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UKE Paper of the Month April 2013
Journal of Sexual Medicine, April 2013, PMID: 23347202
Genital Abnormalities in Early Childhood in Sexual Homicide Perpetrators
Martin Rettenberger, Andreas Hill, Arne Dekker, Wolfgang Berner, and Peer Briken
ABSTRACT: INTRODUCTION: The present study investigates the relevance of genital abnormalities (GA) like cryptorchidism, hypospadias, and phimosis usually diagnosed in early childhood for the development of psychosexual problems and deficits in a sample of N = 163 convicted sexual homicide perpetrators. AIMS: The first aim was to investigate the prevalence of early childhood GA in a sample of sexual homicide perpetrators. The second was to explore differences in the psychosexual development of participants with GA in early childhood compared with those without GA. It was expected that offenders with GA show specific problems in their psychosexual development compared with offenders without GA. METHODS: The data for the present study were obtained by reanalyzing an existing database derived from a large-scale re-search project about sexual homicide. Using a predominantly exploratory design we, therefore, divided the total sample into two subgroups (with vs. without indicators of GA). MAIN OUTCOME MEASURES: Main outcome measures were the number of sexual homicide perpetrators showing GA in early childhood and the differences of subjects with and without GA with regard to their psychosexual development (i.e., according to sexual deviant interests or sexual dysfunctions). RESULTS: The prevalence of GA is substantially higher in this sample than epidemiological studies indicated in the normal population. This result provided first support for the importance of GA in the population of sexual homicide perpetrators. Further analyses indicate significant differences between both subgroups: Offenders with GA in early childhood showed indicators for more sexual dysfunctions (e.g., erectile dysfunction) in adulthood and a distinct tendency of more masochistic sexual interests. CONCLUSION: Even if the exploratory design of the present investigation allows no causal conclusions between GA and sexual homicide offenses, the result provided support for the relevance of early childhood sexual diseases in the assessment (and treatment) of offenders who have committed severe sexual violence.
STATEMENT: The present study is the first investigation of the relevance of genital-related physical problems and abnormalities in early childhood in sexual offenders by using the internationally largest sample of sexual homicide perpetrators. Despite the fact that early developmental experiences are especially significant for the formation of sexual deviance and sexual violence, nothing was known about the role of genital abnormalities in sexual offender samples before. There is now evidence that genital-related physical problems and abnormalities may play a relevant role in the sexual biographies of sexual offenders, so the present study will provide new starting points for future research about the etiology, assessment, and treatment of offenders who have committed severe sexual violence.
BACKGROUND: The present study was conducted by current and former members of the Institute for Sex Research and Forensic Psychiatry at the University Medical Center Hamburg-Eppendorf. The last author, Peer Briken, is the current director of the institute and the successor of Wolfgang Berner (also co-author of the present study and former director of the institute). The data collection of the present study was part of a large-scale investigation about sexual homicide per-petrators supported by the Deutsche Forschungsgemeinschaft (Grant Nos. BE 2280/2-1 and BE 2280/2-2). .
UKE Paper of the Month März 2013
Neuron, März 2013, PMID: 23522046
Developmental refinement of vesicle cycling at Schaffer collateral synapses
Tobias Rose, Philipp Schoenenberger, Karel Jezek , Thomas G. Oertner
ABSTRACT: At synapses formed between dissociated neurons, about half of all synaptic vesicles are refractory to evoked release, forming the so-called ''resting pool.'' Here, we use optical measurements of vesicular pH to study developmental changes in pool partitioning and vesicle cycling in cultured hippocampal slices. Two-photon imaging of a genetically encoded two-color release sensor (ratio-sypHy) allowed us to perform calibrated measurements at individual Schaffer collateral boutons. Mature boutons released a large fraction of their vesicles during simulated place field activity, and vesicle retrieval rates were 7-fold higher compared to immature boutons. Saturating stimulation mobilized essentially all vesicles at mature synapses. Resting pool formation and a concomitant reduction in evoked release was induced by chronic depolarization but not by acute inhibition of the protein phosphatase calcineurin. We conclude that synapses in CA1 undergo a prominent refinement of vesicle use during early postnatal development that is not recapitulated in dissociated neuronal culture.
STATEMENT: Our work challenges the textbook view that small excitatory synapses in the brain use only a small fraction of their total vesicle reserve. This idea was originally based on experiments on dissociated neurons grown on glass cover slips and found support by recent in-vivo studies that used dye uptake as a proxy for neurotransmitter release. In hippocampal tissue, we found evidence for a resting pool of vesicles only in very young neurons, but not after 2-3 weeks of maturation. We show that normal exploratory activity of an adult rat is accompanied by activity patterns in the hippocampus that trigger the release and rapid recycling of most transmitter vesicles. Our findings demonstrate that excitatory synapses dramatically improve their speed and efficiency during early postnatal development.
BACKGROUND: Imaging experiments were performed by Tobias Rose at the Friedrich Miescher Institute in Basel and at the Institute for Synaptic Physiology, Center for Molecular Neurobiology Hamburg. Activity of slice cultures was characterized by Philipp Schoenenberger in the Oertner lab. In vivo recordings from rat hippocampus were performed by Karel Jezek at the Kavli Institute for Systems Neuroscience in Trondheim, Norway. The work was funded by the Novartis Research Foundation, SystemsX.ch, the Kavli Foundation, and the University Medical Center Hamburg-Eppendorf.
UKE Paper of the Month February 2013
The Journal of Cell Biology, February 2013, (PMID: 23401003)
Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin
Joachim Albers, Johannes Keller, Anke Baranowsky, Frank Timo Beil, Philip Catala-Lehnen, Jochen Schulze, Michael Amling and Thorsten Schinke
ABSTRACT: Although Wnt signaling is considered a key regulatory pathway for bone formation, inactivation of ß-catenin in osteoblasts does not affect their activity but rather causes increased osteoclastogenesis due to insufficient production of osteoprotegerin (Opg). By monitoring the expression pattern of all known genes encoding Wnt receptors in mouse tissues and bone cells we identified Fzd8 as a candidate regulator of bone remodeling. Fzd8-deficient mice displayed osteopenia with normal bone formation and increased osteoclastogenesis, but this phenotype was not associated with impaired Wnt signaling or Opg production by osteoblasts. The deduced direct negative influence of canonical Wnt signaling on osteoclastogenesis was confirmed in vitro and through the generation of mice lacking ß-catenin in the osteoclast lineage. Here we observed increased bone resorption despite normal Opg production and a resistance to the anti-osteoclastogenic effect of Wnt3a. These results demonstrate that Fzd8 and ß-catenin negatively regulate osteoclast differentiation independent of osteoblasts and that canonical Wnt signaling controls bone resorption by two different mechanisms.
STATEMENT: Since the discovery of the putative Wnt co-receptor LRP5 as a major determinant of bone formation in humans (Gong et al., Cell, 2001; Boyden et al., N. Engl. J. Med., 2001), several studies have been performed to address the role of Wnt signaling in bone-forming osteoblasts. These included the generation of mouse models lacking ß-catenin, the major intracellular mediator of canonical Wnt signalling, in osteoblasts, where results from three different groups have led to the consensus, that this pathway does not control bone formation, but bone resorption by activating expression of the osteoclastogenesis inhibitor osteoprotegerin.
In our manuscript we provide in vitro- and in vivo-evidence demonstrating that ß-catenin-dependent Wnt signaling mediates a direct negative influence on osteoclastogenesis, independent of osteoprotegerin expression in osteoblasts. Importantly, we could also show that the Wnt receptor Fzd8 is involved in this process, which is particularly relevant, since Fzd receptors, based on their serpentine structure, are considered as excellent drug targets.
BACKGROUND: The Institute of Osteology and Biomechanics (IOBM) was founded in 2010 and is specialized on the osteologic assessment of patients and on research regarding the molecular mechanisms underlying skeletal development and remodeling as well as the pathogenic principles causing genetic and acquired skeletal disorders. This particular project was performed in the molecular biology unit of the IOBM, located in the Campus-Forschung building (N27) and received funding form the Deutsche Forschungsgemeinschaft as a subproject of the Research group FOR793 (Mechanisms of fracture healing and bone regeneration in osteoporosis).
UKE Paper of the Month Januar 2013
Blood, January 2013, (PMID: 23315166)
Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase
Florian Langer, Brigitte Spath, Cornelia Fischer, Moritz Stolz, Francis A. Ayuk, Nicolaus Kröger, Carsten Bokemeyer, Wolfram Ruf
ABSTRACT: Lymphocyte depletion with antithymocyte globulin (ATG) can be complicated by systemic coagulation activation. We found that ATG activated tissue factor procoagulant activity (TF PCA) on monocytic cells more potently than other stimuli that decrypt TF, including cell disruption, TFPI inhibition or calcium ionophore treatment. Induction of TF PCA by ATG was dependent on lipid raft integrity and complement activation. We showed that ATG-mediated TF activation required complement activation until assembly of the C5b-7 membrane insertion complex, but not lytic pore formation by the membrane attack complex C5b-9. Consistently, induction of TF PCA by ATG did not require maximal phosphatidylserine membrane exposure and was not correlated with the magnitude of complement-induced lytic cell injury. Blockade of free thiols, an inhibitory monoclonal antibody to protein disulfide isomerase (PDI) and the small-molecule PDI antagonist quercetin-3-rutinosid prevented ATG-mediated TF activation, and C5 complement activation resulted in oxidation of cell surface PDI. This rapid and potent mechanism of cellular TF activation represents a novel connection between the complement system and cell surface PDI-mediated thiol-disulfide exchange. The delineation of this clinically relevant mechanism of activation of the extrinsic coagulation pathway during immunosuppressive therapy with ATG may have broader implications for vascular thrombosis associated with inflammatory disorders.
STATEMENT: Although TF has well established roles in the initiation of thrombosis, the mechanisms that activate this receptor on hematopoietic cells remain incompletely understood. Thiol-disulfide exchange has been implicated in TF activation, but up to date no clear evidence has been presented that cell surface PDI-mediated TF activation contributes to thromboembolism. Our report delineates the mechanism enabling monocytes to promote rapid coagulation activation when exposed to ATG, a potent and potentially thrombogenic immunosuppressive drug. We show that ATG triggers Fc-mediated complement- and PDI-dependent TF activation specifically on myelomonocytic cells. This report is thus the first to demonstrate PDI-dependent TF activation in a clinically relevant context. By revealing a novel crosstalk between inflammation and coagulation, our findings may also be of broader significance for other prothrombotic disorders characterized by deregulated complement activation.
BACKGROUND: This work was conducted at the II. Medizinische Klinik und Poliklinik in the group Experimentelle Hämostaseologie led by the first author in collaboration with the Interdisziplinäre Klinik für Stammzelltransplantation and Prof. Ruf from The Scripps Research Institute in La Jolla, CA. The group of PD Dr. Langer has long-term interests in revealing the cellular and molecular events underlying coagulation activation and thrombus formation in various disease states, particularly in cancer and inflammation.
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