Aggression differentially modulates neural correlates of social intention attribution to benevolent, tickling and taunting laughter: An fMRI study in children and adolescents.

Human laughter is a powerful means of communicating social intention, ranging from welcoming and friendly to hostile and ridiculing. To be communicated accurately, the recipient must correctly identify the laugher's underlying social intention. Regular misattribution of the social intention of others has been associated with maladaptive psychosocial development, in particular with aggressive behavior. We investigated the relationship between self-reported aggressive behavior and the neural correlates of social intention attributions to different audiovisual laughter types in 50 healthy children and adolescents (29 female, 10-18 years, M 15.5, SD 2.2) using functional magnetic resonance imaging. Trial-by-trial associations of neural response and behavioral attributions were distinctly modulated by aggression for benevolent versus taunting and tickling laughter. With increasing aggression, hostile misattributions of benevolent laughter were associated with decreased dorsolateral prefrontal and anterior insular cortex activation. In contrast, hostile attributions of taunting and tickling laughter were associated with increased superior frontal, superior temporal, medial prefrontal, supplementary motor, and anterior and mid-cingulate cortex activation. We argue that aggression may be associated with down-regulated emotional saliency of benevolent laughter, whereas up-regulated neural responses to taunting laughter may underlie a heightened sensitivity to hostility or acceptance of taunting behavior in more aggressive individuals.

[Handling of potentially critical items in acute psychiatry (a study of the Federal Directors Conference)]. / Umgang mit potenziell kritischen Gegenständen in der Akutpsychiatrie (eine Studie der Bundesdirektorenkonferenz).

BACKGROUND: In Germany, an average of 25 people per day died by suicide in 2018. This rate has been declining steadily since the 1980s and has so far halved; however, there is no absolute prevention of suicide; even under optimal protected conditions through therapy and care, approximately 5% of successful suicides occur in psychiatric institutions. Despite the high level of awareness of the risk of potentially dangerous objects, there is a lack of uniform written instructions for action. OBJECTIVE: The aim of the study was to evaluate the handling of potentially critical objects in acute care units during the treatment of suicidal patients, with special emphasis on the handling of disposable razors. METHODS: A 10-item questionnaire on the handling of potentially critical items in closed/facultatively open intensive care/acute care units was developed and sent to 100 psychiatric hospitals throughout Germany. RESULTS AND DISCUSSION: The nationwide survey provided feedback from 39 psychiatric hospitals throughout Germany. The results confirmed a broad critical awareness of potentially dangerous objects; however, the handling of these objects proved to be heterogeneous. Psychiatric clinics and departments have been practicing the control and securing of these objects for decades but there is a lack of written recommendations for handling them. In everyday life, the handling of these objects is taught within the ward, through the ward rules and/or orally. This illustrates a lack of uniform nationwide regulations or guidelines in Germany and thus the lack of corresponding written instructions for handling.

Aggression modulates neural correlates of hostile intention attribution to laughter in children.

The tendency to interpret nonverbal social signals as hostile in intention is associated with aggressive responding, poor social functioning and mental illness, and can already be observed in childhood. To investigate the neural correlates of such hostile attributions of social intention, we performed a functional magnetic imaging study in 10-18 year old children and adolescents. Fifty healthy participants rated videos of laughter, which they were told to imagine as being directed towards them, as friendly versus hostile in social intention. Hostile intention ratings were associated with neural response in the right temporal voice area (TVA). Moreover, self-reported trait physical aggression modulated this relationship in both the right TVA and bilateral lingual gyrus, with stronger associations between hostile intention ratings and neural activation in children with higher trait physical aggression scores. Functional connectivity results showed decreased connectivity between the right TVA and left dorsolateral prefrontal cortex with increasing trait physical aggression for making hostile social intention attributions. We conclude that children's social intention attributions are more strongly related to activation of early face and voice-processing regions with increasing trait physical aggression.

Nitroxide-nitroxide and nitroxide-metal distance measurements in transition metal complexes with two or three paramagnetic centres give access to thermodynamic and kinetic stabilities.

Fundamentally, the stability of coordination complexes and of templated (bio)macromolecular assemblies depends on the thermodynamic and kinetic properties of the intermediates and final complexes formed. Here, we used pulse EPR (electron paramagnetic resonance) spectroscopy to determine the stabilities of nanoscopic assemblies formed between one or two nitroxide spin-labelled tridentate 2,2':6',2''-terpyridine (tpy) ligands and divalent metal ions (FeII, ZnII, CoII and CuII). In three distinct approaches we exploited (a) the modulation depth of pulsed electron-electron double resonance (PELDOR) experiments in samples with increasing metal-to-ligand ratios, (b) the frequencies of PELDOR under broadband excitation using shaped pulses and (c) the distances recovered from well-resolved PELDOR data in fully deuterated solvents measured at 34 GHz. The results demonstrate that PELDOR is highly sensitive to resolving the stability of templated dimers and allows to readily distinguish anti-cooperative binding (for CuII ions) from cooperative binding (for CoII or FeII ions). In the case of paramagnetic ions (CoII and CuII) the use of broadband PELDOR allowed to identify the cooperativity of binding from the time domain and distance data. By using a second labelled tpy ligand and by mixing two homoleptic complexes of the same metal centre we could probe the kinetic stability on a timescale of tens of seconds. Here, tpy complexes of CuII and ZnII were found to be substitutionally labile, CoII showed very slow exchange and FeII was inert under our conditions. Not only do our chemical models allow studying metal-ligand interactions via PELDOR spectroscopy, the design of our study is directly transferable to (bio)macromolecular systems for determining the kinetic and thermodynamic stabilities underpinning (templated) multimerisation. Considering the limited methods available to obtain direct information on the composition and stability of complex assemblies we believe our approach to be a valuable addition to the armoury of methods currently used to study these systems.

Correction: Assessing dimerisation degree and cooperativity in a biomimetic small-molecule model by pulsed EPR.

Correction for 'Assessing dimerisation degree and cooperativity in a biomimetic small-molecule model by pulsed EPR' by K. Ackermann et al., Chem. Commun., 2015, 51, 5257-5260.

Assessing dimerisation degree and cooperativity in a biomimetic small-molecule model by pulsed EPR.

Pulsed electron paramagnetic resonance (EPR) spectroscopy is gaining increasing importance as a complementary biophysical technique in structural biology. Here, we describe the synthesis, optimisation, and EPR titration studies of a spin-labelled terpyridine Zn(II) complex serving as a small-molecule model system for tuneable dimerisation.

A novel antagonist of the prostaglandin E(2) EP(4) receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models.

BACKGROUND AND PURPOSE: Rheumatoid arthritis (RA) is an autoimmune disorder involving subsets of activated T cells, in particular T helper (Th) 1 and Th17 cells, which infiltrate and damage tissues and induce inflammation. Prostaglandin E(2) (PGE(2)) enhances the Th17 response, exacerbates collagen-induced arthritis (CIA) and promotes inflammatory pain. The current study investigated whether selective antagonism of the PGE(2) EP(4) receptor would suppress Th1/Th17 cell development and inflammatory arthritis in animal models of RA. EXPERIMENTAL APPROACH: Effects of PGE(2) and a novel EP(4) receptor antagonist ER-819762 on Th1 differentiation, interleukin-23 (IL-23) production by dendritic cells (DCs), and Th17 development were assessed in vitro. The effect of ER-819762 was evaluated in CIA and glucose-6-phosphate isomerase (GPI)-induced arthritis models. In addition, the effects of ER-819762 on pain were evaluated in a model of chronic inflammatory pain induced by complete Freund's adjuvant (CFA) in the rat. KEY RESULTS: Stimulation of the EP(4) receptor enhanced Th1 differentiation via phosphatidylinositol 3 kinase signalling, selectively promoted Th17 cell expansion, and induced IL-23 secretion by activated DCs, effects suppressed by ER-819762 or anti-PGE(2) antibody. Oral administration of ER-19762 suppressed Th1 and Th17 cytokine production, suppressed disease in collagen- and GPI-induced arthritis in mice, and suppressed CFA-induced inflammatory pain in rats. CONCLUSION AND IMPLICATIONS: PGE(2) stimulates EP(4) receptors to promote Th1 differentiation and Th17 expansion and is critically involved in development of arthritis in two animal models. Selective suppression of EP(4) receptor signalling may have therapeutic value in RA both by modifying inflammatory arthritis and by relieving pain.

The Phenion full-thickness skin model for percutaneous absorption testing.

In recent years many efforts have been made to replace dermal toxicity testing of chemicals in the animal by in vitro assays. As a member of a German research consortium, we have previously contributed to the validation of an in vitro test protocol for percutaneous absorption studies on the basis of reconstructed human epidermis and both human and pig skin ex vivo. Aiming to assess the barrier properties of a newly developed reconstructed skin model, this protocol has now been transferred to the Phenion Full-Thickness Skin Model (FT model). The permeation of testosterone and caffeine was quantified in parallel to that of pig skin using Franz-type diffusion cells. In addition, the permeation of benzoic acid and nicotine was studied. As expected, the FT model is more permeable than pig skin, yet its barrier properties are well in accordance with those of reconstructed human epidermis when compared to previous data. In fact, the FT model most efficiently retards testosterone as the compound of highest lipophilicity, which can be explained by an additional uptake by a reservoir formed by the dermis equivalent. Thus, the structure closely parallels human skin. In consequence, the Phenion FT model appears to be suitable for percutaneous absorption studies in hazard analysis and should be subjected to a catch-up validation study.

Metastases and multiple myeloma generate distinct transcriptional footprints in osteocytes in vivo.

Osteocytes are the most abundant bone cells, playing important roles in tissue maintenance. Little is known of how they react in vivo to cancer stress. Here we present a comparative study of the effect of a bone-residing tumour (myeloma) and metastases of bone-remote cancers on osteocytes. While no differences in morphology of the bone are seen, the changes in the transcriptome of osteocytes are specifically related to the tumour stress present. Screening approximately 22 000 genes in osteocytes prepared from cryosections of native bone using laser-supported microdissection, we observed approximately 1400 and approximately 1800 gene expression differences between osteocytes dissected from normal bone compared with those associated with metastases and multiple myeloma, respectively. The genes up-regulated due to the stress exerted by metastases were repressed by multiple myeloma and vice versa, indicating stress-specific footprints in the transcriptome of osteocytes. Functionally, the stressors seem to impose selective pressures on signalling pathways such as that of TGFbeta, a major player in bone biology. Our data show for the first time that the transcriptome of osteocytes in vivo becomes strongly affected by cancer stress, generating gene expression footprints which, in contrast to comparable morphological changes, appear to relate to the nature of cancer and might thus become helpful in distinguishing different bone diseases.

Control of methionine biosynthesis genes by protein kinase CK2-mediated phosphorylation of Cdc34.

Methionine and metabolites such as S-adenosylmethionine (AdoMet) are of vital importance for eukaryotes; AdoMet is the main donor of methyl groups and is involved in expression control of the methionine biosynthesis genes (MET genes). Genome-wide expression profiling of protein kinase CK2 deletion strains of the budding yeast Saccharomyces cerevisiae has indicated a function for CK2 in MET gene control. Deletion of the regulatory CK2 subunits leads to MET gene repression, presumably due to an impaired phosphorylation of the ubiquitin-conjugating enzyme Cdc34, which controls the central MET gene transcription factor Met4. We show that CK2 phosphorylates Cdc34 at two sites and one of these, Ser282, has a significant impact on MET gene expression in vivo, and that high AdoMet levels inhibit CK2. The data provide evidence for a control of MET gene expression by protein kinase CK2-mediated phosphorylation of Cdc34, and appear to suggest a feedback control loop in which high AdoMet-levels are limiting CK2 activity and thus MET gene expression.

Galantamine: a cholinergic patch in the treatment of alcoholism: a randomized, placebo-controlled trial.

OBJECTIVES: The involvement of the central cholinergic system in alcohol abuse behavior is well known. It is possible that the reinforcing effects of ethanol are partially mediated by nicotinic receptors, which modulate neurotransmitter release. It was demonstrated that the application of a cholinesterase inhibitor reduces alcohol consumption in alcohol-preferring rats. This suggests that galantamine (GAL), a cholinesterase inhibitor, could be effective when seeking to prolong abstinence in recently detoxified alcoholics. This study represents the first reported clinical trial of a cholinergic drug in alcohol-relapse prevention. PATIENTS AND METHODS: We investigated the efficacy and safety of GAL by conducting a 24-week randomized, placebo-controlled, multicentric clinical trial on 149 recently detoxified alcoholics. Survival analyses (Kaplan-Meier) were performed to reveal evidence of prolonged abstinence periods in patients who received GAL. RESULTS: Our findings did not support our hypothesis. GAL did not extend the time to first severe relapse. However, additional post hoc analyses suggest that relapsed patients treated with GAL consume less ethanol per drinking day than patients treated with placebo. CONCLUSIONS: GAL seems to be ineffective when used in relapse prevention of detoxified alcoholics. It is possible that alcohol needs to be "on board" for GAL to be beneficial. This could explain why our post hoc analysis showed that GAL possibly reduces the alcohol consumption of relapsers. If confirmed, GAL could play a role in the reduction of harmful alcohol use and at-risk consumption.

Neuroimaging of gender differences in alcohol dependence: are women more vulnerable?

BACKGROUND: Alcoholic brain damage has been demonstrated in numerous studies using neuropathology and brain imaging techniques. However, gender differences were addressed only in a few studies. Recent research has shown that development, course, and consequences of alcohol dependence may differ between female and male patients. Our investigation was built upon earlier research where we hypothesized that women develop alcoholic brain damage more readily than men do. To further compare the impact of alcohol dependence between men and women, we examined brain atrophy in female and male alcoholics by means of computed tomography (CT). METHODS: The study group consisted of a total of 158 subjects (76 women: 42 patients, 34 healthy controls; 82 age-matched men: 34 patients, 48 healthy controls). All patients had a DSM-IV and ICD-10 diagnosis of alcohol dependence. CT with digital volumetry was performed twice in patients (at the beginning and end of the 6-week inpatient treatment program) and once in controls. RESULTS: Patients of both genders had consumed alcohol very heavily. Although the average alcohol consumption in the year before the study was significantly lower in female alcoholics, this gender difference disappeared when controlled for weight. However, women had a significantly shorter duration of alcohol dependence. Despite this fact, both genders developed brain atrophy to a comparable extent. Brain atrophy was reversible in part after 6 weeks of treatment; it did not reach the level in the control groups. CONCLUSIONS: Gender-specific differences in the onset of alcohol dependence were confirmed. This is in line with the telescoping effect, where a later onset and a more rapid development of dependence in women were described. Under the assumption of a gradual development of consequential organ damage, brain atrophy seems to develop faster in women. As shown in other organs (i.e., heart, muscle, liver), this may confirm a higher vulnerability to alcohol among women.

Ets1 is a common element in directing transcription of the alpha and beta genes of human protein kinase CK2.

Protein kinase CK2 is a conserved and vital Ser/Thr phosphotransferase with various links to malignant diseases, occurring as a tetramer composed of two catalytically active (CK2alpha and/or CK2alpha') and two regulatory subunits (CK2beta). There is balanced availability of CK2alpha and CK2beta transcripts in proliferating and differentiating cultured cells. Examination of the human CK2beta gene for transcriptionally active regions by systematic deletions and reporter gene assays indicates strong promoter activity at positions -42 to 14 and 12 to 72 containing transcription start sites 1 and 2 of the gene (positions +1 and 33), respectively, an upstream and a downstream enhancer activity at positions -241 to -168 and 123 to 677, respectively, and silencer activity at positions -241 to -261. Of the various transcription factor binding motifs present in those regions, Ets1 and CAAT-related motifs turned out to be of particular importance, Ets1 for promoter activation and CAAT-related motifs for enhancer activation. In addition, there are contributions by Sp1. Most strikingly, the Ets1 region representing two adjoining consensus motifs also occurs with complete identity in the recently characterized promoter of the CK2alpha gene [Krehan, A., Ansuini, H., Böcher, O., Grein, S., Wirkner, U. & Pyerin, W. (2001) J. Biol. Chem. 275, 18327-18336], and affects comparably, when assayed in parallel, the promoters of both CK2 genes, both by motif mutations and by Ets1 overexpression. The data strongly support the hypothesis that Ets1 acts as a common regulatory element of the CK2alpha and CK2beta genes involved in directing coordinate transcription and contributing to the balanced availability of transcripts.

Elliptic flow in Au+Au collisions at square root(S)NN = 130 GeV.

Elliptic flow from nuclear collisions is a hadronic observable sensitive to the early stages of system evolution. We report first results on elliptic flow of charged particles at midrapidity in Au+Au collisions at square root(S)NN = 130 GeV using the STAR Time Projection Chamber at the Relativistic Heavy Ion Collider. The elliptic flow signal, v2, averaged over transverse momentum, reaches values of about 6% for relatively peripheral collisions and decreases for the more central collisions. This can be interpreted as the observation of a higher degree of thermalization than at lower collision energies. Pseudorapidity and transverse momentum dependence of elliptic flow are also presented.

Genes targeted by protein kinase CK2: a genome-wide expression array analysis in yeast.

Protein kinase CK2, a tetramer composed of two catalytically active (CK2alpha isoforms) and two regulatory (CK2beta isoforms) subunits, is suspected to have, among others, a role in gene transcription. To identify the genes targeted by CK2, the transcriptional effect of silencing the CK2 subunit genes in Saccharomyces cerevisiae (CK2alpha isoform genes: CKA1 and CKA2; CK2beta isoform genes: CKB1 and CKB2) was examined using genome-wide expression array analysis (oligonucleotide array chips). Silencing did not influence the overwhelming majority (5801) of the over six thousand open reading frames composing the yeast genome. Cells knocked-out for both CKA1 and CKA2 and plasmid-rescued by Cka1 affected specifically at 2-fold discrimination level the transcription of 57 genes, and when rescued by Cka2, the transcription of 118 genes. In CKB1/CKB2 double knock-outs, transcription of 54 genes was specifically altered. Interestingly, aside overlaps between the gene spectra affected by CKA1 and CKA2 silencing, there were overlaps also between those influenced by CK2alpha and CK2beta isoform silencing. The data indicate a distinct role of CK2 in gene transcription control, identify specific functional differences between the two catalytic subunits in gene targeting, and reveal independent effects by the regulatory subunits.

Transcriptional coordination of the genes encoding catalytic (CK2alpha) and regulatory (CK2beta) subunits of human protein kinase CK2.

Little is known of how protein kinase CK2 genes are regulated, and it is unclear whether there are mechanisms of transcriptional coordination. Response elements present in the promoter sequences of the human catalytic (CK2alpha) and regulatory (CK2beta) subunit genes have been examined for the significance in transcriptional control using reporter gene assays, electrophoretic mobility shift assays, site-directed mutagenesis, ectopic protein expressions, and transcript assessments. Most strikingly, in both promoters the regions of highest transcriptional activity contain two adjoining, completely identical and conserved Ets1 response elements, and both the mutation of motifs and the overexpression of Ets1 affect significantly transcriptional activity. Also in common are Sp1 response elements that cooperate with Ets1, and Sp1 is phosphorylatable by CK2 holoenzyme but not by individual CK2alpha, the phosphorylation negatively affecting DNA binding. CK2alpha and CK2beta transcript levels and stoichiometries of mRNA species turned out quite constant in cultured cells despite progressing through various stages of proliferation and differentiation. The data seem to indicate transcriptional coordination of the human genes encoding CK2alpha and CK2beta based on an Ets1 double motif common to both genes cooperating with Sp1 motifs and amenable to negative feedback control by the gene products which, following complexation into CK2 holoenzyme, could phosphorylate Sp1 (and Ets1?) and thus downregulate transcription and contribute to the observed constant cellular CK2alpha and CK2beta transcripts situation.

A tissue engineered cell-occlusive device for hard tissue regeneration--a preliminary report.

Tissue engineering is an emerging discipline that applies engineering principles to create devices for the study, restoration, modification, and assembly of functional tissues and organs from native or synthetic sources. In the field of guided bone regeneration (GBR), cellular matter engineering has been applied, more or less successfully, to the development of biodegradable and bioresorbable devices with chemical, physical, or mechanical properties, structure, or form that permit active tissue integration with desirable cell types and tissue components. The employment of synthetic and naturally occurring polymers as well as sophisticated manufacturing technologies allow the tissue engineering of matrix configurations so that the biophysical limitations of mass transfer can be satisfied. The configuration of such a hybrid matrix can also be manipulated to vary the surface area available for cell attachment, as well as to optimize the exposure of the attached cells to nutrients. A biodegradable and bioresorbable device made of synthetic and natural polymers was engineered specifically for GBR procedures. The degradation and resorption kinetics as well as the mechanical properties give the device the potential to function as a carrier for bone growth factors. This innovative device was applied as a GBR membrane in a clinical investigation in seven patients.

Sex differences of carbohydrate-deficient transferrin, gamma-glutamyltransferase, and mean corpuscular volume in alcohol-dependent patients.

BACKGROUND: Biological markers like carbohydrate-deficient transferrin (CDT), gamma-glutamyltransferase (GGT), and mean corpuscular volume (MCV) are used widely to screen for alcoholism. Most research has focused on male alcoholics, and there are few studies on female patients. The results are inconsistent; in general, they show lower sensitivities for all markers for women. METHODS: We compared the diagnostic value of CDT, GGT, and MCV in 126 alcohol-dependent patients (91 men, 35 women) who entered an inpatient treatment program. For the receiver operating characteristic (ROC) analyses, we investigated a control group of 112 patients (64 men, 38 women) from the Department of Psychiatry at the University of Tübingen with no diagnosis of substance abuse or substance dependency. RESULTS: Mean levels of CDT and MCV were significantly different in male and female patients. CDT showed higher test results in men (4.4% vs. 2.8%, p < 0.05), whereas mean levels of MCV were higher in women (99.7 fl vs. 96.4 fl,p < 0.01). The sensitivities of CDT and GGT were higher in men than in women (CDT: 76% vs. 54%,p < 0.1; GGT: 68% vs. 43%,p < 0.05), and the sensitivity of MCV was significantly higher in women (71% vs. 41%,p < 0.01). The superiority of MCV in women also was supported by ROC analyses (p < 0.01). The combined use of markers showed satisfactory sensitivity rates of > or = 80% not only in men but also in women. Yet, the specificity rates were partly below the recommended 90% for identifying alcohol abuse; therefore, these markers must be combined with caution. CONCLUSIONS: If combined, the biological markers CDT and GGT are useful diagnostic instruments for both alcohol-dependent men and women. According to our results, the "forgotten" marker MCV is superior in women and is a marker of second choice in men. The combination GGT and MCV is the most cost-effective choice for men and women.