Mónika Ditta Tóth

What Are Reasons for the Large Gender Differences in the Lethality of Suicidal Acts? An Epidemiological Analysis in Four European Countries

Background In Europe, men have lower rates of attempted suicide compared to women and at the same time a higher rate of completed suicides, indicating major gender differences in lethality of suicidal behaviour. The aim of this study was to analyse the extent to which these gender differences in lethality can be explained by factors such as choice of more lethal methods or lethality differences within the same suicide method or age. In addition, we explored gender differences in the intentionality of suicide attempts. Methods and Findings Methods. Design: Epidemiological study using a combination of self-report and official data. Setting: Mental health care services in four European countries: Germany, Hungary, Ireland, and Portugal. Data basis: Completed suicides derived from official statistics for each country (767 acts, 74.4% male) and assessed suicide attempts excluding habitual intentional self-harm (8,175 acts, 43.2% male). Main Outcome Measures and Data Analysis. We collected data on suicidal acts in eight regions of four European countries participating in the EU-funded “OSPI-Europe”-project (www.ospi-europe.com). We calculated method-specific lethality using the number of completed suicides per method * 100 / (number of completed suicides per method + number of attempted suicides per method). We tested gender differences in the distribution of suicidal acts for significance by using the χ2-test for two-by-two tables. We assessed the effect sizes with phi coefficients (φ). We identified predictors of lethality with a binary logistic regression analysis. Poisson regression analysis examined the contribution of choice of methods and method-specific lethality to gender differences in the lethality of suicidal acts. Findings Main Results Suicidal acts (fatal and non-fatal) were 3.4 times more lethal in men than in women (lethality 13.91% (regarding 4106 suicidal acts) versus 4.05% (regarding 4836 suicidal acts)), the difference being significant for the methods hanging, jumping, moving objects, sharp objects and poisoning by substances other than drugs. Median age at time of suicidal behaviour (35–44 years) did not differ between males and females. The overall gender difference in lethality of suicidal behaviour was explained by males choosing more lethal suicide methods (odds ratio (OR) = 2.03; 95% CI = 1.65 to 2.50; p < 0.000001) and additionally, but to a lesser degree, by a higher lethality of suicidal acts for males even within the same method (OR = 1.64; 95% CI = 1.32 to 2.02; p = 0.000005). Results of a regression analysis revealed neither age nor country differences were significant predictors for gender differences in the lethality of suicidal acts. The proportion of serious suicide attempts among all non-fatal suicidal acts with known intentionality (NFSAi) was significantly higher in men (57.1%; 1,207 of 2,115 NFSAi) than in women (48.6%; 1,508 of 3,100 NFSAi) (χ2 = 35.74; p < 0.000001). Main limitations of the study Due to restrictive data security regulations to ensure anonymity in Ireland, specific ages could not be provided because of the relatively low absolute numbers of suicide in the Irish intervention and control region. Therefore, analyses of the interaction between gender and age could only be conducted for three of the four countries. Attempted suicides were assessed for patients presenting to emergency departments or treated in hospitals. An unknown rate of attempted suicides remained undetected. This may have caused an overestimation of the lethality of certain methods. Moreover, the detection of attempted suicides and the registration of completed suicides might have differed across the four countries. Some suicides might be hidden and misclassified as undetermined deaths. Conclusions Men more often used highly lethal methods in suicidal behaviour, but there was also a higher method-specific lethality which together explained the large gender differences in the lethality of suicidal acts. Gender differences in the lethality of suicidal acts were fairly consistent across all four European countries examined. Males and females did not differ in age at time of suicidal behaviour. Suicide attempts by males were rated as being more serious independent of the method used, with the exceptions of attempted hanging, suggesting gender differences in intentionality associated with suicidal behaviour. These findings contribute to understanding of the spectrum of reasons for gender differences in the lethality of suicidal behaviour and should inform the development of gender specific strategies for suicide prevention.

Celebrity suicide on the railway network: Can one case trigger international effects?

BACKGROUND After the railway suicide of the German national goalkeeper Robert Enke in 2009, a significant increase of railway suicides was observed nationally. This study analyses whether this incident also triggered copycat effects in other European countries. Additionally, media coverage proxied by Google Trends and long-term changes taking into account general changes in suicide rates and kilometres driven by trains were examined. METHODS The numbers of railway suicides before and after Enke´s suicide were analysed for short and long-term periods (2 weeks and 2 years post-event) across five European countries. Incidence ratios and resulting percentage changes were computed. RESULTS Similar to Germany, there were significant short and long-term effects for the combined data of the four other countries (increase of 93.9%; p=0.004 and 16.7%; p=0.003). There was no indication that long-term effects are a mere reflection of an overall increase in suicide frequencies or due to increased numbers of kilometres driven by trains. Analyses on country level revealed heterogeneous results. LIMITATIONS Due to incomplete data, analyses regarding age and gender were not performed. Media coverage was only proxied by a Google Trends analysis. The study includes a small sample of European countries. CONCLUSIONS Enkes suicide in 2009 was followed by increasing train suicide numbers in Europe. Although this incident may have reinforced an existing European trend of growing railway suicides, an international copycat effect and/or an increased overall awareness about this particular suicide method appears to be one likely explanation for the changes.

Depression Awareness and Self-Management Through the Internet: Protocol for an Internationally Standardized Approach

Background Depression incurs significant morbidity and confers increased risk of suicide. Many individuals experiencing depression remain untreated due to systemic and personal barriers to care. Guided Internet-based psychotherapeutic programs represent a promising means of overcoming such barriers and increasing the capacity for self-management of depression. However, existing programs tend to be available only in English and can be expensive to access. Furthermore, despite evidence of the effectiveness of a number of Internet-based programs, there is limited evidence regarding both the acceptability of such programs and feasibility of their use, for users and health care professionals. Objective This paper will present the protocol for the development, implementation, and evaluation of the iFightDepression tool, an Internet-based self-management tool. This is a cost-free, multilingual, guided, self-management program for mild to moderate depression cases. Methods The Preventing Depression and Improving Awareness through Networking in the European Union consortium undertook a comprehensive systematic review of the available evidence regarding computerized cognitive behavior therapy in addition to a consensus process involving mental health experts and service users to inform the development of the iFightDepression tool. The tool was implemented and evaluated for acceptability and feasibility of its use in a pilot phase in 5 European regions, with recruitment of users occurring through general practitioners and health care professionals who participated in a standardized training program. Results Targeting mild to moderate depression, the iFightDepression tool is based on cognitive behavioral therapy and addresses behavioral activation (monitoring and planning daily activities), cognitive restructuring (identifying and challenging unhelpful thoughts), sleep regulation, mood monitoring, and healthy lifestyle habits. There is also a tailored version of the tool for young people, incorporating less formal language and additional age-appropriate modules on relationships and social anxiety. The tool is accompanied by a 3-hour training intervention for health care professionals. Conclusions It is intended that the iFightDepression tool and associated training for health care professionals will represent a valuable resource for the management of depression that will complement existing resources for health care professionals. It is also intended that the iFightDepression tool and training will represent an additional resource within a multifaceted approach to improving the care of depression and preventing suicidal behavior in Europe.

Increased yield of ribosome dimers from the rat seminal vesicle following castration

It has been reported by Reader and Stanners [l] that free ribosomes from certain animal cells which are inactive in protein synthesis can associate, through a Mgz’ and temperature dependent reaction, to form dimers which are relatively resistant to the action of ribonuclease. They have provided evidence that this type of dimer is an artefact which is formed under certain conditions from ribosomes not bound to messenger RNA. In actual fact, these ribosomes exist in the tissues as monomers. Following castration of normal adult rats, the RNA/DNA ratio in their seminal vesicles drops from 2.0-3.0 to a value of about 0.5 within about a week. After testosterone administration to castrated rats, the same ratio is increased about sixfold and attains its maximum within a week [2]. These data obviously reflect a dramatic change in the polyribosome content of the vesicular cells following castration or after replacement of testosterone, since the major portion of total cellular RNA is comprised in this particulate material [3]. Provided that the disappearance of various messenger RNAs after orchiectomy is more rapid than that of the ribosomes, a relative accumulation of ribosomes not linked to messenger RNA may be expected. The results reported by Reader and Stanners offered a useful tool for the detection of such ribosomes.

Growth inhibitory effect of rapamycin in Hodgkin-lymphoma cell lines characterized by constitutive NOTCH1 activation

Growing evidence suggests that deregulation of signalling elements of Notch and mammalian target of rapamycin (mTOR) pathways contribute to tumorigenesis. These signals play important roles in cellular functions and malignancies. Their tumorigenic role in T-cell acute lymphoblastic leukaemia (T-ALL) is well known; however, their potential interactions and functions are poorly characterized in Hodgkin lymphoma (HL). The aim of our study was to characterize mTOR and Notch signalling elements in HL cell lines (DEV, L1236, KMH2) and human biopsies and to investigate their cross-talk in the tumorous process. High mTOR activity and constitutive NOTCH1 activation was confirmed in HL cell lines, without any known oncogenic mutations in key elements, including those common to both pathways. The anti-tumour effect of Notch inhibitors are well known from several preclinical models but resistance and side effects occur in many cases. Here, we tested mTOR and Notch inhibitors and their combinations in gamma-secretase inhibitor (GSI) resistant HL cells in vitro and in vivo. mTOR inhibitor alone or in combination was able to reduce tumour growth; furthermore, it was more effective in xenograft models in vivo. Based on these results, we suggest that constitutively activated NOTCH1 may be a potential target in HL therapy; furthermore, mTOR inhibitors may be effective for decreasing tumour growth if resistance to Notch inhibitors develop.

Risk factors for multiple suicide attempts among Roma in Hungary

In recent years, suicide rates in Hungary have been among the highest in the European Union. Attempted suicide rates in the Roma population are 2–3 times higher than in the non-Roma population. Since individuals making multiple attempts have a higher pro-bability of eventual death by suicide, and there are limited data on suicidal behaviour of the Roma population, the aim of this study was to explore the sociodemographic and psychological background factors of multiple suicide attempts in the Hungarian Roma population. Semistructured interviews were conducted with 150 individuals admitted to hospital toxicology departments, who made suicide attempts by deliberate self-poisoning, 65 of whom were multiple attempters. Detailed information regarding the current attempt and previous suicidal acts was recorded. Patients also completed the Shortened Beck Depression, the Beck Hopelessness Questionnaire, and the Social Support Questionnaire. Independent samples t-tests were used to evaluate differences in psychological variables between the Roma (N = 90) and non-Roma (N = 60) groups. Stepwise linear regression and odds ratios analyses were performed to identify potential background factors of multiple suicide attempts. There was a significantly higher level of previous suicidal events among the Roma in the sample population (3.53 vs. 0.84, p < .001). Roma ethnicity was found to be a strong predictor of multiple suicide attempts. Current major depression, hopelessness, and diagnosed mood disorder were identified as significant risk factors of repeated attempts. Smoking (OR = 5.4), family history of suicide (OR = 4.9), and long-term unemployment (OR = 4.6) were additional risk factors among Roma patients. A thorough understanding of the ethnicity-specific risk factors for multiple suicide attempts could facilitate the development of effective intervention and postvention programmes.

Cytosolic localization of NADH cytochrome b5 oxidoreductase (Ncb5or)

Acyl‐CoA desaturation in the endoplasmic reticulum (ER) membrane depends on cytosolic NADH or NADPH, whereas NADPH in the ER lumen is utilized by prereceptor glucocorticoid production. It was assumed that NADH cytochrome b5 oxidoreductase (Ncb5or) might connect Acyl‐CoA desaturation to ER luminal redox. We aimed to clarify the ambiguous compartmentalization of Ncb5or and test the possible effect of stearoyl‐CoA on microsomal NADPH level. Amino acid sequence analysis, fluorescence microscopy of GFP‐tagged protein, immunocytochemistry, and western blot analysis of subcellular fractions unequivocally demonstrated that Ncb5or, either endogenous or exogenous, is localized in the cytoplasm and not in the ER lumen in cultured cells and liver tissue. Moreover, the involvement of ER‐luminal reducing equivalents in stearoyl‐CoA desaturation was excluded.

Abstract B47: mTOR C1/2 activities - related protein expression and its potential prognostic/therapeutic importance in certain lymphoid malignancies

There is increasing attention for PI3K/Akt/mTOR pathway as a potential target in tumor therapy. The high activity of mTOR is a characteristic feature of many tumors including hematological malignancies. However, the pathological characterisation of mTOR activity of lymphoid malignancies - especially the activity of different complexes – is still incomplete. We studied the mTOR activity related phospho-proteins and the elements of mTOR complexes by using different techniques (ELISA, Western blot, different immunohistochemical stainings, flow cytometry) depending on the tumor sample type (fresh/fixed human tissues, isolated human cells from blood or bone marrow, cell lines). The expression and activity results were compared in order to find correlation with clinical data or to mTOR inhibitor sensitivity in vitro. The proliferation and apoptotic effects after in vitro treatments were detected by Alamar Blue assay and flow cytometry. We established the in situ measurement for the amount of mTORC1, C2 complexes by Duolink stainings to compare the effects of different mTOR inhibitors to the mTORC1/C2 complex availability in lymphoma cell cultures. Our studies described high mTOR activity in all acute lymphoid leukemia (ALL) cases and in the majority of mantle cell lymphomas, anaplastic large cell lymphomas, Burkitt lymphomas, diffuse large B cell lymphomas (DLBCL), Hodgkin lymphomas (HL) and in certain cutan T lymphomas. Further characterisation of HLs, DLBCLs and ALL cases showed that high mTOR activity especially with the presence of mTORC2 is a sign of unfavorable prognosis. mTOR activity related to p-S6 and p-4EBP1 expression (ELISA and flow cytometry) at diagnosis was significantly higher in patients with poor prognosis in ALL cases. In DLBCL patient9s the results showed that high mTOR activity with Rictor overexpression significantly correlated to the worse prognosis and shorter survival. We also detected the sign of high mTOR activity in more than 90% of HLs (HLs usually with favorable prognosis), however, in these cases Rictor was not found (the mTOR activity related to mTORC1). In the different lymphoma cell lines increased mTOR activity was detected and we could describe different Rictor, Raptor and mTOR-Rictor complex expression. Moreover, the inhibitor sensitivity of the cell lines and the different expression of the elements related to mTORC1 and C2 correlated. Our results confirmed the increased mTOR activity related to mTORC1 and/or C2 complexes in certain lymphomas and ALLs. According to these analyses, the activity and expression of mTOR complexes should have potential prognostic value and high importance before mTOR inhibitor treatment, especially in the cases with high mTORC2 related protein expression. The study was supported by OTKA816624, OTKA 84262 projects and Tumor Progression Research Group of Joint Research Organization of the Hungarian Academy of Sciences and Semmelweis University Citation Format: Anna Sebestyen, Noemi Nagy, Agnes Mark, Anna Molnar, Titanilla Danko, Melinda Hajdu, Monika Toth, Botond Timar, Monika Csoka, Laszlo Kopper. mTOR C1/2 activities - related protein expression and its potential prognostic/therapeutic importance in certain lymphoid malignancies. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B47.

EPA-1023 - The 4-level approach to prevent suicides in Hungary: Results from EAAD and OSPI-Europe

Study objectives The suicide rate in Hungary is high in international comparison. The four-level intervention program of the European Alliance Against Depression (EAAD) is designed to improve the care of depression and to prevent suicidal behaviour. Our aim was evaluating the effectiveness of the EAAD on suicide rates in different areas. Method The program was implemented in Szolnok, a town in a region of Hungary with exceptionally high suicide rate and in Miskolc, a town in a region with high unemployment and also high suicide rate. Effectiveness was assessed by comparing changes in suicide rates before to after the start of the intervention in the intervention region to corresponding changes of national suicide rates. In addition, changes in suicide rates were compared to those in a control region (Szeged). In Miskolc also the number of suicide attempts was used to measure the effectiveness of the program. Results For the duration of the program and the follow-up year, suicide rates in Szolnok were significantly lower than the average of the previous three years (p=.0076). The suicide rate thus went down from 30.1 per 100,000 in 2004 to 13.2 in 2005 (-56.1%), 14.6 in 2006 (-51.4%) and 12.0 in 2007 (-60.1%). This decrease of annual suicide rates in Szolnok after the onset of the intervention was significantly stronger than that observed in Hungary (p=.017). Men had the same decrease in suicide rates as women in Szolnok. In Miskolc we observed changes in the types of suicide attempts, especially among males.