Accumulated environmental risk in young refugees – A prospective evaluation

Background: Recently, we reported a strong, disease-independent relationship between accumulated pre-adult environmental risks and violent aggression later in life. Risk factors were interchangeable, and migration was among the explored risks. Alarmed by these data, we assessed collected risk loadin young ‘healthy’ refugees as a specifics group of current migration streams and evaluated first signals of behavioral abnormalities. Methods: In 9 German refugee centers, n=133 young refugees, not previously in contact with the health system, were recruited, many of them unaccompanied minors. Risk factors experienced apart from migration/refuge were carefully assessed: Traumatic experiences before/during/after flight (including war,genocide, human trafficking, torture, murder, slavery, terrorist attacks), urbanicity, physical and sexual abuse, problematic alcohol and cannabis use (lifetime). Evaluation comprised physical exam and psychopathology screening. Findings: Refugees arrived in Germany via Eastern Mediterranean/Balkanroute (34.6%), from Africa via Central Mediterranean route (39.1%), by plane (17.3%) or other routes, such as Western Mediterranean or Atlantic (9.0%). Flight reasons were war/expulsion (25.6%), persecution/threats to life (51.9%), economical/others (22.5%). Interpretation: refugees from hosting countries with alarming 'risk burden', should be considered as highly vulnerable towards development of global functional deficits, behavioral abnormalities, and neuropsychiatric disorders. Rapid proactive integration or sustainable support of those who will return to rebuild their countries are mandatory

The importance of initial-final state correlations for the formation of fragments in heavy ion collisions

Using quantum molecular dynamics simulations, we investigate the formation of fragments in symmetric reactions between beam energies of E=30AMeV and 600AMeV. After a comparison with existing data we investigate some observables relevant to tackle equilibration: dsigma/dErat, the double differential cross section dsigma/pt.dpz.dpt,... Apart maybe from very energetic E>400AMeV and very central reactions, none of our simulations gives evidence that the system passes through a state of equilibrium. Later, we address the production mechanisms and find that, whatever the energy, nucleons finally entrained in a fragment exhibit strong initial-final state correlations, in coordinate as well as in momentum space. At high energy those correlations resemble the ones obtained in the participant-spectator model. At low energy the correlations are equally strong, but more complicated; they are a consequence of the Pauli blocking of the nucleon-nucleon collisions, the geometry, and the excitation energy. Studying a second set of time-dependent variables (radii, densities,...), we investigate in details how those correlations survive the reaction especially in central reactions where the nucleons have to pass through the whole system. It appears that some fragments are made of nucleons which were initially correlated, whereas others are formed by nucleons scattered during the reaction into the vicinity of a group of previously correlated nucleons.Comment: 45 pages text + 20 postscript figures Accepted for publication in Physical Review

Preadult polytoxicomania—strong environmental underpinnings and first genetic hints

Considering the immense societal and personal costs and suffering associated with multiple drug use or “polytoxicomania”, better understanding of environmental and genetic causes is crucial. While previous studies focused on single risk factors and selected drugs, effects of early-accumulated environmental risks on polytoxicomania were never addressed. Similarly, evidence of genetic susceptibility to particular drugs is abundant, while genetic predisposition to polytoxicomania is unexplored. We exploited the GRAS data collection, comprising information on N~2000 deep-phenotyped schizophrenia patients, to investigate effects of early-life environmental risk accumulation on polytoxicomania and additionally provide first genetic insight. Preadult accumulation of environmental risks (physical or sexual abuse, urbanicity, migration, cannabis, alcohol) was strongly associated with lifetime polytoxicomania (p  = 1.5 × 10−45; OR = 31.4), preadult polytoxicomania with OR = 226.6 (p = 1.0 × 10−33) and adult polytoxicomania with OR = 17.5 (p = 3.4 × 10−24). Parallel accessibility of genetic data from GRAS patients and N~2100 controls for genome-wide association (GWAS) and phenotype-based genetic association studies (PGAS) permitted the creation of a novel multiple GWAS–PGAS approach. This approach yielded 41 intuitively interesting SNPs, potentially conferring liability to preadult polytoxicomania, which await replication upon availability of suitable deep-phenotyped cohorts anywhere world-wide. Concisely, juvenile environmental risk accumulation, including cannabis and alcohol as starter/gateway drugs, strongly predicts polytoxicomania during adolescence and adulthood. This pivotal message should launch more effective sociopolitical measures to prevent this deleterious psychiatric condition

Amino acid variation in HLA class II proteins is a major determinant of humoral response to common viruses

The magnitude of the human antibody response to viral antigens is highly variable. To explore the human genetic contribution to this variability, we performed genome-wide association studies of the immunoglobulin G response to 14 pathogenic viruses in 2,363 immunocompetent adults. Significant associations were observed in the major histocompatibility complex region on chromosome 6 for influenza A virus, Epstein-Barr virus, JC polyomavirus, and Merkel cell polyomavirus. Using local imputation and fine mapping, we identified specific amino acid residues in human leucocyte antigen (HLA) class II proteins as the most probable causal variants underlying these association signals. Common HLA-DRβ1 haplotypes showed virus-specific patterns of humoral-response regulation. We observed an overlap between variants affecting the humoral response to influenza A and EBV and variants previously associated with autoimmune diseases related to these viruses. The results of this study emphasize the central and pathogen-specific role of HLA class II variation in the modulation of humoral immune response to viral antigens in humans

Auditory verbal hallucinations and childhood trauma subtypes across the psychosis continuum:a cluster analysis

Introduction: A strong link between voice-hearing experience and childhood trauma has been established. The aim of this study was to identify whether there were unique clusters of childhood trauma subtypes in a sample across the clinical spectrum of auditory verbal hallucinations (AVH) and to examine clinical and phenomenological features across these clusters. Methods: Combining two independent international datasets (the Netherlands and Australia), childhood trauma subtypes were examined using hierarchical cluster analysis. Clinical and phenomenological characteristics were compared across emerging clusters using MANOVA and chi-squared analyses. Results: The total sample (n = 413) included 166 clinical individuals with a psychotic disorder and AVH, 122 non-clinical individuals with AVH and 125 non-clinical individuals without AVH. Three clusters emerged: (1) low trauma (n = 299); (2) emotion-focused trauma (n = 71); (3) multi-trauma (n = 43). The three clusters differed significantly on their AVH ratings of amount of negative content, with trend-level effects for loudness, degree of negative content and degree of experienced distress. Furthermore, perceptions of voices being malevolent, benevolent and resistance towards voices differed significantly. Conclusion: The data revealed different types of childhood trauma had different relationships between clinical and phenomenological features of voice-hearing experiences. Thus, implicating different mechanistic pathways and a need for tailored treatment approaches

Breakup Conditions of Projectile Spectators from Dynamical Observables

Momenta and masses of heavy projectile fragments (Z >= 8), produced in collisions of 197Au with C, Al, Cu and Pb targets at E/A = 600 MeV, were determined with the ALADIN magnetic spectrometer at SIS. An analysis of kinematic correlations between the two and three heaviest projectile fragments in their rest frame was performed. The sensitivity of these correlations to the conditions at breakup was verified within the schematic SOS-model. The data were compared to calculations with statistical multifragmentation models and to classical three-body calculations. Classical trajectory calculations reproduce the dynamical observables. The deduced breakup parameters, however, differ considerably from those assumed in the statistical multifragmentation models which describe the charge correlations. If, on the other hand, the analysis of kinematic and charge correlations is performed for events with two and three heavy fragments produced by statistical multifragmentation codes, a good agreement with the data is found with the exception that the fluctuation widths of the intrinsic fragment energies are significantly underestimated. A new version of the multifragmentation code MCFRAG was therefore used to investigate the potential role of angular momentum at the breakup stage. If a mean angular momentum of 0.75$\hbar$/nucleon is added to the system, the energy fluctuations can be reproduced, but at the same time the charge partitions are modified and deviate from the data. PACS numbers: 25.70.Mn, 25.70.Pq, 25.75.Ld, 25.75.-qComment: 38 pages, RevTeX with 21 included figures; Also available from http://www-kp3.gsi.de/www/kp3/aladin_publications.htm

Temperatures of Exploding Nuclei

Breakup temperatures in central collisions of 197Au + 197Au at bombarding energies E/A = 50 to 200 MeV were determined with two methods. Isotope temperatures, deduced from double ratios of hydrogen, helium, and lithium isotopic yields, increase monotonically with bombarding energy from 5 MeV to 12 MeV, in qualitative agreement with a scenario of chemical freeze-out after adiabatic expansion. Excited-state temperatures, derived from yield ratios of states in 4He, 5Li, 6Li, and 8Be, are about 5 MeV, independent of the projectile energy, and seem to reflect the internal temperature of fragments at their final separation from the system. PACS numbers: 25.70.Mn, 25.70.Pq, 25.75.-qComment: 10 pages, RevTeX with 4 included figures; Also available from http://www-kp3.gsi.de/www/kp3/aladin_publications.htm

Cosmic-ray strangelets in the Earth's atmosphere

If strange quark matter is stable in small lumps, we expect to find such lumps, called ``strangelets'', on Earth due to a steady flux in cosmic rays. Following recent astrophysical models, we predict the strangelet flux at the top of the atmosphere, and trace the strangelets' behavior in atmospheric chemistry and circulation. We show that several strangelet species may have large abundances in the atmosphere; that they should respond favorably to laboratory-scale preconcentration techniques; and that they present promising targets for mass spectroscopy experiments.Comment: 28 pages, 4 figures, revtex

Factors predisposing to humoral autoimmunity against brain-antigens in health and disease Analysis of 49 autoantibodies in over 7000 subjects

Background:Circulating autoantibodies (AB) against brain-antigens, often deemed pathological, receive increasing attention. We assessed predispositions and seroprevalence/characteristics of 49 AB in >7000 individuals.Methods:Exploratory cross-sectional cohort study, investigating deeply phenotyped neuropsychiatric patients and healthy individuals of GRAS Data Collection for presence/characteristics of 49 brain-directed serum-AB. Predispositions were evaluated through GWAS of NMDAR1-AB carriers, analyses of immune check-point genotypes, APOE4 status, neurotrauma. Chi-square, Fisher’s exact tests and logistic regression analyses were used.Results:Study of N=7025 subjects (55.8% male; 41±16 years) revealed N=1133 (16.13%) carriers of any AB against 49 defined brain-antigens. Overall, age dependence of seroprevalence (OR=1.018/year; 95% CI [1.015-1.022]) emerged, but no disease association, neither general nor with neuropsychiatric subgroups. Males had higher AB seroprevalence (OR=1.303; 95% CI [1.144-1.486]). Immunoglobulin class (N for IgM:462; IgA:487; IgG:477) and titers were similar. Abundant were NMDAR1-AB (7.7%). Low seroprevalence (1.25%-0.02%) was seen for most AB (e.g. amphiphysin, KCNA2, ARHGAP26, GFAP, CASPR2, MOG, Homer-3, KCNA1, GLRA1b, GAD65). Non-detectable were others. GWAS of NMDAR1-AB carriers revealed three genome-wide significant SNPs, two intergenic, one in TENM3, previously autoimmune disease-associated. Targeted analysis of immune check-point genotypes (CTLA4, PD1, PD-L1) uncovered effects on humoral anti-brain autoimmunity (OR=1.55; 95% CI [1.058-2.271]) and disease likelihood (OR=1.43; 95% CI [1.032-1.985]). APOE4 carriers (∼19%) had lower seropositivity (OR=0.766; 95% CI [0.625-0.933]). Neurotrauma predisposed to NMDAR1-AB seroprevalence (IgM: OR=1.599; 95% CI [1.022-2.468]).Conclusions:Humoral autoimmunity against brain-antigens, frequent across health and disease, is predicted by age, gender, genetic predisposition, and brain injury. Seroprevalence, immunoglobulin class, or titers do not predict disease

A single gene defect causing claustrophobia

Claustrophobia, the well-known fear of being trapped in narrow/closed spaces, is often considered a conditioned response to traumatic experience. Surprisingly, we found that mutations affecting a single gene, encoding a stress-regulated neuronal protein, can cause claustrophobia. Gpm6a-deficient mice develop normally and lack obvious behavioral abnormalities. However, when mildly stressed by single-housing, these mice develop a striking claustrophobia-like phenotype, which is not inducible in wild-type controls, even by severe stress. The human GPM6A gene is located on chromosome 4q32-q34, a region linked to panic disorder. Sequence analysis of 115 claustrophobic and non-claustrophobic subjects identified nine variants in the noncoding region of the gene that are more frequent in affected individuals (P=0.028). One variant in the 3′untranslated region was linked to claustrophobia in two small pedigrees. This mutant mRNA is functional but cannot be silenced by neuronal miR124 derived itself from a stress-regulated transcript. We suggest that loosing dynamic regulation of neuronal GPM6A expression poses a genetic risk for claustrophobia