 densities appeared progressively reduced with a considerable decline at the myelocyte stage. In B lymphopoiesis, the earliest CD34+ CD10+ B-cell precursor (BCP) cells, further subdivided by expression of CD19, displayed the highest MIC2 density of BM leukocytes. All later BCP stages showed lower MIC2 expression levels, with a remarkable reduction concomitant with loss of the CD34 antigen at the CD10+CD20- surface mu-chain- stage, and a subsequent slight upregulation along with maturation to CD10-CD20high surface mu-chain+ BCPs. The brightest MIC2 expression of all cells tested was displayed by the most immature thymic T-lineage cells characterized by the antigenic profile CD34weakor- CD7++ surface CD3-CD1a(weak) CD4weak CD8-or weak. Common thymocytes stained slightly less intense with 12E7, whereas all subsequent stages of T-lineage cells in thymus, PB, or BM showed markedly reduced MIC2 levels. Mature peripheral CD4+ as well as CD8+ T cells displayed a bimodal distribution of MIC2. In the CD4+ population, the distinct MIC2 levels were related to the well-studied functional subdivision by differential expression of CD45 isoforms, the helper-inducer/memory subset showing higher MIC2 expression than helper-suppressor/naive CD4+ T cells. Similarly high MIC2 densities were found on CD16+ natural killer cells and on CD14+ monocytes, whereas mature peripheral B cells exhibited low or intermediate expression, and granulocytes exhibited no or only dim expression. These results document that the MIC2 antigen (1) is expressed on all leukocyte lineages; (2) is differentially expressed during T- and B-lymphoid, as well as granulocytic maturation; (3) shows highest expression in the most immature lymphocytic and granulocytic developmental stages; and (4) is also differentially expressed on functional T-cell subsets. We speculate that these observations imply a functional significance of MIC2 in the network of hematopoietic adhesion pathways.

[Bernard-Soulier syndrome. An important differential diagnosis in chronic thrombocytopenia with bleeding complications]. / Das Bernard-Soulier-Syndrom. Eine wichtige Differentialdiagnose bei chronischer Thrombozytopenie mit Blutungskomplikationen.

Hereditary types of thrombocytopenia are often clinically misdiagnosed as chronic autoimmune thrombocytopenia. The Bernard-Soulier syndrome is a recessively inherited thrombocytopenia and -pathy associated with giant platelets. Bleeding time is usually prolonged, hemorrhage can be severe. In a Turkish thrombocytopenic boy autoimmune thrombocytopenia was diagnosed at the age of 11 months because the platelet count raised from 40.000/microliter to 100.000/microliters under treatment with steroids. The correct diagnosis of Bernard-Souiler syndrome was made at the age of 2 1/2 years. His also affected 13 year old sister had been treated for chronic autoimmune thrombocytopenia for years and suffered from severe hypermenorrhoea. Family history revealed consanguinity of the parents. Diagnosis of Bernard-Soulier syndrome was made by crossimmunoelectrophoresis and immunofluorescence showing absence of the glycoprotein complex Ib/IX.

Results of conservative treatment of partial tears of the anterior cruciate ligament.

The diagnosis of an acute partial tear of the anterior cruciate ligament was made in 56 patients who did not undergo surgical repair. After a period of up to 5 years, 39 returned for follow up evaluation. They were divided into three groups according to clinical analysis of the knee and the Lysholm-Gillquist score. Our aim was to determine their long term functional limitations. 56% had progressed to anterior cruciate ligament deficiency at the time of follow up. This came about not only after resuming sporting activities, but also occurred in those who were not so active. Our results suggests that a partial tear leaves an irreversible defect which may progress to a complete tear, especially in young athletes engaged in active sport.

Skeletal muscle damage during tourniquet-induced ischaemia. The initial step towards atrophy after orthopaedic surgery?

Muscle biopsies from the vastus lateralis muscle of patients who had undergone anterior cruciate ligament surgery under conditions of tourniquet-induced ischaemia were examined under the electron microscope at different periods of time up to 90 min of ischaemia. The severity of the alterations in ultrastructure appeared to depend on the period of ischaemia. The pathological changes consisted of accumulation of lysosomes, persistent intrafibre oedema, and some extracellular oedema. Signs of fibre necrosis were found after 90 min of ischaemia. Capillary ultrastructure was only altered with regard to some swelling of the endothelium and marked thickening of the basement membrane. It was concluded that skeletal muscle could be severely affected even during relatively short periods of ischaemia, which might facilitate the development of muscle atrophy during immobilization after orthopaedic surgery.

Influence of CGP 361A, propranolol and diazepam on autonomous reactions to different stressors.

1. To evaluate the influence of beta-blockers and minor tranquilizers on autonomous stress response, 40 healthy subjects selected with regard to personality traits were randomly assigned to 5 groups. 2. Mental arithmetic induced the most pronounced increase in heart rate (HR), blood pressure and epinephrine secretion. 3. Beta-blockers reduced HR increases due to mental stress, whereas the minor tranquilizer reduced skin conductance level throughout the whole trial. 4. Our data provide evidence that different structured situations induce specific response patterns that are differentially modified by beta-blockers and minor tranquilizer.

[Arthrography of the ankle joint]. / Die Arthrographie des oberen Sprunggelenks.

Arthrography of the ankle joint was first carried out by Johnson and Palmer at the Military Hospital in Stockholm in 1940. Arthrography can be used for judging the integrity of the articular cartilage, of osteochondritis dissecans, arthritis or adhesive capsulitis. The literature shows, however, that more than 95% of the patients on whom this examination has been performed had suffered from acute trauma.