Measuring interpersonal trauma: Development and validation of the German version of the victimization experience schedule (VES).

OBJECTIVE: Interpersonal victimization experiences (VEs) significantly affect mental and physical health, particularly in disorders associated with life-time adversities, like fibromyalgia syndrome (FMS) and major depressive disorder (MDD). However, assessing VEs comprehensively remains challenging due to limited tools that encompass sub-traumatic events, such as bullying or discrimination, and contextual dimensions. We aimed to address this gap by validating the Victimization Experience Schedule (VES) in German, examining its reliability, and assessing VEs in clinical populations with FMS and MDD. METHODS: We investigated the relationship between VEs and clinical symptoms in individuals with FMS, MDD and healthy controls (N = 105) in a case-control study. We also analyzed correlations between different types of VEs and categories of early childhood abuse and posttraumatic-stress-disorder instruments. Additionally, we validated our findings in an independent sample of individuals with FMS (N = 97) from a clinical study. RESULTS: We observed excellent inter-rater reliability (Kw = 0.90-0.99), and VEs assessed using the VES were in alignment with subcategories of early childhood abuse. The prevalence of VEs extended beyond the categories covered by traditional survey instruments and was higher in individuals with MDD (4.0 ± 2.6) and FMS (5.9 ± 3.1) compared to controls (1.5 ± 1.7). We consistently identified a significant association between the number of VEs, the associated subjective distress, and clinical scores. Furthermore, distinct correlation patterns between VEs and clinical outcomes emerged across different cohorts. CONCLUSION: Our study emphasizes the VES's value in understanding VEs within MDD and FMS. These experiences span from traumatic to sub-traumatic and correlate with posttraumatic-stress and clinical symptoms, underscoring the VES's importance as an assessment tool.

Clinical Phenomenology of Fibromyalgia Syndrome in Male Patients: Same But Different.

The majority of knowledge about fibromyalgia syndrome (FMS) derives from studies of female patients. Little is known about the clinical characteristics and treatment outcomes of male patients with FMS. In this retrospective cohort study with a prospective posttreatment follow-up, we investigated whether male patients with FMS differ from female patients in terms of 1) symptom burden, 2) psychological characteristics, and 3) clinical treatment response. We identified 263 male (4%) out of 5,541 patients with FMS completing a 3-week multimodal pain-treatment program. Male patients (51.3 ± 9.1 years) were age- and time-matched (1:4) with female patients (N = 1,052, 51.3 ± 9.0 years). Data on clinical characteristics, psychological comorbidities, and treatment responses were obtained from medical records and validated questionnaires. Levels of perceived pain, psychological comorbidity, and functional capacity were similar between genders, although male patients with FMS showed a higher prevalence of alcohol abuse. Compared to female patients, male patients experienced themselves less often as overly accommodating (Cohen's d = -.42) but more often as self-sacrificing (d = .26) or intrusive (d = .23). Regarding pain coping, male patients were less likely to utilize mental distraction, rest- and relaxation techniques, or counteractive activities (d = .18-.27). Male patients showed a slightly worse overall response rate than women (69% vs 77%), although differences between individual outcome measures were small (d < .2). Although male and female patients in our cohort were similar in clinical presentation and treatment response, the gender-specific differences in interpersonal problems and pain coping suggest consideration of these aspects in the treatment of male patients with FMS. PERSPECTIVE: Knowledge about fibromyalgia mostly derives from studies of female patients. Identifying and understanding gender-specific differences in fibromyalgia is an important roadmap in the treatment of this syndrome by focusing on specific gender aspects such as differences in interpersonal problems and pain coping mechanisms.

Distribution and Cytokine Profile of Peripheral B Cell Subsets Is Perturbed in Pediatric IBD and Partially Restored During a Successful IFX Therapy.

BACKGROUND: The role of B cells in inflammatory bowel disease (IBD) is ambiguous, as B cells may have both pathogenic and protective functions in IBD. We studied B cell subsets before and after initiation of an anti-tumor necrosis factor alpha (anti-TNFα) therapy in pediatric IBD. The aim of the study was to examine the behavior of B cells in pediatric IBD patients undergoing an anti-TNFα therapy and, more specifically, to clarify their association with a successful or an unsuccessful infliximab (IFX) treatment. METHODS: A total of N = 42 pediatric IBD patients (Crohn disease, n = 30; ulcerative colitis, n = 12) for whom an anti-TNFα therapy with and without a concomitant azathioprine (AZA) medication was administered were recruited. Fourteen healthy age-matched children served as control patients. Blood samples were collected before initiation of the anti-TNFα therapy, before the fourth infusion at the end of the induction phase, and after 6 and 12 months under therapy maintenance. Flow cytometry (CD20, CD27, CD38, CD138) and intracellular staining (interleukin 10 [IL10], TNFα, granzyme B) were performed. Responders to successful IFX therapy were classified exhibiting a fecal calprotectin level of below 100 µg/g or achieving levels of <10% of the baseline value at initiation than at the end of the 12-month follow-up period. RESULTS: Before initiation of anti-TNFα therapy, flow cytometry revealed increased percentages of naïve B cells whereas transitional B cells were reduced compared with those in the healthy control patients. The IL10-producing B cells of both ulcerative colitis and Crohn disease patients were reduced at the initiation of IFX therapy, whereas TNFα-producing transitional CD24hiCD38hi B cells in ulcerative colitis patients were increased compared with those in healthy control patients. After 12 months of therapy, we detected a significant increase of IL10-producing transitional B cells in responding patients.The IFX trough levels in the responding patients showed a significant increase until 6 months after IFX initiation, attaining mean values of 9.9 µg/mL, whereas the IFX dosage was significantly lower than that in the nonresponding patients. The IFX trough levels in AZA-treated patients reached earlier therapeutic levels than in patients without AZA comedication, whereas during the course of the IFX therapy, comedication with AZA had no significant effect on the outcome. CONCLUSIONS: Attaining a normalization of IL10 production among CD24hiCD38hi B cells after 12 months of therapy may represent additional information about the reconstitution of a patient's immune system in responding patients. The achievement of an IFX trough level of ~10 µg/mL at 6 months of treatment is associated with a successful anti-TNFα therapy. In addition, AZA comedication supports an earlier achievement of therapeutic IFX trough levels.

Y-Box Binding Protein 1 Expression in Trophoblast Cells Promotes Fetal and Placental Development.

Y-box binding protein 1 (YB-1) is pivotal for the regulation of cancerogenesis and inflammation. However, its involvement in pregnancy processes such as fetal and placental development remains to be elucidated. We studied Ybx1 (YB-1)+/- heterozygous intercrossings and compared them to YB-1+/+ wild-type (WT) combinations. Additionally, we generated trophoblast-specific YB-1-deficient mice by pairing FVB Cyp19-Cre females to YB-1fl/fl males. YB-1fl/fl-paired FVB WT females served as controls. Serial in vivo ultrasound measurements were performed to assess fetal and placental parameters. After sacrificing the females, implantation and abortion rates were recorded, spiral artery (SA) remodeling was analyzed and fetal and placental weights were determined. Compared to YB-1+/+ counterparts, YB-1+/- females showed reduced implantation areas at gestation day (GD)10, insufficiently remodeled SAs at GD12, increased placental diameter/thickness ratios at GD14 and reduced placental and fetal weights at GD14. Compared to WT, Cyp19-Cre females with YB-1-deficient placentas showed reduced implantation areas at GD8, 10 and 12; decreased placental areas and diameters at GD10 and 12; diminished placental thicknesses at GD12; as well as reduced placental weights at GD12 and 14. In conclusion, our data suggest haploinsufficiency of YB-1 resulting in disturbed fetal and placental development. Moreover, we provide the first evidence for the relevance of trophoblast-specific YB-1 for placentation.

TERT expression is susceptible to BRAF and ETS-factor inhibition in BRAFV600E/TERT promoter double-mutated glioma.

The BRAF gene and the TERT promoter are among the most frequently altered genomic loci in low-grade (LGG) and high-grade-glioma (HGG), respectively. The coexistence of BRAF and TERT promoter aberrations characterizes a subset of aggressive glioma. Therefore, we investigated interactions between those alterations in malignant glioma. We analyzed co-occurrence of BRAFV600E and TERT promoter mutations in our clinical data (n = 8) in addition to published datasets (n = 103) and established a BRAFV600E-positive glioma cell panel (n = 9) for in vitro analyses. We investigated altered gene expression, signaling events and TERT promoter activity upon BRAF- and E-twenty-six (ETS)-factor inhibition by qRT-PCR, chromatin immunoprecipitation (ChIP), Western blots and luciferase reporter assays. TERT promoter mutations were significantly enriched in BRAFV600E-mutated HGG as compared to BRAFV600E-mutated LGG. In vitro, BRAFV600E/TERT promoter double-mutant glioma cells showed exceptional sensitivity towards BRAF-targeting agents. Remarkably, BRAF-inhibition attenuated TERT expression and TERT promoter activity exclusively in double-mutant models, while TERT expression was undetectable in BRAFV600E-only cells. Various ETS-factors were broadly expressed, however, only ETS1 expression and phosphorylation were consistently downregulated following BRAF-inhibition. Knock-down experiments and ChIP corroborated the notion of a functional role for ETS1 and, accordingly, all double-mutant tumor cells were highly sensitive towards the ETS-factor inhibitor YK-4-279. In conclusion, our data suggest that concomitant BRAFV600E and TERT promoter mutations synergistically support cancer cell proliferation and immortalization. ETS1 links these two driver alterations functionally and may represent a promising therapeutic target in this aggressive glioma subgroup.

Fibrin hydrogels as a xenofree and rapidly degradable support for transplantation of retinal pigment epithelium monolayers.

Recent phase 1 trials of embryonic stem cell and induced pluripotent stem cell (iPSCs) derived RPE transplants for the treatment of macular degeneration have demonstrated the relative safety of this process. However, there is concern over clumping, thickening, folding, and wrinkling of the transplanted RPE. To deliver a flat RPE monolayer, current phase 1 trials are testing synthetic substrates for RPE transplantation. These substrates, however, cause localized inflammation and fibrosis in animal models due to long degradation times. Here we describe the use of thin fibrin hydrogels as a support material for the transplantation of RPE. Fibrin was formed into a mechanically rigid support that allow for easy manipulation with standard surgical instruments. Using fibrinolytic enzymes, fibrin hydrogels were degraded on the scale of hours. The rate of degradation could be controlled by varying the fibrinolytic enzyme concentration used. RPE cells degraded fibrin spontaneously. To preserve the fibrin support during differentiation of iPSCs to RPE, media was supplemented with the protease inhibitor aprotinin. iPSC-RPE on fibrin gels remained viable, generated monolayers with characteristic cobblestone appearance and dark pigmentation, and expressed mRNA and protein markers characteristic of RPE in the eye. Following differentiation of the cells, addition of fibrinolytic enzymes fully and rapidly degraded the fibrin support leaving behind an intact, viable iPSC-RPE monolayer. In conclusion, human fibrin hydrogels provide a xeno-free support on which iPSCs can be differentiated to RPE cells for transplant which can be rapidly degraded under controlled conditions using fibrinolytic enzymes without adverse effects to the cells. STATEMENT OF SIGNIFICANCE: Stem cell-derived retinal pigment epithelial (RPE) cell transplantation is currently in phase 1 clinical trials for macular degeneration (MD). A major obstacle in these studies is delivering the RPE as a living, flat sheets without leaving behind foreign materials in the retina. Here we investigate the suitability of using hydrogels made from human blood-derived proteins for RPE transplant. Our data shows that these fibrin hydrogels are rigid enough for use in surgery, support growth of stem cell-derived RPE, and are easily degraded within hours without damage to the RPE sheet. These fibrin hydrogels offer a promising solution to transplant RPE for patients with MD.