When the systems fail to communicate. Cerebral resting state networks in schizophrenia spectrum disorders.

There have been numerous attempts to reveal the neurobiological basis of schizophrenia spectrum disorders. Results however, remain as heterogeneous as the schizophrenia spectrum disorders itself. Therefore, one aim of this thesis was to divide patients affected by this disorder into subgroups in order to homogenize the results of future studies. In a first study it is suggested that psychopathological rating scales should focus on symptoms-clusters that may have a common neurophysiological background. The here presented Bern Psychopathology Scale (BPS) proposes that alterations in three wellknown brain systems (motor, language, and affective) are largely leading to the communication failures observable on a behavioral level, but also - as repeatedly hypothesized - to dysconnectivity within and between brain systems in schizophrenia spectrum disorders. The external validity of the motor domain in the BPS was tested against the objective measure of 24 hours wrist actigraphy, in a second study. The subjective, the quantitative, as well as the global rating of the degree of motor disorders in this patient group showed significant correlations to the acquired motor activity. This result confirmed in a first step the practicability of the motor domain of the BPS, but needs further validation regarding pathological brain alterations. Finally, in a third study (independent from the two other studies), two cerebral Resting State Networks frequently altered in schizophrenia were investigated for the first time using simultaneous EEG/fMRI: The well-known default mode network and the left working memory network. Besides the changes in these fMRI-based networks, there are well-documented findings that patients exhibit alterations in EEG spectra compared to healthy controls. However, only through the multimodal approach it was possible to discover that patients with schizophrenia spectrum disorders have a slower driving frequency of the Resting State Networks compared to the matched healthy controls. Such a dysfunctional coupling between neuronal frequency and functional brain organization could explain in a uni- or multifactorial way (dysfunctional cross-frequency coupling, maturational effects, vigilance fluctuations, task-related suppression), how the typical psychotic symptoms might occur. To conclude, the major contributions presented in this thesis were on one hand the development of a psychopathology rating scale that is based on the assumption of dysfunctional brain networks, as well as the new evidence of a dysfunctional triggering frequency of Resting State Networks from the simultaneous EEG/fMRI study in patients affected by a schizophrenia spectrum disorder.

The transverse-momentum spectrum of Higgs bosons near threshold at NNLO

We give next-to-next-to-leading order (NNLO) predictions for the Higgs production cross section at large transverse momentum in the threshold limit. Near the partonic threshold, all radiation is either soft or collinear to the final state jet which recoils against the Higgs boson. We find that the real emission corrections are of moderate size, but that the virtual corrections are large. We discuss the origin of these corrections and give numerical predictions for the transverse-momentum spectrum. The threshold result is matched to the known NLO result and implemented in the public code PeTeR.

Michel decay spectrum for a muon bound to a nucleus

The spectrum of electrons from muons decaying in an atomic bound state is significantly modified by their interaction with the nucleus. Somewhat unexpectedly, its first measurement, at the Canadian laboratory TRIUMF, differed from basic theory. We show, using a combination of techniques developed in atomic, nuclear, and high-energy physics, that radiative corrections eliminate the discrepancy. In addition to solving that outstanding problem, our more precise predictions are potentially useful for interpreting future high-statistics muon experiments that aim to search for exotic interactions at 10−16 sensitivity.

BCL2 mutation spectrum in B-cell non-Hodgkin lymphomas and patterns associated with evolution of follicular lymphoma

BCL2 is a target of somatic hypermutation in t(14;18) positive and also in a small fraction of t(14;18) negative diffuse large B-cell lymphoma (DLBCL), suggesting an aberrant role of somatic hypermutation (ASHM). To elucidate the prevalence of BCL2 mutations in lymphomas other than DLBCL, we Sanger-sequenced the hypermutable region of the BCL2 gene in a panel of 69 mature B-cell lymphomas, including Richter's syndrome DLBCL, marginal-zone lymphomas, post-transplant lymphoproliferative disorders, HIV-associated and common-variable immunodeficiency-associated DLBCL, all known to harbour ASHM-dependent mutations in other genes, as well as 16 t(14,18) negative and 21 t(14;18) positive follicular lymphomas (FLs). We also investigated the pattern of BCL2 mutations in longitudinal samples from 10 FL patients relapsing to FL or transforming to DLBCL (tFL). By direct sequencing, we found clonally represented BCL2 mutations in 2/16 (13%) of t(14;18) negative FLs, 2/16 (13%) HIV-DLBCLs, 1/9 (11%) of Richter's syndrome DLBCL, 1/17 (6%) of post-transplant lymphoproliferative disorders and 1/2 (50%) common-variable immunodeficiency-associated DLBCL. The proportion of mutated cases was significantly lower than in FLs carrying the t(14;18) translocation (15/21, 71%). However, the absence of t(14;18) by FISH or PCR and the molecular features of the mutations strongly suggest that BCL2 represents an additional target of ASHM in these entities. Analysis of the BCL2 mutation pattern in clonally related FL/FL and FL/tFL samples revealed two distinct scenarios of genomic evolution: (i) direct evolution from the antecedent FL clone, with few novel clonal mutations acquired by the tFL major clone, and (ii) evolution from a common mutated long-lived progenitor cell, which subsequently acquired distinct mutations in the FL and in the relapsed or transformed counterpart. Copyright © 2014 John Wiley & Sons, Ltd.

Cenesthopathy in adolescence: An appraisal of diagnostic overlaps along the anxiety–hypochondriasis–psychosis spectrum

Objective To discuss the diagnostic validity of unusual bodily perceptions along the spectrum from age-specific, often transitory and normal, to pathological phenomena in adolescence to hypochondriasis and finally to psychosis. Methods Critical literature review of the cornerstone diagnostic groups along the spectrum embracing anxiety and cenesthopathy in adolescence, hypochondriasis, and cenesthopathy and psychosis, followed by a discussion of the diagnostic overlaps along this spectrum. Results The review highlights significant overlaps between the diagnostic cornerstones. It is apparent that adolescents with unusual bodily perceptions may conceptually qualify for more than one diagnostic group along the spectrum. To determine whether cenesthopathies in adolescence mirror emerging psychosis, a number of issues need to be considered, i.e. age and mode of onset, gender, level of functioning and drug use. The role of overvalued ideas at the border between hypochondriasis and psychosis must be considered. Conclusion As unusual bodily symptoms may in some instances meet formal psychosis risk criteria, a narrow understanding of these symptoms may lead to both inappropriate application of the new DSM-5 attenuated psychosis syndrome and of treatment selection. On the other hand, the possibility of a psychotic dimension of unusual bodily symptoms in adolescents must always be considered as most severe expression of the cenesthopathy spectrum.

Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of the ITGA2B and ITGB3 Genes in a Large International Cohort.

We report the largest international study on Glanzmann thrombasthenia (GT), an inherited bleeding disorder where defects of the ITGA2B and ITGB3 genes cause quantitative or qualitative defects of the αIIbβ3 integrin, a key mediator of platelet aggregation. Sequencing of the coding regions and splice sites of both genes in members of 76 affected families identified 78 genetic variants (55 novel) suspected to cause GT. Four large deletions or duplications were found by quantitative real-time PCR. Families with mutations in either gene were indistinguishable in terms of bleeding severity that varied even among siblings. Families were grouped into type I and the rarer type II or variant forms with residual αIIbβ3 expression. Variant forms helped identify genes encoding proteins mediating integrin activation. Splicing defects and stop codons were common for both ITGA2B and ITGB3 and essentially led to a reduced or absent αIIbβ3 expression; included was a heterozygous c.1440-13_c.1440-1del in intron 14 of ITGA2B causing exon skipping in 7 unrelated families. Molecular modeling revealed how many missense mutations induced subtle changes in αIIb and β3 domain structure across both subunits thereby interfering with integrin maturation and/or function. Our study extends knowledge of Glanzmann thrombasthenia and the pathophysiology of an integrin. This article is protected by copyright. All rights reserved.

Trust, Competition and Cooperation in Autism Spectrum Disorder

Objective: Impaired social interactions and repetitive behavior are key features of autism spectrum disorder (ASD). In the present study we compared social decision-making in subjects with and without ASD. Subjects performed five social decision-making games in order to assess trust, fairness, cooperation & competition behavior and social value orientation. Methods: 19 adults with autism spectrum disorder and 17 controls, matched for age and education, participated in the study. Each subject performed five social decision-making tasks. In the trust game, subjects could maximize their gain by sharing some of their money with another person. In the punishment game, subjects played two versions of the Dictator’s Dilemma. In the dictator condition they could share an amount of 0-100 points with another person. In the punishment condition, the opponent was able to punish the subject if he/she was not satisfied with the amount of points received. In the cooperation game, subjects played with a small group of 3 people. Each of them could (anonymously) select an amount of 5, 7.5 or 10 Swiss francs. The goal of the game was to achieve a high group minimum. In the competition game, subjects performed a dexterity task. Before performing the task, they were asked whether they wanted to compete (winner takes it all) or cooperation (sharing the joint achieved amount of points) with a randomly selected person. Lastly, subjects performed a social value orientation task where they were playing for themselves and for another person. Results: There was no overall difference between healthy controls an ASD subjects in investment in the trust game. However, healthy controls increased their investment over number of trials whereas ASD subjects did not. A similar pattern was found for the punishment game. Furthermore, ASD subjects revealed a decreased investment in the dictator condition of the punishment game. There were no mean differences in competition behavior and social value orientation. Conclusions: The results provide evidence for differences between ASD subjects and healthy controls in social decision-making. Subjects with ASD showed a more consistent behavior than healthy controls in the trust game and the dictator dilemma. The present findings provide evidence for impaired social learning in ASD.

High Prevalence of Extended-Spectrum β-Lactamase, Plasmid-Mediated AmpC and Carbapenemase genes in Food for Pets

We evaluated the pet food contained in thirty packages as potential origin of extended-spectrum cephalosporin-resistant Gram-negative organisms and β-lactamase genes (bla). Alive bacteria were not detected by selective culture. However, PCR investigations on food DNA extracts indicated that samples harbored blaCTX-M-15 (53.3%), blaCMY-4 (20%), and blaVEB-4-like (6.7%). Particularly worrisome was the presence of blaOXA-48-like carbapenemases (13.3%). Original pet food ingredients and/or the production process were highly contaminated with bacteria carrying clinically relevant acquired bla genes.

Suprasellar chordoid neoplasm with expression of thyroid transcription factor 1: evidence that chordoid glioma of the third ventricle and pituicytoma may form part of a spectrum of lineage-related tumors of the basal forebrain.

Chordoid glioma of the third ventricle is a rare neuroepithelial tumor characterized by a unique histomorphology and exclusive association with the suprasellar/third ventricular compartment. Variously interpreted as either astrocytic- or ependymal-like, and speculatively ascribed to the lamina terminalis/subcommissural organ, its histogenesis remains, nevertheless, unsettled. Here, we report on a suprasellar chordoid glioma occurring in a 52-year-old man. Although displaying otherwise typical morphological features, the tumor was notable for expression of thyroid transcription factor 1, a marker of tumors of pituicytic origin in the context of the sellar region. We furthermore found overlapping immunoprofiles of this example of chordoid glioma and pituicytic tumors (pituicytoma and spindle cell oncocytoma), respectively. Specifically, phosphorylated ribosomal protein S6, a marker of mTOR pathway activation, was expressed in both groups. Based on these findings, we suggest that chordoid glioma and pituicytic tumors may form part of a spectrum of lineage-related neoplasms of the basal forebrain.

In vivo Evolution of CMY-2 to CMY-33 β-Lactamase in Escherichia coli ST131: Characterization of an Acquired Extended-Spectrum AmpC (ESAC) Conferring Resistance to Cefepime.

Cefepime is frequently prescribed to treat infections caused by AmpC-producing Gram-negative bacteria. CMY-2 is the most common plasmid-mediated AmpC (pAmpC) β-lactamase. Unfortunately, CMY variants conferring enhanced cefepime resistance are reported. Here, we describe the evolution of CMY-2 to an extended-spectrum AmpC (ESAC) in clonally identical E. coli isolates obtained from a patient. The CMY-2-producing E. coli (CMY-2-Ec) was isolated from a wound. Thirty days later, one CMY-33-producing E. coli (CMY-33-Ec) was detected in bronchoalveolar lavage. Two weeks before the isolation of CMY-33-Ec, the patient received cefepime.CMY-33-Ec and CMY-2-Ec were identical by rep-PCR, being of hyperepidemic ST131, but showed different β-lactam MICs (e.g., cefepime 16 vs. ≤0.5 μg/ml). Identical CMY-2-Ec isolates were also found in a rectal swab. CMY-33 differs from CMY-2 by a Leu293-Ala294 deletion. Expressed in E. coli DH10B, both CMYs conferred resistance to ceftazidime (≥256 μg/ml), but cefepime MICs were higher for CMY-33 than CMY-2 (8 vs. 0.25 μg/ml). The kcat/Km or kinact/KI (μM(-1) s(-1)) indicated that CMY-33 possesses an ESBL-like spectrum compared to CMY-2 (cefoxitin: 0.2 vs. 0.4; ceftazidime: 0.2 vs. not measurable; cefepime: 0.2 vs. not measurable; tazobactam 0.0018 vs. 0.0009). Using molecular modeling, we show that a widened active site (∼4 Å shift) may play a significant role in enhancing cefepime hydrolysis. This is the first in vivo demonstration of a pAmpC that under cephalosporin treatment expands its substrate spectrum resembling an ESBL. The prevalence of CMY-2-Ec isolates is rapidly increasing worldwide, therefore awareness that cefepime treatment may select for resistant isolates is critical.

Factor structure of the Bern Psychopathology Scale in a sample of patients with schizophrenia spectrum disorders.

BACKGROUND The Bern Psychopathology Scale (BPS) is based on a system-specific approach to classifying the psychopathological symptom pattern of schizophrenia. It consists of subscales for three domains (language, affect and motor behaviour) that are hypothesized to be related to specific brain circuits. The aim of the study was to examine the factor structure of the BPS in patients with schizophrenia spectrum disorders. METHODS One hundred and forty-nine inpatients with schizophrenia spectrum disorders were recruited at the Department of Psychiatry II, Ulm University, Germany (n=100) and at the University Hospital of Psychiatry, Bern, Switzerland (n=49). Psychopathology was assessed with the BPS. The VARCLUS procedure of SAS(®) (a type of oblique component analysis) was used for statistical analysis. RESULTS Six clusters were identified (inhibited language, inhibited motor behaviour, inhibited affect, disinhibited affect, disinhibited language/motor behaviour, inhibited language/motor behaviour) which explained 40.13% of the total variance of the data. A binary division of attributes into an inhibited and disinhibited cluster was appropriate, although an overlap was found between the language and motor behaviour domains. There was a clear distinction between qualitative and quantitative symptoms. CONCLUSIONS The results argue for the validity of the BPS in identifying subsyndromes of schizophrenia spectrum disorders according to a dimensional approach. Future research should address the longitudinal assessment of dimensional psychopathological symptoms and elucidate the underlying neurobiological processes.

Improved determination of sterile neutrino dark matter spectrum

The putative recent indication of an unidentified 3.55 keV X-ray line in certain astrophysical sources is taken as a motivation for an improved theoretical computation of the cosmological abundance of 7.1 keV sterile neutrinos. If the line is interpreted as resulting from the decay of Warm Dark Matter, the mass and mixing angle of the sterile neutrino are known. Our computation then permits for a determination of the lepton asymmetry that is needed for producing the correct abundance via the Shi-Fuller mechanism, as well as for an estimate of the non-equilibrium spectrum of the sterile neutrinos. The latter plays a role in structure formation simulations. Results are presented for different flavour structures of the neutrino Yukawa couplings and for different types of pre-existing lepton asymmetries, accounting properly for the charge neutrality of the plasma and incorporating approximately hadronic contributions.