Epigenetics of traumatic stress: The association of NR3C1 methylation and posttraumatic stress disorder symptom changes in response to narrative exposure therapy.

Epigenetic processes allow plasticity in gene regulation in response to significant environmental events. Accumulating evidence suggests that effective psychotherapy is accompanied by epigenetic changes, rendering DNA methylation a potential biomarker of therapy success. Due to the central role of glucocorticoid dynamics in stress regulation and the alteration of aversive memories, glucocorticoid receptors are likely involved in the molecular processes that are required to successfully treat Posttraumatic Stress Disorder (PTSD). This study aimed to investigate the relationship between methylation at the glucocorticoid receptor gene (NR3C1) and PTSD treatment success of evidence-based psychotherapy. A sample of N = 153 conflict survivors from Northern Uganda (98 females and 55 males) with PTSD were treated with Narrative Exposure Therapy (NET). Diagnostic interviews and saliva sampling took place at pretreatment and 4 and 10 months after treatment completion. We investigated potential associations between PTSD symptom development and methylation changes at 38 CpG sites spanning NR3C1 over the three times of measurement using the repeated measures correlation. After accounting for multiple comparisons, DNA methylation at CpG site cg25535999 remained negatively associated with PTSD symptoms. These results were followed up by mixed models as well as structural equation modelling. These analyses revealed that treatment responders had a significant cg25535999 methylation increase after treatment with NET. Furthermore, lower methylation at cg25535999 pretreatment predicted a higher symptom improvement. Our results suggest different epigenetic profile dynamics at NR3C1 cg25535999 in therapy responders compared to non-responders and underscore the central role of glucocorticoid signaling in trauma-focused therapy.

Sex differences in PTSD risk: evidence from post-conflict populations challenges the general assumption of increased vulnerability in females.

Background: Next to the dose-dependent effect of trauma load, female sex represents a well-established risk factor for PTSD. Exposure to particularly toxic traumatic event types, different coping styles, and biological risk factors are frequently listed as potential causes for the increased PTSD vulnerability in females. Nevertheless, sex differences have not been consistently observed in all study populations. Objective: To investigate sex differences in PTSD risk in post-conflict populations from different countries while considering trauma load. Method: In civilian post-conflict samples from Northern Uganda (N = 1665), Rwanda (N = 433), Syria (N = 974) and Sri Lanka (N = 165), we investigated sex differences in PTSD risk while taking trauma load into account. PTSD and trauma load were assessed using standardized diagnostic interviews. Potential sex differences in PTSD risk were analysed by logistic regression analyses considering trauma load. Results: Across all samples, males reported more traumatic events than females. Both sexes predominantly reported war-related traumatic events. Without considering trauma load, sex effects in PTSD risk were only detected in the Syrian sample. When taking trauma load into account, evidence for an increased PTSD vulnerability in females was found in the Syrian sample, and, to a much lesser extent, in the Northern Ugandan sample. Conclusion: In contrast to the literature, we did not find evidence for a general increased PTSD vulnerability in females. The dose-response effect of trauma load was a much stronger predictor of PTSD risk than sex across all samples.

Antecedentes: Junto al efecto dosis-dependiente de la carga traumática, el sexo femenino representa un factor de riesgo bien establecido para el desarrollo del trastorno de estrés postraumático (TEPT). La exposición a tipos de eventos particularmente tóxicos, diferentes estilos de afrontamiento y factores de riesgo biológicos se enumeran con frecuencia como causas potenciales del aumento de la vulnerabilidad al TEPT en las mujeres. Sin embargo, no se ha observado de manera consistente la diferencia según sexo en todas las poblaciones estudiadas.Objetivo: Investigar las diferencias según sexo para el desarrollo del TEPT en poblaciones post-conflicto de diferentes países teniendo en consideración la carga traumática.Métodos: Se investigaron diferencias en el TEPT según sexo tomando en consideración la carga traumática a partir de muestras post-conflicto de población civil en el norte de Uganda (N = 1665), Ruanda (N = 433), Siria (N = 947) y Sri Lanka (N = 165). El TEPT y la carga traumática se evaluaron empleando entrevistas diagnósticas. Se analizaron las potenciales diferencias según sexo para el riesgo de desarrollar el TEPT empleando un análisis de regresión logística y considerando la carga traumática.Resultados: En todas las muestras, los varones reportaron mayor número de eventos traumáticos que las mujeres. Ambos sexos reportaron predominantemente eventos traumáticos relacionados a la guerra. Dejando de lado la carga traumática, los efectos del sexo para el riesgo de desarrollar el TEPT solo se encontraron en la muestra siria. Cuando se toma en consideración la carga traumática, se encontró un incremento en la vulnerabilidad para el desarrollo del TEPT en mujeres dentro de la muestra siria y, en menor medida, en la del norte de Uganda.Conclusión: En contraste con la literatura, no se encontró evidencia de un incremento generalizado de la vulnerabilidad para el desarrollo del TEPT en mujeres. El efecto dosis-respuesta de la carga traumática fue un predictor mucho más fuerte para el riesgo del desarrollo del TEPT que el sexo en todas las muestras.

Cell-cell adhesion regulates Merlin/NF2 interaction with the PAF complex.

The PAF complex (PAFC) coordinates transcription elongation and mRNA processing and its CDC73/parafibromin subunit functions as a tumour suppressor. The NF2/Merlin tumour suppressor functions both at the cell cortex and nucleus and is a key mediator of contact inhibition but the molecular mechanisms remain unclear. In this study we have used affinity proteomics to identify novel Merlin interacting proteins and show that Merlin forms a complex with multiple proteins involved in RNA processing including the PAFC and the CHD1 chromatin remodeller. Tumour-derived inactivating mutations in both Merlin and the CDC73 PAFC subunit mutually disrupt their interaction and growth suppression by Merlin requires CDC73. Merlin interacts with the PAFC in a cell density-dependent manner and we identify a role for FAT cadherins in regulating the Merlin-PAFC interaction. Our results suggest that in addition to its function within the Hippo pathway, Merlin is part of a tumour suppressor network regulated by cell-cell adhesion which coordinates post-initiation steps of the transcription cycle of genes mediating contact inhibition.

Does cumulative exposure to traumatic stressors predict treatment outcome of community-implemented exposure-based therapy for PTSD?

Background: Posttraumatic Stress Disorder (PTSD) is associated with high levels of functional impairments such as difficulties in academic or occupational performance and in social relationships. With an increasing number of traumatic event types experienced (trauma load), PTSD risk increases in a dose-dependent manner. Accordingly, high rates of PTSD can impair the reconstruction process in post-conflict societies. In order to meet these high needs for mental health services in societies with little access to professional care, task shifting approaches and community-based interventions have been suggested. Narrative Exposure Therapy (NET) has been developed as a short and pragmatic exposure-based PTSD treatment that can be easily trained to lay personnel. Yet, it remains unclear whether NET can be effectively provided by trained lay counsellors even at high levels of trauma load. Objective: To investigate whether trauma load influences the treatment effectiveness of NET provided by trained and supervised local lay counsellors. Method: Linear mixed models were calculated to investigate the influence of trauma load on treatment effectiveness in a sample of N = 323 rebel war survivors from Northern Uganda with PTSD. Results: We found a strong reduction of PTSD symptoms following NET, which was not influenced by trauma load. However, individuals with higher levels of trauma load reported higher PTSD symptoms before therapy as well as 4 and 10 months following treatment completion compared to individuals with lower trauma load. Conclusions: Treatment with NET by lay counsellors is effective independent of trauma load. However, individuals with higher trauma load have a higher probability to show residual symptoms, which might require additional time, sessions or treatment modules.

Antecedentes: El trastorno de estrés traumático (TEPT) se asocia con altos niveles de discapacidad funcional, tales como dificultades en el desempeño académico uocupacional yen las relaciones sociales. Con un número creciente de los tipos de eventos traumáticos experimentados (carga traumática), el riesgo de TEPT aumenta en una forma dependiente de la dosis. De la misma forma, altas tasas de TEPT pueden afectar el proceso de reconstrucción en las sociedad post-conflicto. Para abordar estas crecientes necesidades por servicios de salud mental en sociedades con poco acceso acuidado profesional, se ha sugerido el enfoque de cambio de tareas ylas intervenciones basadas en la comunidad. La Terapia de Exposición Narrativa (NET en su sigla en inglés) ha sido desarrollada como un tratamiento de TEPT basado en la exposición, breve ypragmático que puede ser fácilmente entrenado al personal laico. Aun así, permanece incierto si la NET puede ser implementada efectivamente por consejeros laicos entrenados, incluso aaltos niveles de carga traumática.Objetivo: Investigar si la carga traumática influencia la efectividad del tratamiento de la NET proporcionado por consejeros laicos locales entrenados ysupervisados.Método: Los modelos mixtos lineales se calcularon para investigar la influencia de la carga traumática en la efectividad del tratamiento, en una muestra de N= 323 sobrevivientes de guerra rebelde desde Uganda del Norte con TEPT.Resultados: Encontramos una clara reducción de los síntomas TEPT luego de la NET, la cual no fue influenciada por la carga traumática. Sin embargo, los individuos con altos niveles de carga traumática reportaron altos niveles de síntomas TEPT antes de la terapia como también 4 y 10 meses luego del término del tratamiento comparado alos individuos con carga traumáticamás baja.Conclusiones: El tratamiento con la NET administrada por consejeros laicos es efectiva independiente de la carga traumática. Sin embargo, los individuos con carga traumáticamás alta tienen una probabilidadmás alta de mostrar síntomas residuales, los cuales podrían requerir tiempo, sesiones omódulos de tratamiento adicionales.

A combination of combat experience, early abduction, and severe traumatization fuels appetitive aggression and violence among abductees of rebel war in Northern Uganda.

Individuals who perpetrate violence may likely perceive violence as appealing and infliction of violence to derive pleasure is termed as appetitive aggression. Individuals who were abducted as children into an armed group often experience a higher number of traumatic event types, that is traumatic load and are usually socialized in a violence-endorsing environment. This study aims to investigate the interaction between age at initial abduction with that of traumatic load, and their influence on appetitive aggression along with perpetration of violent acts by former members of an armed rebel group of both sexes. Semi-structured interviews were conducted among a target group of formerly abducted rebel-war survivors (including participants with and without combat experience) from Northern Uganda. Participants included 596 women and 570 men with N = 1,166 (Mage = 32.58, SDage = 9.76, range: 18-80 years). We conducted robust linear regression models to investigate the influence of age at initial abduction, traumatic load, combat experience, and biological sex on appetitive aggression as well as their perpetrated violent acts. Our study shows, appetitive aggression and the number of perpetrated violent acts were specifically increased in individuals who were abducted young, experienced several traumatic events in their lifetime, and with previous combat experience. For perpetrated violence men showed increased levels whereas for appetitive aggression the association was independent of biological sex. Therefore, early abducted individuals with a higher traumatic load, who have combat experience, need to be given special intervention to prevent any further violence.

Integrated genetic, epigenetic, and gene set enrichment analyses identify NOTCH as a potential mediator for PTSD risk after trauma: Results from two independent African cohorts.

The risk of developing posttraumatic stress disorder (PTSD) increases with the number of traumatic event types experienced (trauma load) in interaction with other psychobiological risk factors. The NOTCH (neurogenic locus notch homolog proteins) signaling pathway, consisting of four different trans-membrane receptor proteins (NOTCH1-4), constitutes an evolutionarily well-conserved intercellular communication pathway (involved, e.g., in cell-cell interaction, inflammatory signaling, and learning processes). Its association with fear memory consolidation makes it an interesting candidate for PTSD research. We tested for significant associations of common genetic variants of NOTCH1-4 (investigated by microarray) and genomic methylation of saliva-derived DNA with lifetime PTSD risk in independent cohorts from Northern Uganda (N1 = 924) and Rwanda (N2 = 371), and investigated whether NOTCH-related gene sets were enriched for associations with lifetime PTSD risk. We found associations of lifetime PTSD risk with single nucleotide polymorphism (SNP) rs2074621 (NOTCH3) (puncorrected = 0.04) in both cohorts, and with methylation of CpG site cg17519949 (NOTCH3) (puncorrected = 0.05) in Rwandans. Yet, none of the (epi-)genetic associations survived multiple testing correction. Gene set enrichment analyses revealed enrichment for associations of two NOTCH pathways with lifetime PTSD risk in Ugandans: NOTCH binding (pcorrected = 0.003) and NOTCH receptor processing (pcorrected = 0.01). The environmental factor trauma load was significant in all analyses (all p < 0.001). Our integrated methodological approach suggests NOTCH as a possible mediator of PTSD risk after trauma. The results require replication, and the precise underlying pathophysiological mechanisms should be illuminated in future studies.

Bioecological Implications of Narrative Exposure Therapy in Low-Resource Settings: Individual, Family, Community, and Socio-Political Contexts.

Traumatic stress can have detrimental effects on individuals, families, and communities. Narrative Exposure Therapy (NET) is an evidence-based intervention for decreasing individuals' posttraumatic stress disorder (PTSD) symptoms and has been tested in some of the most challenging contexts, such as in post-conflict refugee camps. Although the focus of NET is on reducing individual PTSD symptoms, the impact of NET can be seen beyond the individual level. The purpose of this manuscript was to examine some of the ecological implications of using NET with trauma-affected populations in low-resource settings. We highlight select implications of NET that extend beyond the individual to systemic effects at the family, community, and sociopolitical levels using several case examples. Finally, we outline limitations and future directions for improving the delivery of NET in settings with limited resources.

Genetic variation is associated with PTSD risk and aversive memory: Evidence from two trauma-Exposed African samples and one healthy European sample.

The probability to develop posttraumatic stress disorder (PTSD), characterized by vivid, intrusive emotional memories of the encountered traumatic events, depends - among other factors - on the number of previous traumatic experiences (traumatic load) and individual genetic vulnerability. So far, our knowledge regarding the biological underpinnings of PTSD is relatively sparse. Genome-wide association studies (GWAS) followed by independent replication might help to discover novel, so far unknown biological mechanisms associated with the development of traumatic memories. Here, a GWAS was conducted in N = 924 Northern Ugandan rebel war survivors and identified seven suggestively significant single nucleotide polymorphisms (SNPs; p ≤ 1 × 10-5) for lifetime PTSD risk. Of these seven SNPs, the association of rs3852144 on chromosome 5 was replicated in an independent sample of Rwandan genocide survivors (N = 370, p < .01). While PTSD risk increased with accumulating traumatic experiences, the vulnerability was reduced in carriers of the minor G-allele in an additive manner. Correspondingly, memory for aversive pictures decreased with higher number of the minor G-allele in a sample of N = 2698 healthy Swiss individuals. Finally, investigations on N = 90 PTSD patients treated with Narrative Exposure Therapy indicated an additive effect of genotype on PTSD symptom change from pre-treatment to four months after treatment, but not between pre-treatment and the 10-months follow-up. In conclusion, emotional memory formation seems to decline with increasing number of rs3852144 G-alleles, rendering individuals more resilient to PTSD development. However, the impact on therapy outcome remains preliminary and further research is needed to determine how this intronic marker may affect memory processes in detail.

Stigmatization Is Associated With Increased PTSD Risk After Traumatic Stress and Diminished Likelihood of Spontaneous Remission-A Study With East-African Conflict Survivors.

Studies in conflict population have repeatedly documented that the number of traumatic event types experienced (trauma load) increases the risk to develop posttraumatic stress disorder (PTSD) in a dose-dependent manner. Misconceptions about survivors' experiences and actions during the war, as well as mental health symptoms frequently lead to stigmatization by their own families and the community, which might render them even more vulnerable for PTSD development and prevent successful recovery. We therefore investigated whether stigmatization affects trauma-related psychopathology beyond the well-known effect of trauma load. The study sample comprised N = 1131 survivors of the rebel war led by the Lord's Resistance Army (LRA) in Northern Uganda, including a large proportion of formerly abducted individuals and child soldiers. We investigated how the experience of stigmatization affects PTSD risk and the likelihood of spontaneous remission, taking trauma load into account. Further, the association of stigmatization with treatment outcome was determined in a subsample of N = 284 individuals with PTSD who received trauma-focused psychotherapy. More than one third of the total sample, and almost two-thirds of the therapy subsample, reported experiences of stigmatization. The main reasons for stigmatization were related to an association with a rebel group (e.g., being called a rebel), followed by mental health problems/PTSD symptoms and HIV/AIDS. Stigmatization was strongly associated with a higher prevalence of lifetime and current PTSD, a diminished probability of spontaneous remission and higher PTSD symptoms before and after trauma-focused psychotherapy, beyond the effect of trauma load. In sum, our results support the assumption that stigmatization aggravates trauma-related psychopathology and impede symptom improvement. In post-conflict regions, community and family interventions which aim at reducing stigmatization and discrimination might therefore complement individual psychotherapy in order to allow survivors to recover and reintegrate into society.

In vivo generation of human CD19-CAR T cells results in B-cell depletion and signs of cytokine release syndrome.

Chimeric antigen receptor (CAR) T cells brought substantial benefit to patients with B-cell malignancies. Notwithstanding, CAR T-cell manufacturing requires complex procedures impeding the broad supply chain. Here, we provide evidence that human CD19-CAR T cells can be generated directly in vivo using the lentiviral vector CD8-LV specifically targeting human CD8+ cells. Administration into mice xenografted with Raji lymphoma cells and human peripheral blood mononuclear cells led to CAR expression solely in CD8+ T cells and efficacious elimination of CD19+ B cells. Further, upon injection of CD8-LV into mice transplanted with human CD34+ cells, induction of CAR T cells and CD19+ B-cell depletion was observed in 7 out of 10 treated animals. Notably, three mice showed elevated levels of human cytokines in plasma. Tissue-invading CAR T cells and complete elimination of the B-lymphocyte-rich zones in spleen were indicative of a cytokine release syndrome. Our data demonstrate the feasibility of in vivo reprogramming of human CD8+ CAR T cells active against CD19+ cells, yet with similar adverse effects currently notorious in the clinical practice.

CD30-targeted oncolytic viruses as novel therapeutic approach against classical Hodgkin lymphoma.

Classical Hodgkin lymphoma (cHL) is a hematopoietic malignancy with a characteristic cellular composition. The tumor mass is made up of infiltrated lymphocytes and other cells of hematologic origin but only very few neoplastic cells that are mainly identified by the diagnostic marker CD30. While most patients with early stage cHL can be cured by standard therapy, treatment options for relapsed or refractory cHL are still not sufficient, although immunotherapy-based approaches for the treatment of cHL patients have gained ground in the last decade. Here, we suggest a novel therapeutic concept based on oncolytic viruses selectively destroying the CD30+-positive cHL tumor cells. Relying on a recently described CD30-specific scFv we have generated CD30-targeted measles virus (MV-CD30) and vesicular stomatitis virus (VSV-CD30). For VSV-CD30 the VSV glycoprotein G reading frame was replaced by those of the CD30-targeted MV glycoproteins. Both viruses were found to be highly selective for CD30-positive cells as demonstrated by infection of co-cultures of target and non-target cells as well as through blocking infection by soluble CD30. Notably, VSV-CD30 yielded much higher titers than MV-CD30 and resulted in a more rapid and efficient killing of cultivated cHL-derived cell lines. Mouse tumor models revealed that intratumorally, as well as systemically injected VSV-CD30, infected cHL xenografts and significantly slowed down tumor growth resulting in a substantially prolonged survival of tumor-bearing mice. Taken together, the data support further preclinical testing of VSV-CD30 as novel therapeutic agent for the treatment of cHL and other CD30+-positive malignancies.

How 'The Urge to Kill' Feels: Articulations of Emic 'Appetitive Aggression' Experiences Among Former Forcefully Recruited Children and Youth in the Acholi Region of Northern Uganda.

Based on 10 months of fieldwork in the Acholi region of northern Uganda among youth and adults who were forcefully recruited into the Lord's Resistance Army (LRA) during the war, this article provides qualitative details to research on 'appetitive aggression.' Through two case-stories the article unfolds first person articulations of how 'appetitive aggression' is experienced as 'the urge to kill' and how it relates to the emic Acholi spiritual concept of 'cen'; a local Luo expression used to describe places and human beings possessed by evil spirits. The analysis illuminates what the individual and social implications of 'the urge to kill' and 'cen' entail for two Acholi men; first in a militia and then in a civil post-war context. The analysis then relates these findings to soldier experiences across cultures and time periods. While our analysis supports the findings in 'appetitive aggression' studies that appetitive aggression serves as a resilient protective factor against developing post-traumatic stress disorder (PTSD), this study documents that once the former forcefully recruited return to civilian life, 'appetitive aggression' and 'the urge to kill' precipitate individual and at times lethal social and moral complications in a fragile post-war community. Thus, the article argues that appetitive aggression and the emic perceptions and experiences of it among the local population are essential to consider in studies, processes and programs targeting demobilization, rehabilitation, reconciliation and re-integration.

Does trauma event type matter in the assessment of traumatic load?

Background: The likelihood of developing Posttraumatic Stress Disorder (PTSD) depends on the interaction of individual risk factors and cumulative traumatic experiences. Hence, the identification of individual susceptibility factors warrants precise quantification of trauma exposure. Previous research indicated that some traumatic events may have more severe influences on mental health than others; thus, the assessment of traumatic load may be improved by weighting event list items rather than calculating the simple sum score. Objective: We compared two statistical methods, Random Forests using Conditional Interference (RF-CI) and Least Absolute Shrinkage and Selection Operator (LASSO), based on their ability to rank traumatic experiences according to their importance for predicting lifetime PTSD. Methods: Statistical models were initially fitted in a sample of N1 = 441 survivors of the Northern Ugandan rebel war. The ability to correctly predict lifetime PTSD was then tested in an independent sample of N2 = 211, and subsequently compared with predictions by the simple sum score of different traumatic event types experienced. Results: Results indicate that RF-CI and LASSO allow for a ranking of traumatic events according to their predictive importance for lifetime PTSD. Moreover, RF-CI showed slightly better prediction accuracy than the simple sum score, followed by LASSO when comparing prediction results in the validation sample. Conclusion: Given the expense in time and calculation effort by RF-CI and LASSO, and the relatively low increase in prediction accuracy by RF-CI, we recommend using the simple sum score to measure the environmental factor traumatic load, e.g., in analyses of gene × environment interactions.

A Complex of Htm1 and the Oxidoreductase Pdi1 Accelerates Degradation of Misfolded Glycoproteins.

A quality control system in the endoplasmic reticulum (ER) efficiently discriminates polypeptides that are in the process of productive folding from conformers that are trapped in an aberrant state. Only the latter are transported into the cytoplasm and degraded in a process termed ER-associated protein degradation (ERAD). In the ER, an enzymatic cascade generates a specific N-glycan structure of seven mannosyl and two N-acetylglucosamine residues (Man7GlcNAc2) on misfolded glycoproteins to facilitate their disposal. We show that a complex encompassing the yeast lectin-like protein Htm1 and the oxidoreductase Pdi1 converts Man8GlcNAc2 on glycoproteins into the Man7GlcNAc2 signal. In vitro the Htm1-Pdi1 complex processes both unfolded and native proteins albeit with a preference for the former. In vivo, elevated expression of HTM1 causes glycan trimming on misfolded and folded proteins, but only degradation of the non-native species is accelerated. Thus, modification with a Man7GlcNAc2 structure does not inevitably commit a protein for ER-associated protein degradation. The function of Htm1 in ERAD relies on its association with Pdi1, which appears to regulate the access to substrates. Our data support a model in which the balanced activities of Pdi1 and Htm1 are crucial determinants for the efficient removal of misfolded secretory glycoproteins.

Endocannabinoid concentrations in hair are associated with PTSD symptom severity.

The endocannabinoid system has been implicated in the regulation of the stress response, fear memory formation, and inflammatory processes. Posttraumatic stress disorder (PTSD) can result from exposure to extreme stress and is characterized by strong, associative memories for the traumatic events experienced. Furthermore, an elevated physical disease risk has been observed in PTSD, likely to be mediated by inflammatory processes. Therefore, altered endocannabinoid regulation can be expected in individuals with PTSD. However, attempts to assess PTSD-associated differences in the endocannabinoid system from human blood samples have provided inconsistent results, possibly due to fluctuating levels of endocannabinoids. In hair, these neuromodulators are accumulated over time and thus give access to a more stable and reliable assessment. We therefore investigated PTSD-associated differences in hair concentrations of endocannabinoids (N-acyl-ethanolamides palmitoylethanolamide [PEA], oleoylethanolamide [OEA] and stearoylethanolamide [SEA]) in 38 rebel war survivors from Northern Uganda suffering from PTSD and N=38 healthy rebel war survivors without current and lifetime PTSD. PTSD diagnosis and symptom severity were assessed in structured clinical interviews employing the Posttraumatic Diagnostic Scale (PDS). A significant group difference was observed for OEA, with PTSD patients showing reduced hair concentrations. Regression analyses further revealed strong negative relationships between all investigated N-acyl-ethanolamides and symptom severity of PTSD. The observed reductions in endocannabinoids might account for the increased inflammatory state as well as for the failure to extinguish fear memories observed in PTSD. Our findings add to the accumulating evidence suggesting the endocannabinoid system as a target for pharmacological enhancement of exposure-based psychotherapy for PTSD.

How to quantify exposure to traumatic stress? Reliability and predictive validity of measures for cumulative trauma exposure in a post-conflict population.

BACKGROUND: While studies with survivors of single traumatic experiences highlight individual response variation following trauma, research from conflict regions shows that almost everyone develops posttraumatic stress disorder (PTSD) if trauma exposure reaches extreme levels. Therefore, evaluating the effects of cumulative trauma exposure is of utmost importance in studies investigating risk factors for PTSD. Yet, little research has been devoted to evaluate how this important environmental risk factor can be best quantified. METHODS: We investigated the retest reliability and predictive validity of different trauma measures in a sample of 227 Ugandan rebel war survivors. Trauma exposure was modeled as the number of traumatic event types experienced or as a score considering traumatic event frequencies. In addition, we investigated whether age at trauma exposure can be reliably measured and improves PTSD risk prediction. RESULTS: All trauma measures showed good reliability. While prediction of lifetime PTSD was most accurate from the number of different traumatic event types experienced, inclusion of event frequencies slightly improved the prediction of current PTSD. CONCLUSIONS: As assessing the number of traumatic events experienced is the least stressful and time-consuming assessment and leads to the best prediction of lifetime PTSD, we recommend this measure for research on PTSD etiology.

Exclusive Transduction of Human CD4+ T Cells upon Systemic Delivery of CD4-Targeted Lentiviral Vectors.

Playing a central role in both innate and adaptive immunity, CD4(+) T cells are a key target for genetic modifications in basic research and immunotherapy. In this article, we describe novel lentiviral vectors (CD4-LV) that have been rendered selective for human or simian CD4(+) cells by surface engineering. When applied to PBMCs, CD4-LV transduced CD4(+) but not CD4(-) cells. Notably, also unstimulated T cells were stably genetically modified. Upon systemic or intrasplenic administration into mice reconstituted with human PBMCs or hematopoietic stem cells, reporter gene expression was predominantly detected in lymphoid organs. Evaluation of GFP expression in organ-derived cells and blood by flow cytometry demonstrated exclusive gene transfer into CD4(+) human lymphocytes. In bone marrow and spleen, memory T cells were preferentially hit. Toward therapeutic applications, we also show that CD4-LV can be used for HIV gene therapy, as well as for tumor therapy, by delivering chimeric Ag receptors. The potential for in vivo delivery of the FOXP3 gene was also demonstrated, making CD4-LV a powerful tool for inducible regulatory T cell generation. In summary, our work demonstrates the exclusive gene transfer into a T cell subset upon systemic vector administration opening an avenue toward novel strategies in immunotherapy.

From War to Classroom: PTSD and Depression in Formerly Abducted Youth in Uganda.

BACKGROUND: Trained local screeners assessed the mental-health status of male and female students in Northern Ugandan schools. The study aimed to disclose potential differences in mental health-related impairment in two groups, former child soldiers (n = 354) and other war-affected youth (n = 489), as well as to separate factors predicting mental suffering in learners. METHODS: Participants were randomly selected. We used the Post-Traumatic Diagnostic Scale to assess symptoms of post-traumatic stress disorder (PTSD) and for potential depression the respective section of the Hopkins Symptom Checklist with a locally validated cut-off. RESULTS: Almost all respondents had been displaced at least once in their life. 30% of girls and 50% of the boys in the study reported past abduction history. Trauma exposure was notably higher in the group of abductees. In former child soldiers, a PTSD rate of 32% was remarkably higher than that for non-abductees (12%). Especially in girls rates of potential depression were double those in the group of former abductees (17%) than in the group of non-abductees (8%). In all groups, trauma exposure increased the risk of developing PTSD. A path-analytic model for developing PTSD and potential depression revealed both previous trauma exposure as well as duration of abduction to have significant influences on trauma-related mental suffering. Findings also suggest that in Northern Ugandan schools trauma spectrum disorders are common among war-affected learners. CONCLUSIONS: Therefore, it is suggested the school context should be used to provide mental-health support structures within the education system for war-affected youth at likely risk of developing war-related mental distress.

The challenge of living on: psychopathology and its mediating influence on the readjustment of former child soldiers.

Current civil wars are characterized by the increasing involvement of civilian populations and the systematic employment of child soldiers. An example of such wars was the conflict in Northern Uganda, where the war-affected population is still challenged by the reintegration of formerly abducted children and youths. A cross-sectional, population-based survey, using a multistage cluster sampling approach of 1,113 Northern Ugandans aged between 12 and 25 in camps for internally displaced persons and locally validated instruments was conducted to assess symptoms and diagnoses of Posttraumatic Stress Disorder (PTSD) and probable Depression in war-affected, as well as formerly abducted individuals. Further objectives were to determine predictors of psychopathology and to relate indicators of maladjustment (i.e., impairments in daily and community functioning, somatic complaints, suicidality, aggressiveness and discrimination) to abduction, level of exposure to violence and psychopathology. 43% of the sample reported abduction by the rebel army. Exposure to violence among this group was higher than for non-abducted youths (t = 28.05; p<.001). PTSD point prevalence rates were 25% among former child soldiers and 7% among the comparison group. High suicidal ideation was present in 16% and 6% respectively. A higher amount of experienced and witnessed event-types (ß = . 32. p<.001), loss of first-degree relatives (ß = .13. p<.001) and the number of event-types involving forced perpetration (ß = .23. p<.001) were identified as risk factors of PTSD symptoms in former child soldiers. The associations between abductee-status and indicators of maladjustment were fully mediated by level of trauma exposure and psychopathology. Results show that child soldiering and its psychological sequelae affect a substantial proportion of children and youths. After release or flight, their readjustment depends at least partly on their level of mental traumatization.

Haunted by ghosts: prevalence, predictors and outcomes of spirit possession experiences among former child soldiers and war-affected civilians in Northern Uganda.

Phenomena of spirit possession have been documented in many cultures. Some authors have argued that spirit possession is a type of psychopathology, and should be included as a category in diagnostic manuals of mental disorders. However, there are hardly any quantitative studies that report the prevalence of spirit possession on a population level and that provide evidence for its validity as a psychopathological entity. In an epidemiological study that was carried out in 2007 and 2008 with N = 1113 youths and young adults aged between 12 and 25 years in war-affected regions of Northern Uganda we examined the prevalence, predictors and outcomes of cen, a local variant of spirit possession. Randomly selected participants were interviewed using a scale of cen, measures of psychopathology (PTSD and depression) as well as indicators of functional outcome on different levels, including suicide risk, daily activities, perceived discrimination, physical complaints and aggression. We found that cen was more common among former child soldiers then among subjects without a history of abduction. Cen was related to extreme levels of traumatic events and uniquely predicted functional outcome even when the effects of PTSD and depression were controlled for. Our findings show that a long-lasting war that is accompanied by the proliferation of spiritual and magical beliefs and propaganda can lead to high levels of harmful spirit possession. In addition, we provide evidence for the incremental validity of spirit possession as a trauma-related psychological disorder in this context.