Efficacy and safety of autologous stem cell transplantation in first-line treatment and at relapse in elderly patients with multiple myeloma.

Introduction Although recent data suggest that Melphalan high-dose therapy followed by autologous stem cell transplantation (HDT/ASCT) is safe and effective in eligible multiple myeloma (MM) patients up to the age of 75 years, its value in elderly MM patients is still controversially discussed. Methods We retrospectively analyzed 607 MM patients ≥ 60 years old, who were admitted to our institution for first-line or salvage HDT/ASCT between January 2007 and October 2018. We assigned them to three groups according to age at HDT/ASCT: 60-64 years (S1), 65-69 years (S2) and ≥ 70 years (S3). We compared progression-free and overall survival, duration of hospitalization, complications, transfers to intermediate or intensive care unit, readmissions after discharge and deaths within 100 days after HDT/ASCT between these groups. Results Age did not impact progression-free and overall survival after first-line and salvage HDT/ASCT. Patients ≥ 70 years old at first HDT/ASCT had a longer hospitalization compared to patients 60-64 years old, however, the difference in the length of hospitalization was only marginal. Rates of febrile neutropenia, mucositis, transfers to intermediate or intensive care unit, readmissions after discharge and deaths within 100 days after HDT/ASCT were similar in the three age groups of patients receiving first or salvage HDT/ASCT. Patients with a Charlson Comorbidity Index ≥ 2 receiving first HDT/ASCT had a higher risk for a transfer to intermediate or intensive care unit. Conclusion Our analysis shows that HDT/ASCT is safe and effective in eligible elderly MM patients in first-line treatment and at relapse. A careful patient selection according to biological rather than chronological age is of crucial importance.

[Current Outpatient Psychotherapeutic Care for People with Migration and Refugee Experience in Germany - An Overview]. / Die aktuelle ambulante psychotherapeutische Versorgung von Menschen mit Migrations- und Fluchterfahrung in Deutschland ­ Eine Übersicht.

Although mental health is a human right, even in a country with a well-developed healthcare system like Germany, it is not possible to ensure non-discriminatory access to mental health care for all people, regardless of their origin. For individuals with a history of flight or migration it is particularly difficult to gain access to adequate psychotherapeutic care. This review addresses key barriers contributing to the lack of outpatient care for people with a history of flight or migration. Lack of knowledge about the treatment system, fear of stigma, structural barriers, language barriers, lack of networking of healthcare providers, lack of knowledge of mental health practitioners, as well as stereotypes, discrimination, and racism towards people with a refugee or migration history were identified as the most important barriers with sufficient evidence. Innovative concepts such as peer support can enable non-discriminatory treatment access. In addition, there is an urgent need to train the profession of psychotherapists in racism- and discrimination-sensitive work and to integrate these aspects into psychotherapeutic education and training.

Two γ-zeins induce the unfolded protein response.

The rapid, massive synthesis of storage proteins that occurs during seed development stresses endoplasmic reticulum (ER) homeostasis, which activates the ER unfolded protein response (UPR). However, how different storage proteins contribute to UPR is not clear. We analyzed vegetative tissues of transgenic Arabidopsis (Arabidopsis thaliana) plants constitutively expressing the common bean (Phaseolus vulgaris) soluble vacuolar storage protein PHASEOLIN (PHSL) or maize (Zea mays) prolamins (27-kDa γ-zein or 16-kDa γ-zein) that participate in forming insoluble protein bodies in the ER. We show that 16-kDa γ-zein significantly activates the INOSITOL REQUIRING ENZYME1/BASIC LEUCINE ZIPPER 60 (bZIP60) UPR branch-but not the bZIP28 branch or autophagy-leading to induction of major UPR-controlled genes that encode folding helpers that function inside the ER. Protein blot analysis of IMMUNOGLOBULIN-BINDING PROTEIN (BIP) 1 and 2, BIP3, GLUCOSE REGULATED PROTEIN 94 (GRP94), and ER-localized DNAJ family 3A (ERDJ3A) polypeptides confirmed their higher accumulation in the plant expressing 16-kDa γ-zein. Expression of 27-kDa γ-zein significantly induced only BIP3 and ERDJ3A transcription even though an increase in GRP94 and BIP1/2 polypeptides also occurred in this plant. These results indicate a significant but weaker effect of 27-kDa γ-zein compared to 16-kDa γ-zein, which corresponds with the higher availability of 16-kDa γ-zein for BIP binding, and indicates subtle protein-specific modulations of plant UPR. None of the analyzed genes was significantly induced by PHSL or by a mutated, soluble form of 27-kDa γ-zein that traffics along the secretory pathway. Such variability in UPR induction may have influenced the evolution of storage proteins with different tissue and subcellular localization.

Acceptability and Feasibility of a Guided Biopsychosocial Online Intervention for Cancer Patients Undergoing Chemotherapy.

Chemotherapy is a physically and psychologically highly demanding treatment, and specific Internet-based interventions for cancer patients addressing both physical side effects and emotional distress during chemotherapy are scarce. This study examined the feasibility and acceptability of a guided biopsychosocial online intervention for cancer patients undergoing chemotherapy (OPaCT). A pre-post, within-participant comparison, mixed-methods research design was followed. Patients starting chemotherapy at the outpatient clinic of the National Center for Tumor Diseases in Heidelberg, Germany, were enrolled. Feasibility and acceptability were evaluated through intervention uptake, attrition, adherence and participant satisfaction. As secondary outcomes, PHQ-9, GAD-7, SCNS-SF34-G and CBI-B-D were administered. A total of N = 46 patients participated in the study (female 76.1%). The age of participants ranged from 29 to 70 years (M = 49.3, SD = 11.3). The most prevalent tumour diseases were breast (45.7%), pancreatic (19.6%), ovarian (13.1%) and prostate cancer (10.8%). A total of N = 37 patients (80.4%) completed the OPaCT intervention. Qualitative and quantitative data showed a high degree of participant satisfaction. Significant improvements in the SCNS-SF34 subscale 'psychological needs' were found. Study results demonstrate the feasibility and acceptability of the intervention. The results show that OPaCT can be implemented well, both in the treatment process and in participants' everyday lives. Although it is premature to make any determination regarding the efficacy of the intervention tested in this feasibility study, these results suggest that OPaCT has the potential to reduce unmet psychological care needs of patients undergoing chemotherapy.

Storage, Utilization, and Disposal of Hematopoietic Stem Cell Products in Patients with Multiple Myeloma.

High-dose chemotherapy (HD-CHT) and autologous blood stem cell transplantation (ABSCT) represent the standard of care in multiple myeloma (MM) for transplantation-eligible patients. Up to 3 HD-CHT/ABSCT treatments may be administered during the course of disease, including during late-onset relapse. Transplantation centers routinely collect more than 1 peripheral blood stem cell (PBSC) graft; however, subsequent HD-CHT/ABSCT treatments are often not performed, for various reasons. Currently, little is known about the actual utilization rate of stored PBSCs. The collection, storage, and disposal of PBSC products was analyzed in a large cohort of patients with MM (n = 1114) over a 12-year period with a minimum follow-up of 6 years. The final dataset analysis was performed in March 2019, which was set as the reference date. Based on institution-specific charges, the costs for PBSC collection, processing, and storage were estimated. The median number of sufficient PBSC transplantations per patient was 3 (range, 0 to 6), which were stored in a median of 3 (range, 1 to 11) cryopreserved bags (overall, n = 3644). A total of 95% of all patients (n = 1059) underwent at least 1 HD-CHT/ABSCT treatment. However, multiple ABSCTs were performed in 51% of the patients (n2/3 ABSCTs = 538), and only 14% of the patients underwent ABSCT 3 times (n3 ABSCTs = 149). Only a small proportion of collected PBSC bags (5%; n = 109) were used after being stored for longer than 5 years. Overall, 23% of the products (n = 830) were discarded, and 16% (n = 566) were kept in storage until the reference date. From a retrospective standpoint, the collected and discarded (definitively not used) or stored (potentially not used) cryostored PBSCs were associated with considerable costs for long-term cryostorage of approximately €1,600,000. We identified considerable discrepancies between the collection/storage and utilization of PBSCs. This is associated with significant efforts and costs on the one hand; on the other hand, disposal may raise legal and ethical questions. Therefore, we implemented comprehensive guidelines for the systematic reevaluation of stored PBSC grafts at our institution.

The papain-like protease determines a virulence trait that varies among members of the SARS-coronavirus species.

SARS-coronavirus (CoV) is a zoonotic agent derived from rhinolophid bats, in which a plethora of SARS-related, conspecific viral lineages exist. Whereas the variability of virulence among reservoir-borne viruses is unknown, it is generally assumed that the emergence of epidemic viruses from animal reservoirs requires human adaptation. To understand the influence of a viral factor in relation to interspecies spillover, we studied the papain-like protease (PLP) of SARS-CoV. This key enzyme drives the early stages of infection as it cleaves the viral polyprotein, deubiquitinates viral and cellular proteins, and antagonizes the interferon (IFN) response. We identified a bat SARS-CoV PLP, which shared 86% amino acid identity with SARS-CoV PLP, and used reverse genetics to insert it into the SARS-CoV genome. The resulting virus replicated like SARS-CoV in Vero cells but was suppressed in IFN competent MA-104 (3.7-fold), Calu-3 (2.6-fold) and human airway epithelial cells (10.3-fold). Using ectopically-expressed PLP variants as well as full SARS-CoV infectious clones chimerized for PLP, we found that a protease-independent, anti-IFN function exists in SARS-CoV, but not in a SARS-related, bat-borne virus. This PLP-mediated anti-IFN difference was seen in primate, human as well as bat cells, thus independent of the host context. The results of this study revealed that coronavirus PLP confers a variable virulence trait among members of the species SARS-CoV, and that a SARS-CoV lineage with virulent PLPs may have pre-existed in the reservoir before onset of the epidemic.

Perceived Stress Scale (PSS-10) psychometric properties in migrants and native Germans.

BACKGROUND: With the increasing diversity of the German population, it is important to test the psychometric validity and reliability of the German version Perceived Stress Scale (PSS-10) specifically between German natives and residents with a migration background. METHODS: Using nationally representative data (N = 2527), this study conducted an Exploratory Factor Analysis (EFA) to determine the most appropriate factor structure, a Multi-Group Confirmatory Factor Analysis (MGCFA) to compare the validity of the two-factor structure and tested the PSS-10 measurement invariance between the German native and migrant sub-samples. Lastly, reliability of the PSS-10 was examined via Cronbach's alpha, omega and individual item analyses across the two sub-samples. RESULTS: The EFA results support a two-factor structure in the migrant sample. The MGCFA showed adequate model fit for both sub-samples and the PSS-10 is strict invariant between German natives and migrants. Cronbach's alpha and omega for Perceived Helplessness (PHS: factor 1) and Perceived Self-Efficacy (PSES: factor 2) demonstrate good internal consistency in both German and migrant sub-samples. CONCLUSIONS: The key conclusions are: (1) the German version PSS-10 is suitable for German residents with a migration background. (2) Despite good internal consistency for the total scale, the PSS-10 measures two aspects: (a) perceived helplessness and (b) perceived self-efficacy. Future research would profit from analyzing the two subscales separately, not only using the total score.

The association between recalled parental rearing behavior and depressiveness: a comparison between 1st immigrants and non-immigrants in the population-based Gutenberg Health Study.

BACKGROUND: Studies in immigrant youth have suggested differences in parenting patterns by immigration status. Knowledge of variation in recalled parenting pattern and its distinctive impact on mental health in adult immigrants, however, is limited. Therefore, the purpose of the current study was to investigate similarities and differences in recalled maternal and paternal rearing behavior and its association with depressiveness in adult 1st generation immigrants compared to non-immigrants. METHODS: Seven hundred and forty-three 1st generation immigrants (M = 57.4, SD = 10.1 years) and 6518 non-immigrants (M = 60.3, SD = 10.7 years) participated in a population-based study. Regarding countries of origin, the largest subgroups were immigrants from Eastern-Europe, Former-SU, and Arabic-Islamic countries. All participants completed the ultra-short version of The Recalled Parental Rearing Behavior-questionnaire and the PHQ-9 assessing depressiveness. Multiple linear regressions with depressiveness as outcome variable were analyzed separately for each facet of parental rearing behavior adjusting for socio-demographic and migration-related variables. RESULTS: In addition to differences in depressiveness and socioeconomic status, 1st generation immigrants recalled both their mothers and fathers as more controlling and overprotecting than non-immigrants. Parental emotional warmth was negatively associated with depressiveness across all groups. The relationship between parental control, respectively parental rejection and depressiveness, however, varied in direction and severity between the groups. CONCLUSION: The results support the notion that parental warmth is a universal protective factor against depressiveness, whereas the impact of parental control on mental health might be more culturally influenced. Analyses point to the importance of considering the unique contribution of fathers' rearing behavior on mental health, particularly in immigrant samples.

Noise annoyance predicts symptoms of depression, anxiety and sleep disturbance 5 years later. Findings from the Gutenberg Health Study.

BACKGROUND: Cross-sectional studies have shown that noise annoyance is strongly associated with mental distress, however, its long-term effects on mental health is unknown. We therefore investigated whether noise annoyance predicts depression, anxiety and sleep disturbance in a large, representative sample 5 years later. METHODS: We investigated longitudinal data of N = 11 905 participants of the Gutenberg Health Study, a population-based, prospective, single-centre cohort study in mid-Germany (age at baseline 35-74 years). Noise annoyance was assessed at baseline and 5-year follow-up (sources: road traffic, aircraft, railways, industrial, neighbourhood indoor and outdoor noise; and day vs. nighttime). Depression, anxiety and sleep disturbance were assessed using the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-2. Participants suffering from depression, anxiety or sleep disturbance at baseline were excluded from the respective multivariate analyses of new onset at follow-up. RESULTS: General noise annoyance remained stable. Daytime noise annoyance predicted new onset of depressive, anxiety symptoms (also nighttime annoyance) and sleep disturbance (beyond respective baseline scores). Additional predictors were female sex, lower age and low socioeconomic status (SES). Regarding specific sources, daytime baseline aircraft annoyance predicted depression and anxiety. Sleep disturbance was most consistently predicted by neighbourhood annoyance (baseline and follow-up) and follow-up annoyance by aircraft (night) and road traffic (day and night). CONCLUSIONS: We identified current and past noise annoyances as risk factors for mental distress and sleep disturbance. Furthermore, women, younger adults and those with lower SES are particularly susceptible to noise annoyance. Our results indicate the need to provide regulatory measures in affected areas to prevent mental health problems.

Recalled parental rearing behavior in adult women and men with depressive and anxiety symptoms: Findings from a community study.

Objectives: Addressing the lack of population-based data, the purpose of this representative study was to assess sex- and age-specific associations of maternal and paternal rearing behavior with depressiveness and anxiety controlling for sociodemographic and somatic variables. Methods: 8,175 subjects participating in a population-based study completed standardized questionnaires measuring Recalled Parental Rearing Behavior and distress. Results: Women recalled their fathers as more controlling and warmer, and their mothers as more rejecting than men. Comparisons between age groups (≤ 60 vs. > 60 years) revealed that younger participants recalled more parental control and emotional warmth. In addition to sociodemographic and somatic risk factors, paternal rejection and maternal control were associated with depressiveness and anxiety both for women and men (OR 1.58-1.96; OR 1.37-1.66). Maternal warmth was negatively related to distress (OR 0.66-0.69). Conclusions: Findings suggested sex- and age-specific differences in recalled maternal and paternal rearing behavior. The current results highlighted the important role of recalled parental rearing behavior besides sociodemographic factors and somatic diseases for the occurrence of depression and anxiety symptoms across the age groups.

Parenting in the face of serious illness: Childhood cancer survivors remember different rearing behavior than the general population.

OBJECTIVE: A child's cancer diagnosis and treatment affect the whole family. While it has been recognized that parents are an important resource for their children, little is known about the specifics of parenting in the face of serious illness. METHODS: We used the Recalled Parental Rearing Behavior Questionnaire in a register-based cohort of adult childhood cancer survivors (CCS) (N = 951) and a representative population sample of the same age range (N = 2042). The questionnaire assesses behavior of mothers and fathers with three scales (emotional warmth, rejection/punishment, and control/overprotection) by querying the (former) child. We compared the two groups using general linear models. With a hierarchical linear regression analysis, we tested associations of recalled rearing behavior with disease- and treatment-related factors. RESULTS: Compared with the general population, CCS remembered both parents as emotionally warmer, more overprotective, and less punishing/rejecting and less ambitious. The regression analysis showed that having received radiotherapy (ß = 0.092; P = .009) and chemotherapy (ß = 0.077; P = .027) was positively related to memories of maternal emotional warmth. CONCLUSIONS: CCS remembered parenting styles which are generally deemed more positive. The extent of recalled control and overprotection deviated from the population in different directions, suggesting that parenting in childhood cancer entails more complex adaptations than being affectionate and giving comfort. The results suggest an adaptation of parental behavior to particularly challenging treatments. They highlight potential vulnerability and resilience factors, some of which were sex-dependent.

Interferon γ is a strong, STAT1-dependent direct inducer of BCL6 expression in multiple myeloma cells.

B-cell CLL/lymphoma 6 (BCL6) is a transcriptional master regulator that can repress more than 1200 potential target genes. It exerts oncogenic effects through the inhibition of differentiation, DNA damage sensing and apoptosis in several human hematopoietic malignancies, including multiple myeloma (MM). The multifunctional cytokine interferon γ (IFNγ) exerts pro-apoptotic and anti-proliferative effects on MM cells in vitro, at least partially through the inhibition of the effects of interleukin 6 (IL6), one of the most important growth factor of MM and a strong inducer of BCL6 expression. However, IFNγ was also reported to directly upregulate BCL6 in several cell types. These observations prompted us to analyze the effect of IFNγ on BCL6 expression in MM cells. We discovered that among several myeloma growth/survival factors tested (including IL6, oncostatin M, insulin-like growth factor 1, tumor necrosis factor α and IFNα) IFNγ was the strongest inducer of BCL6 mRNA and protein expression in MM cell lines. IFNγ induced upregulation of BCL6 was dependent on the classical STAT1 signaling pathway, and affected both major BCL6 variants. Interestingly, although IFNα induced stronger STAT1 phosphorylation than IFNγ, it only slightly upregulated BCL6 in MM lines. We proved that IFNα induced BCL6 upregulation was limited by the concomitant activation of STAT5 signaling. We assume that BCL6 upregulation may represent a potentially pro-tumorigenic effect of IFNγ signaling in MM cells.

Declining Sexual Activity and Desire in Men-Findings From Representative German Surveys, 2005 and 2016.

BACKGROUND: Surveys have indicated an increase of sexual activity in aging men; recently, however, a decrease of sexual activity has been reported in young men. AIM: To assess (i) sexual activity and desire and their determinants across the age range in a population-based male sample and (ii) their changes over 11 years. METHODS: A representative survey of men (N = 1,095) 18 to 93 years old from 2016 was compared with a survey from 2005 (N = 1,106 men) with the same age range. Samples were drawn from the German population at random using standardized sampling procedures. Questions were filled out by participants in the presence of a trained interviewer. Sexual activity was compared using logistic regression with the factors survey (2005 vs 2016), living with a partner (yes vs no), and age. Frequency of sexual desire was compared using analysis of covariance with the factors survey (2005 vs 2016), living with a partner (yes vs no), and the covariate age. OUTCOMES: Sexual activity was assessed as having been intimate with someone in the past year; frequency of sexual desire was evaluated within the past 4 weeks. RESULTS: The great majority of men cohabiting with a partner in 2016 was sexually active and indicated sexual desire until 70 years of age; half did so at an older age. Across the age range, men living without a partner reported considerably less sexual activity and desire. Compared with 2005, fewer men reported living with a partner. The overall proportion of men reporting sexual activity deceased from 81% to 73% in 2016 and absent sexual desire increased from 8% to 13%. CLINICAL TRANSLATION: The findings highlight the relevance of living with a partner for sexual activity and desire. We advocate using a measure of sexual activity that encompasses many variants of intimate behavior. STRENGTHS AND LIMITATIONS: Large and methodologically comparable population-based samples were compared. However, interpretations are limited by the absence of longitudinal data. We did not assess the effect of having a partner living elsewhere. CONCLUSION: Sexual activity and desire decreased, especially in the young and middle-age groups. The decrease of men living with a partner contributed to this decreased sexual activity and desire. There was a generation effect, with younger and middle-age men living without a partner becoming less sexually active and experiencing less desire compared with the previous survey. The findings unveil changes in sexual activity and desire in a short time span. Beutel ME, Burghardt J, Tibubos AN, et al. Declining Sexual Activity and Desire in Men-Findings From Representative German Surveys, 2005 and 2016. J Sex Med 2018;15:750-756.

Is assessment of depression equivalent for migrants of different cultural backgrounds? Results from the German population-based Gutenberg Health Study (GHS).

BACKGROUND: Bearing in mind the multicultural background of a national population, little is known about the measurement invariance across different cultures or ethnicities of frequently used screeners for depression. For this reason, the main objective of the current study is to assess the measurement invariance of the Patient Health Questionnaire (PHQ-9) across groups with different migration backgrounds. METHODS: We provided psychometric analyses (descriptive statistics at item and scale level, reliability analysis, exploratory [EFA] and confirmatory factor analyses [CFA]) comparing a native population with first- and second-generation migrants of the German population-based Gutenberg Health Study with N = 13,973 participants completing the PHQ-9. Furthermore, we conducted measurement invariance analyses among different groups of first-generation migrants. RESULTS: Comparing the native population with first- and second-generation migrants, a higher prevalence for mental distress was found for first generation. Although mean score patterns were similar for all groups, analyses of item loadings among first-generation migrants yielded some variance in patterns pointing out that certain items have a distinct impact on depression for specific groups. With regard to the factorial validity for all groups, EFA and CFA provided evidence for the proposed one latent factor structure of the PHQ-9. Depression assessed by the PHQ-9 turned out to be equivalent from a psychometric perspective across different groups stratified by their migration background. CONCLUSIONS: Overall, results of thorough scale and item analyses, especially multigroup confirmatory analyses, provided support that depression, assessed by the PHQ-9, can be considered as psychometrically equivalent across all analyzed groups.

Electron Accepting Units of the Diheme Cytochrome c TsdA, a Bifunctional Thiosulfate Dehydrogenase/Tetrathionate Reductase.

The enzymes of the thiosulfate dehydrogenase (TsdA) family are wide-spread diheme c-type cytochromes. Here, redox carriers were studied mediating the flow of electrons arising from thiosulfate oxidation into respiratory or photosynthetic electron chains. In a number of organisms, including Thiomonas intermedia and Sideroxydans lithotrophicus, the tsdA gene is immediately preceded by tsdB encoding for another diheme cytochrome. Spectrophotometric experiments in combination with enzymatic assays in solution showed that TsdB acts as an effective electron acceptor of TsdA in vitro when TsdA and TsdB originate from the same source organism. Although TsdA covers a range from -300 to +150 mV, TsdB is redox active between -100 and +300 mV, thus enabling electron transfer between these hemoproteins. The three-dimensional structure of the TsdB-TsdA fusion protein from the purple sulfur bacterium Marichromatium purpuratum was solved by X-ray crystallography to 2.75 Å resolution providing insights into internal electron transfer. In the oxidized state, this tetraheme cytochrome c contains three hemes with axial His/Met ligation, whereas heme 3 exhibits the His/Cys coordination typical for TsdA active sites. Interestingly, thiosulfate is covalently bound to Cys330 on heme 3. In several bacteria, including Allochromatium vinosum, TsdB is not present, precluding a general and essential role for electron flow. Both AvTsdA and the MpTsdBA fusion react efficiently in vitro with high potential iron-sulfur protein from A. vinosum (Em +350 mV). High potential iron-sulfur protein not only acts as direct electron donor to the reaction center in anoxygenic phototrophs but can also be involved in aerobic respiratory chains.

Large-scale hypomethylated blocks associated with Epstein-Barr virus-induced B-cell immortalization.

Altered DNA methylation occurs ubiquitously in human cancer from the earliest measurable stages. A cogent approach to understanding the mechanism and timing of altered DNA methylation is to analyze it in the context of carcinogenesis by a defined agent. Epstein-Barr virus (EBV) is a human oncogenic herpesvirus associated with lymphoma and nasopharyngeal carcinoma, but also used commonly in the laboratory to immortalize human B-cells in culture. Here we have performed whole-genome bisulfite sequencing of normal B-cells, activated B-cells, and EBV-immortalized B-cells from the same three individuals, in order to identify the impact of transformation on the methylome. Surprisingly, large-scale hypomethylated blocks comprising two-thirds of the genome were induced by EBV immortalization but not by B-cell activation per se. These regions largely corresponded to hypomethylated blocks that we have observed in human cancer, and they were associated with gene-expression hypervariability, similar to human cancer, and consistent with a model of epigenomic change promoting tumor cell heterogeneity. We also describe small-scale changes in DNA methylation near CpG islands. These results suggest that methylation disruption is an early and critical step in malignant transformation.

Loneliness in the general population: prevalence, determinants and relations to mental health.

BACKGROUND: While loneliness has been regarded as a risk to mental and physical health, there is a lack of current community data covering a broad age range. This study used a large and representative German adult sample to investigate loneliness. METHODS: Baseline data of the Gutenberg Health Study (GHS) collected between April 2007 and April 2012 (N = 15,010; 35-74 years), were analyzed. Recruitment for the community-based, prospective, observational cohort study was performed in equal strata for gender, residence and age decades. Measures were provided by self-report and interview. Loneliness was used as a predictor for distress (depression, generalized anxiety, and suicidal ideation) in logistic regression analyses adjusting for sociodemographic variables and mental distress. RESULTS: A total of 10.5% of participants reported some degree of loneliness (4.9% slight, 3.9% moderate and 1.7% severely distressed by loneliness). Loneliness declined across age groups. Loneliness was stronger in women, in participants without a partner, and in those living alone and without children. Controlling for demographic variables and other sources of distress loneliness was associated with depression (OR = 1.91), generalized anxiety (OR = 1.21) and suicidal ideation (OR = 1.35). Lonely participants also smoked more and visited physicians more frequently. CONCLUSIONS: The findings support the view that loneliness poses a significant health problem for a sizeable part of the population with increased risks in terms of distress (depression, anxiety), suicidal ideation, health behavior and health care utilization.

[Psychological Distress and Acceptance of Violence Legitimizing Masculinity Norms among Adolescents]. / Psychische Belastung und die Akzeptanz von gewaltlegitimierenden Männlichkeitsnormen bei Jugendlichen.

The proportion of adolescent migrants in Germany aged 15-20 years has risen to about 29.5% in 2014 according to Federal census statistics. The purpose of the current study was to describe and to compare the psychological strains of adolescent 1st and 2nd generation migrants with non-migrants in a representative school survey. Acceptance of violence legitimizing masculinity norms was explored and its correlation with psychological strain was analyzed. Self-reported data of psychological strain (internalizing and externalizing problems) and acceptance of violence legitimizing masculinity were gathered among 8 518 pupils aged 12-19 years across different school types. Among the surveyed adolescents, 27.6% reported a migration background (5.8% 1st generation migrants; 21.8% 2nd generation migrants). Particularly 1st generation migrants scored higher in internalizing and externalizing problems than 2nd generation migrants or non-migrants. The differences, however, were small. Adolescents with migration background suffered from educational disadvantage, especially 1st generation migrants. Male adolescents reported significantly higher acceptance of violence legitimizing masculinity norms than their female counterparts. Strong agreement with the measured concept of masculinity was found among pupils of lower secondary school and adolescents reported regularly tobacco and cannabis consumption. The acceptance of violence legitimizing masculinity norms was greater among migrants, particularly 1st generation migrants, than non-migrants. Overall, high acceptance of violence legitimizing masculinity norms was related to externalizing problems, which can be understood as dysfunctional coping mechanisms of social disadvantage and a lack of prospects.

Exosomes derived from Burkitt's lymphoma cell lines induce proliferation, differentiation, and class-switch recombination in B cells.

Exosomes, nano-sized membrane vesicles, are released by various cells and are found in many human body fluids. They are active players in intercellular communication and have immune-suppressive, immune-regulatory, and immune-stimulatory functions. EBV is a ubiquitous human herpesvirus that is associated with various lymphoid and epithelial malignancies. EBV infection of B cells in vitro induces the release of exosomes that harbor the viral latent membrane protein 1 (LMP1). LMP1 per se mimics CD40 signaling and induces proliferation of B lymphocytes and T cell-independent class-switch recombination. Constitutive LMP1 signaling within B cells is blunted through the shedding of LMP1 via exosomes. In this study, we investigated the functional effect of exosomes derived from the DG75 Burkitt's lymphoma cell line and its sublines (LMP1 transfected and EBV infected), with the hypothesis that they might mimic exosomes released during EBV-associated diseases. We show that exosomes released during primary EBV infection of B cells harbored LMP1, and similar levels were detected in exosomes from LMP1-transfected DG75 cells. DG75 exosomes efficiently bound to human B cells within PBMCs and were internalized by isolated B cells. In turn, this led to proliferation, induction of activation-induced cytidine deaminase, and the production of circle and germline transcripts for IgG1 in B cells. Finally, exosomes harboring LMP1 enhanced proliferation and drove B cell differentiation toward a plasmablast-like phenotype. In conclusion, our results suggest that exosomes released from EBV-infected B cells have a stimulatory capacity and interfere with the fate of human B cells.