High-Dose Mycobacterium tuberculosis H37rv Infection in IL-17A- and IL-17A/F-Deficient Mice.

During experimental tuberculosis (TB), interleukin (IL)-17A appears to be involved in the formation of lung granulomas, possibly through the attraction of neutrophils to the sites of infection. However, the protective impact of cytokine appears to depend on the degree of its induction. Hence, robust production of IL-17A in mice infected with the hypervirulent isolate Mycobacterium tuberculosis (Mtb) HN878 mediates protection, while the cytokine is dispensable for protective immune responses against low-dose infection with the less virulent strain H37rv. Here, we show that after experimental infection with high doses of Mtb H37rv, IL-17A-deficient (-/-) mice exhibited high susceptibility to the infection, which was mediated by the strong accumulation of neutrophils in the infected lung tissue. Accordingly, we observed nearly unrestricted bacterial replication within the neutrophils, indicating that they may serve as a survival niche for Mtb. By use of IL-17A/IL-17F-double-deficient mice, we demonstrated that the susceptibility in the absence of IL-17A is mediated by a compensatory expression of IL-17F, which, however, appeared not to be dependent on neutrophils. Together, our results illustrate the compensatory potential of the Th17-secreted cytokines IL-17A and IL-17F in the context of experimental TB and once again emphasize the detrimental effect of excessive neutrophil infiltration in response to Mtb.

Interleukin-23 instructs protective multifunctional CD4 T cell responses after immunization with the Mycobacterium tuberculosis subunit vaccine H1 DDA/TDB independently of interleukin-17A.

Interleukin (IL)-17A-producing T helper (Th)17 cells are increasingly being acknowledged to be associated with protective immunity to Mycobacterium tuberculosis (Mtb). Subunit vaccines potently promote protective immune responses against Mtb infection that correlate with an expansion of IL-23-dependent Th17 cells. Previous studies revealed that after vaccination, IL-23 is required for protection against challenge with Mtb but the underlying IL-23-dependent-and possibly IL-17A-mediated-mechanisms remain elusive. Therefore, we here analyzed the early outcome of Mtb infection in C57BL/6, IL-23p19-deficient (-/-), and IL-17A-/- mice after vaccination with the subunit vaccine H1-DDA/TDB to investigate the role of the IL-23-Th17 immune axis for the instruction of vaccine-induced protection. While in IL-23p19-/- mice the protective effect was reduced, protection after vaccination was maintained in IL-17A-/- animals for the course of infection of 6 weeks, indicating that after vaccination with H1-DDA/TDB early protection against Mtb is-although dependent on IL-23-not mediated by IL-17A. In contrast, IL-17A deficiency appears to have an impact on maintaining long-term protection. In fact, IL-23 instructed the vaccine-induced memory immunity in the lung, in particular the sustained expansion of tumor necrosis factor (TNF)+IL-2+ multifunctional T cells, independently of IL-17A. Altogether, a targeted induction of IL-23 during vaccination against Mtb might improve the magnitude and quality of vaccine-induced memory immune responses. KEY MESSAGES: After subunit Mtb vaccination with H1-DDA/TDB, IL-23 but not IL-17A contributes to vaccine-induced early protection against infection with Mtb. IL-17F does not compensate for IL-17A deficiency in terms of H1-DDA/TDB-induced protection against Mtb infection. IL 23 promotes the H1-DDA/TDB-induced accumulation of effector memory T cells independently of IL 17A. IL-23 arbitrates the induction of H1-specific IFN-γ-TNF+IL-2+ double-positive multifunctional CD4 T cells after subunit Mtb vaccination in an IL-17A-independent manner.

DGCR8 deficiency impairs macrophage growth and unleashes the interferon response to mycobacteria.

The mycobacterial cell wall glycolipid trehalose-6,6-dimycolate (TDM) activates macrophages through the C-type lectin receptor MINCLE. Regulation of innate immune cells relies on miRNAs, which may be exploited by mycobacteria to survive and replicate in macrophages. Here, we have used macrophages deficient in the microprocessor component DGCR8 to investigate the impact of miRNA on the response to TDM. Deletion of DGCR8 in bone marrow progenitors reduced macrophage yield, but did not block macrophage differentiation. DGCR8-deficient macrophages showed reduced constitutive and TDM-inducible miRNA expression. RNAseq analysis revealed that they accumulated primary miRNA transcripts and displayed a modest type I IFN signature at baseline. Stimulation with TDM in the absence of DGCR8 induced overshooting expression of IFNß and IFN-induced genes, which was blocked by antibodies to type I IFN. In contrast, signaling and transcriptional responses to recombinant IFNß were unaltered. Infection with live Mycobacterium bovis Bacille Calmette-Guerin replicated the enhanced IFN response. Together, our results reveal an essential role for DGCR8 in curbing IFNß expression macrophage reprogramming by mycobacteria.

Interleukin-27 in Tuberculosis: A Sheep in Wolf's Clothing?

In tuberculosis (TB), protective inflammatory immune responses and the pathological sequelae of chronic inflammation significantly depend on a timely balance of cytokine expression. In contrast to other anti-inflammatory cytokines, interleukin (IL)-27 has fundamental effects in experimental Mycobacterium tuberculosis (Mtb) infection: the absence of IL-27-mediated signalling promotes a better control of mycobacterial growth on the one hand side but also leads to a chronic hyperinflammation and immunopathology later during infection. Hence, in the context of novel host-directed therapeutic approaches and vaccination strategies for the management of TB, the timely restricted blockade of IL-27 signalling may represent an advanced treatment option. In contrast, administration of IL-27 itself may allow to treat the immunopathological consequences of chronic TB. In both cases, a better knowledge of the cell type-specific and kinetic effects of IL-27 after Mtb infection is essential. This review summarizes IL-27-mediated mechanisms affecting protection and immunopathology in TB and discusses possible therapeutic applications.

The Role of gp130 Cytokines in Tuberculosis.

Protective immune responses to Mycobacterium tuberculosis (Mtb) infection substantially depend on a delicate balance within cytokine networks. Thus, immunosuppressive therapy by cytokine blockers, as successfully used in the management of various chronic inflammatory diseases, is often connected with an increased risk for tuberculosis (TB) reactivation. Hence, identification of alternative therapeutics which allow the treatment of inflammatory diseases without compromising anti-mycobacterial immunity remains an important issue. On the other hand, in the context of novel therapeutic approaches for the management of TB, host-directed adjunct therapies, which combine administration of antibiotics with immunomodulatory drugs, play an increasingly important role, particularly to reduce the duration of treatment. In both respects, cytokines/cytokine receptors related to the common receptor subunit gp130 may serve as promising target candidates. Within the gp130 cytokine family, interleukin (IL)-6, IL-11 and IL-27 are most explored in the context of TB. This review summarizes the differential roles of these cytokines in protection and immunopathology during Mtb infection and discusses potential therapeutic implementations with respect to the aforementioned approaches.

IL-6 is not Absolutely Essential for the Development of a TH17 Immune Response after an Aerosol Infection with Mycobacterium Tuberculosis H37rv.

Anti-inflammatory treatment of chronic inflammatory diseases often increases susceptibility to infectious diseases such as tuberculosis (TB). Since numerous chronic inflammatory and autoimmune diseases are mediated by interleukin (IL)-6-induced T helper (TH) 17 cells, a TH17-directed anti-inflammatory therapy may be preferable to an IL-12-dependent TH1 inhibition in order to avoid reactivation of latent infections. To assess, however, the risk of inhibition of IL-6-dependent TH17-mediated inflammation, we examined the TH17 immune response and the course of experimental TB in IL-6- and T-cell-specific gp130-deficient mice. Our study revealed that the absence of IL-6 or gp130 on T cells has only a minor effect on the development of antigen-specific TH1 and TH17 cells. Importantly, these gene-deficient mice were as capable as wild type mice to control mycobacterial infection. Together, in contrast to its key function for TH17 development in other inflammatory diseases, IL-6 plays an inferior role for the generation of TH17 immune responses during experimental TB.

Patterns of Substance Abuse in Offenders With Schizophrenia- Illness-Related or Criminal Life-Style?

Objective: The impact of substance abuse on violent behavior in patients suffering from schizophrenia is well-known. However, the association between the pattern of substance abuse and certain aspects of criminal behavior like the severity of offense, the previous history of violence and the age at onset of the criminal career is still unclear. Method: To assess the relationship between substance abuse, schizophrenia and violent behavior we examined healthy non-offenders; healthy offenders; non-offenders suffering from schizophrenia; and offenders suffering from schizophrenia, with respect to different patterns of substance abuse (none, alcohol only, illicit drugs only, and multiple substances). Results: Healthy offenders as well as offenders and non-offenders suffering from schizophrenia are characterized by increased rates of alcohol and illicit drug abuse. Especially multiple substance abuse appears to lower the threshold of aggression and illegal behavior. This effect is more pronounced in subjects suffering from schizophrenia. In both offender groups the abuse of psychoactive substances is associated with an earlier onset of the criminal career, but has no impact on the severity of the offenses. Conclusion: Our results point to the need for a differentiated view on the contribution of substance abuse to the criminality of subjects suffering from schizophrenia.

The increased protection and pathology in Mycobacterium tuberculosis-infected IL-27R-alpha-deficient mice is supported by IL-17A and is associated with the IL-17A-induced expansion of multifunctional T cells.

During Mycobacterium tuberculosis (Mtb) infection, mice lacking the IL-27R exhibit lower bacterial burdens but develop an immunopathological sequelae in comparison to wild-type mice. We here show that this phenotype correlates with an enhanced recruitment of antigen-specific CCR6+ CD4+ T cells and an increased frequency of IL-17A-producing CD4+ T cells. By comparing the outcome of Mtb infection in C57BL/6, IL-27R-deficient and IL-27R/IL-17A-double deficient mice, we observed that both the increased protection and elevated immunopathology are supported by IL-17A. Whereas IL-17A neither impacts the development of Tr1 cells nor the expression of PD1 and KLRG1 on T cells in IL-27R-deficient mice during infection, it regulates the presence of multifunctional T-cells in the lungs, co-expressing IFN-γ, IL-2 and TNF. Eventually, IL-17A supports Cxcl9, Cxcl10 and Cxcl13 expression and the granulomatous response in the lungs of infected IL-27R-deficient mice. Taken together, IL-17A contributes to protection in Mtb-infected IL-27R-deficient mice probably through a chemokine-mediated recruitment and strategic positioning of multifunctional T cells in granulomas. As IL-27 limits optimal antimycobacterial protection by inhibiting IL-17A production, blocking of IL-27R-mediated signaling may represent a strategy for improving vaccination and host-directed therapy in tuberculosis. However, because IL-27 also prevents IL-17A-mediated immunopathology, such intervention has to be tightly controlled.

[Alcohol- and substance abuse among mentally ill patients with migration background in Austria]. / Alkohol- und Drogenmissbrauch bei psychisch kranken PatientInnen mit Migrationshintergrund in Österreich.

The refugee movements of the recent years are confronting the health care with new challenges. However, it has turned out that in Austria data on the mental health of migrants are nearly not available. Especially data on the frequency and patterns of comorbid substance abuse of migrants with mental disorders do not exist even from international studies. We analyzed data from 1819 patients (1726 first generation, 93 second generation) treated in the outpatient clinic for transcultural psychiatry and migration related disorders at the Vienna General Hospital: In first-generation migrants the cultural and religious background of the region of origin has the greatest impact on the frequency and the patterns of misused substances. In second-generation migrants the consumer habits approximate to those of the majority of the society. The primary diagnosis plays a minor role. Only patients with personality disorders exhibit higher rates of illicit substance compared with other diagnoses.

[Unemployment, suicide- and homicide-rates in the EU countries]. / Arbeitslosigkeit, Suizid- und Tötungsraten in den EU-Staaten.

BACKGROUND: While the link between the unemployment and the national suicide rates is confirmed by various studies, there are few investigations on the impact of unemployment on homicide rates. In particular, it is not known whether suicide and homicide are associated with the same socio-economic factors. METHODS: Using linear regression method, the influence of unemployment rates, per capita incomes and annual alcohol consumption on suicide and homicide rates was examined in the 27 EU states. RESULTS: We found a positive correlation between suicide and homicide rates. Unemployment among men is a strong predictor not only for suicide- but also for homicide rates. Suicide rates in men are also affected by the annual alcohol consumption. The suicide rates in women, however, correlate neither with socio-economic variables nor with alcohol consumption. CONCLUSIONS: Unemployment seems to have a stronger impact on the male than on the female identity. Since the former is still highly dependent on predetermined social roles.

[The traces of violence: Suicide and homicide rates in the former Bloodlands]. / Die Spuren der Gewalt: Suizid- und Homizidraten in den ehemaligen Bloodlands.

BACKGROUND: Suicide and homicide rates are the ultimate expressions of violence. The rates are globally almost distributed mirror-reverted. Rich, modern democratic countries with a functioning legal system have high suicide and low homicide rates, traditional states with a weak central government high homicide and low suicide rates. Exceptions are some Eastern European countries, in which both, the rates of homicide and suicide are very high. These states are located on the territory of the former Bloodlands (Snyder, Bloodlands: Europa zwischen Hitler und Stalin, 2011), where between 1930 and 1945 14 million people were civilian victims of the Soviets and the National Socialists. We addressed the question of whether these eight countries (Poland, Lithuania, Estonia, Latvia, Moldova, Belarus, Russia and Ukraine) differ from the other European countries of the former East bloc, from the Asian countries of the former USSR and the Western European countries in social, economic and psychosocial factors. METHODS: The data used for analyses were taken of various data sets from the WHO, the UN and the CIA. The statistical comparison of the four regions was carried out by nonparametric tests. RESULTS: The States on the grounds of the former Bloodlands and the other European countries of the former East bloc are comparable concerning important social and economic parameters such as level of modernization, Democracy-index and Rule of Law-Index. Statistically significant differences were found only in the annual alcohol consumption per capita and the divorce rates. CONCLUSIONS: We hypothesize that the high suicide and homicide rates in some Eastern European countries may be the result of the traumatic experience of extreme violence of nearly the entire population between 1930 and 1945. Possible paths of the transgenerational transmission as well as conceivable chains of causality between the trauma in the first generation and suicidal or homicidal behavior in the following generations are presented.

[Religion and suicide - part 1: the attitudes of religions towards suicide]. / Religion und Selbsttötung - teil 1: die Einstellungen der Religionen zum Suizid.

OBJECTIVE: While suicide is known in all human societies, national suicide rates vary to a high degree. Different interacting social, economic and biological factors may explain a part of the variance. Religions are supposed to have a protective effect against suicidal behavior. It is still unexplained, whether or not this holds true for all religions and whether this has an effect on the national suicide rates. For this purpose it is necessary to illustrate the positions of the single religions towards suicide in the context of their idea of a human being as well as their concepts of death and afterworld. METHOD: Our considerations are based upon a research on the religious- and culture-historical literature on this topic. RESULTS: None of the world religions argues for suicide, however, the degree of refusal is varying. Mosaic religions (Judaism, Christianity, Islam), which are based on the idea of a human being as the image of God, have a more pronounced position against suicide than Eastern religions with a concept of transmigration and rebirth. Atheistic positions, which are not attached to transcendent norms, show a broad range of opinions from radical refusal to cautious approval. CONCLUSIONS: The positions of the different religions towards suicide are leading to assumptions of their effect on national suicide rates that have to be tested empirically.

[Religion and suicide - part 2: confessions, religiousness, secularisation and national suicide rates]. / Religion und Selbsttötung - teil 2 Konfessionen, Säkularisierung, Religiosität und die Nationalen Suizidraten.

OBJECTIVE: National suicide rates differ remarkably. The influence of religion on the frequency of suicides was already stressed by Durkheim, however, character and dimension of this influence are still unclear. Our study claims to assess the association between (a) the distribution of believers of different religions, (b) the secularization, (c) the religiousness and the national suicide rates by gender. METHOD: Data of the distribution of religious confessions and of the religiousness of the inhabitants of the single countries were correlated with the national suicide rates and illustrated by means of Scatter/Dot-Plots. RESULTS: Independent of gender, low suicide rates were found in Islamic countries. Buddhist countries showed high suicide rates in women, and countries with a high percentage of inhabitants without confession high suicide rates in men. Only catholic countries showed an association between secularisation and suicide rates. In countries with a high proportion of religious inhabitants we found low suicide rates. CONCLUSIONS: Although none of the World religions support the human right of suicide, the mosaic religions of resurrection refuse suicide more strictly than the Eastern religions of reincarnation. All in all our study supports the hypothesis that religiousness can be seen as a protective factor against suicide.

Culture and the prevalence of hallucinations in schizophrenia.

OBJECTIVE: Besides demographic, clinical, familial, and biographical factors, culture and ethnicity may plausibly influence the manifestation of hallucinations. The purpose of this study was to investigate the influence of culture on the frequency of different kinds of hallucinations in schizophrenia. METHOD: Patients with a clinical diagnosis of schizophrenia were diagnosed by means of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Seven independent samples were consecutively recruited in Austria, Lithuania, Poland, Georgia, Ghana, Nigeria, and Pakistan using identical inclusion/exclusion criteria and assessment procedures (N = 1080 patients total). The association of key demographic factors (sex and age), clinical factors (age at onset and duration of illness), and country of origin with hallucinations of different kinds was examined. RESULTS: The prevalence of various kinds of hallucinations was substantially different in the samples; however, the rank order of their occurrence was similar. Auditory hallucinations were relatively infrequent in Austria and Georgia and more prevalent in patients with an early age at onset of disease. Visual hallucinations were more frequently reported by the West African patients compared with subjects from the other 5 countries. Cenesthetic hallucinations were most prevalent in Ghana and in patients with a long duration of illness. CONCLUSION: We hypothesize that the prevalence of the different kinds of hallucinations in schizophrenia is the result of the interaction of a variety of factors like cultural patterns as well as clinical parameters. According to our study, culture seems to play a decisive role and should be taken into account to a greater extent in considerations concerning the pathogenesis of psychotic symptoms.

[Etiological illness concepts in patients suffering from schizophrenia from Austria and Pakistan with special consideration of the gender aspect]. / Krankheitsmodelle bei PatientInnen mit Schizophrenie in Pakistan und in Österreich unter besonderer Berücksichtigung von Genderaspekten.

OBJECTIVE: Etiological illness concepts of patients with schizophrenia are an important factor for the drug compliance as well as for a successful psychotherapeutic approach. These cognitive representations are influenced by issues like the illness, culture, gender, and age. The aim of this study was the elaboration of the interaction of these factors with special consideration of the gender aspect. METHOD: The notions about the reasons of illness were explored by means of a 41-item standardized self-rating instrument in 240 patients suffering from schizophrenia from Pakistan and Austria. RESULTS: Only in the scale "conflicts" the mean values for Austrian women were statistically significant higher than for their male counterparts. In Pakistani patients we found no significant differences, patients with an early age at onset of illness more frequently reported a magic-religious explanatory model in both cultures. Austrian patients with a longer duration of illness believed more often that the outbreak of the illness was caused by negligent behaviour. CONCLUSION: While gender has important effects on course and outcome of schizophrenia, the influence on etiological illness concepts is rather weak. Two reasons can be postulated: (a) The acquirement of knowledge about the development of mental disorders is culture-specific, but not gender-specific, (b) psychotic disorders are even out originally existing gender differences.

[Mental health beliefs between culture and subjective illness experience]. / Subjektive Krankheitsmodelle zwischen spezifischer Krankheitserfahrung und Kultur.

OBJECTIVE: Subjective health beliefs are representations about pathogenesis, course and treatment options of psychic as well as somatic illnesses. They are important for a psychotherapeutic interaction as well as for a stable drug adherence. However, it remains unclear whether these representations are primarily affected by the cultural background or by an individual's specific illness experiences, a question of increasing importance in our era of globalized migration. METHOD: The study sample consisted of 203 Austrians (125 with schizophrenia, 78 with obsessivecompulsive disorder) and 190 Pakistanis (120 with schizophrenia, 70 with obsessive-compulsive disorder). All patients completed the "Causal Explanations of Mental Disorders" (CEMD), a 41-item self-rating questionnaire. RESULTS: Pakistani patients reported magic-religious oriented mental health beliefs more frequently. In contrast, Austrians' beliefs are more often in line with the bio-psychosocial explanations of Western medicine. Concerning mental health beliefs the cultural background seems to be more important than the subjective experience with a distinctive mental disorder. CONCLUSIONS: Although the subjective experience is of importance for the shape of illnessspecific cognitions, mental health beliefs are primarily caused by the patients' socio-cultural origin. It is a challenge for psychiatry to improve the co-operation with culture-anthropology and other social sciences.

[Depression and culture]. / Depression und Kultur.

It is well established knowledge that, aside from biological and biographical factors, socio-cultural patterns have a major impact in prevalence and phenomenology of depressive disorders. It is the aim of the authors (1) to clarify the different epistemological positions of transcultural research in depression, (2) to present the most important findings of this research, (3) to develop suggestions for culture-sensitive epidemiological research.

Diencephalic serotonin transporter availability predicts both transporter occupancy and treatment response to sertraline in obsessive-compulsive checkers.

BACKGROUND: To our knowledge, no studies have investigated the predictive value of central serotonin transporter (SERT) availability for treatment response to serotonin reuptake inhibitors (SSRIs) in patients with obsessive-compulsive disorder (OCD). This study used brain imaging to examine the relationship between pretreatment SERT availability and transporter occupancy as well as treatment response by sertraline in patients displaying prominent behavioral checking compulsions (OC checkers). METHODS: Single photon emission computed tomography (SPECT) was used to measure thalamic-hypothalamic SERT availability with [(123)I]-2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane in 28 nondepressed OC checkers at baseline and after 14 weeks of treatment with sertraline (175 mg daily). SERT availability was correlated with OC severity and treatment response as assessed with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Associations between individual transporter occupancies and clinical parameters were investigated. RESULTS: 1) Correlation analyses between thalamic-hypothalamic SERT availability and OC severity showed significant negative associations at baseline and after treatment with sertraline. 2) Pretreatment SERT availability correlated significantly with both transporter occupancy and treatment response; in addition, a positive association was found between transporter occupancy and treatment response directly. 3) Using multivariate statistical models, the data demonstrated that higher pretreatment SERT availability significantly predicted higher occupancy rates as well as better treatment response 14 weeks later. CONCLUSIONS: Higher pretreatment thalamic-hypothalamic SERT availability may predict both higher occupancy rates and better treatment response to sertraline. The data suggest a strong connection between transporter occupancy and treatment response.

[The closeness to medical profession and the attitude towards euthanasia]. / Die Nähe zum medizinischen Beruf und die Einstellung zur aktiven Sterbehilfe.

Periodically debates on the legalization of active euthanasia are conducted in the Austrian media. In contrast to most European and North American countries, these debates are not based on local empirical data, because until now no studies on respective attitudes and values exist. In this study notion towards active euthanasia of (1) medical lays, (2) medical students and medical specialists in psychiatry, surgery and internal medicine are explored by means of a semistructured questionnaire. We found that increasing closeness to the medical profession is associated with an increasing refusal of active euthanasia. Among the medical specialists, specialists in internal medicine, who, after the legalization, would be most involved in decision-making processes as well as in the execution of active euthanasia, showed the greatest reservation concerning this question.