Health after Fukushima. A current perspective

This short paper reflects on the current situation after the Fukushima nuclear accident and the potential health consequences of the disaster. We discuss perspectives related to radiation protection activities as well as to epidemiologic monitoring and research in the affected regions in order to assess long-term effects of the accident.     

Socio-economic,trafficking exposures and mental health symptoms of human trafficking returnees in Ethiopia: using a generalized structural equation modelling

Background

Mental health problems among trafficked persons could be the result of concomitantly interwoven effects of various factors. Analyzing the networked relationships concurrently could be a more substantive approach to better understand the role of risk factors in this population. This study aimed to assess the magnitude of mental health symptoms as well as the association among socio-demographic, trafficking related exposure variables, and mental health problems of Ethiopian returnees from trafficking.

Methods

A sample of 1387 returnees who were trafficked via three major human trafficking corridors of Ethiopia were selected consecutively. Data related to socio-economic, trafficking exposure variables, and symptoms of mental illness were collected in personal interviews. Anxiety was measured with a brief measure for generalized anxiety disorder (GAD-7), depression with a patient health questionnaire (PHQ-9), and PTSD with post-traumatic checklist (PCL-C). Generalized structural equation modeling was employed to estimate the relationships among exogenous, mediating, and endogenous variables simultaneously.

Results

The prevalence of symptoms of anxiety was estimated at 51.9% (95% CI 49.3–54.6%); PTSD was estimated at 34.5% (95% CI 32.1–37.1%) and depression at 58.3% (95% CI 55.6–60.9%). Restricted freedom of movement had a direct positive effect on anxiety (β?=?1.24, 95% CI 0.97–1.51), depression (β?=?0.94, 95% CI 0.71–1.17) and PTSD (13.00, 95% CI 11.23–14.77). Violence experienced during the trafficking period was a mediator variable and significantly associated with anxiety (β?=?0.46; 95% CI 0.26–0.66) and PTSD (β?=?4.00; 95% CI 2.06–5.94). History of detention had a positive total effect on GAD (total β?=?1.380, 95% CI 1.074–1.687) and PTSD (total β?=?15.63, 95% CI 13.708–17.545), and direct positive effect on depression (β?=?0.89, 95% CI 0.65–1.13).

Conclusion

Ethiopian trafficked persons were highly likely to return with increased levels of mental health symptoms, namely anxiety, depression, and PTSD. Socio-economic and trafficking related exposures mediated by violence were factors affecting mental health symptoms. Thus, in addition to economic re-integrations of victims, strategies should be designed and implemented to address the prevalent mental health problems.

     

Systematic review on physician's knowledge about radiation doses and radiation risks of computed tomography

Background

The frequent use of computed tomography is a major cause of the increasing medical radiation exposure of the general population. Consequently, dose reduction and radiation protection is a topic of scientific and public concern.

Aim

We evaluated the available literature on physicians’ knowledge regarding radiation dosages and risks due to computed tomography.

Methods

A systematic review in accordance with the Cochrane and PRISMA statements was performed using eight databases. 3091 references were found. Only primary studies assessing physicians’ knowledge about computed tomography were included.

Results

14 relevant articles were identified, all focussing on dose estimations for CT. Overall, the surveys showed moderate to low knowledge among physicians concerning radiation doses and the involved health risks. However, the surveys varied considerably in conduct and quality. For some countries, more than one survey was available. There was no general trend in knowledge in any country except a slight improvement of knowledge on health risks and radiation doses in two consecutive local German surveys.

Conclusions

Knowledge gaps concerning radiation doses and associated health risks among physicians are evident from published research. However, knowledge on radiation doses cannot be interpreted as reliable indicator for good medical practice.     

Awareness and Knowledge of Sexually Transmitted Diseases Among Secondary School Students in Two German Cities

Several western countries have reported increases of sexually transmitted diseases such as gonorrhea, syphilis and chlamydia since the mid-1990s, especially among teenagers 16–19 years old. We conducted a school-based survey to assess awareness and knowledge of STDs among students attending the 8th grade and above in Bremen and Bremerhaven, two cities in northern Germany. Between October and December 2011 students completed an anonymous questionnaire on awareness and knowledge of STDs in 8 different schools. To assess awareness of STDs, the students were asked to indicate which STDs they had heard of. Knowledge of STDs was assessed based on 4 general questions. Furthermore, comprehensive awareness of HPV was assessed based on 3 items. We assessed differences in HPV awareness and knowledge of STDs by key demographic variables such as age, gender and migrant background. A total of 1,148 students aged 12–20 years (response 28 %) completed the questionnaire. 31 % had a migrant background and 55 % were girls. Almost all students had heard of HIV/AIDS, but only 23 % of chlamydia and 13 % of HPV. Significantly more girls than boys had heard of HPV (18 vs. 8 %) and chlamydia (31 vs. 16 %). Generally, low levels of STD knowledge and awareness of HPV were observed. In multivariable analyses, age, gender, and ever having had sex were associated with both STD knowledge and awareness of HPV. HIV/AIDS remains the only sexually transmitted disease most students have heard of. Sex education at school needs to be broadened to include STDs other than HIV/AIDS.     

Epidemiologie von Hodentumoren

Context

Testicular germ cell tumors are generally rare; however, the incidence of these tumors has been slowly increasing over the past years.

Material and methods

Analysis of data provided by the German Centre for Cancer registry data and the Association of population-based Cancer registries as well as by Globocan/IARC; selective literature review in Pubmed focussing on new epidemiological studies.

Results

Incidence rates in Germany are somewhat higher than in many other European countries. In terms of clinical and epidemiological features the unusual age distribution with higher risks in young and middle age is of interest. Cryptorchidism and a genetic disposition are among the few established risk factors, while there is an intense research effort directed towards endocrine disruptors as potential causes. The survival of testicular cancer patients is high and further survival improvements seem feasible mainly for elderly patients.     

Wish for a child and infertility: study on 116 couples. I. Interview and psychodynamic hypotheses

The authors wish to stress the importance of the psychosomatic approach in the investigation of infertility. Following the hypothesis that infertile patients may present emotional conflicts with regard to the wish of having a child, psychodynamic interviews were carried out with 116 infertile couples concomitantly with their first consultation at the Sterility Department. The psychological findings show that severe conflicts with regard to wish of parenthood were present in the majority of the female patients and especially in those without clinically defined organic infertility factors. The relationship between clinical diagnosis and psychological outcome was less evident in the male partners. The 11 pregnancies which occurred in the study group are also discussed with regard to the motivational quality of the wish of child of these patients. A recommendation is made that psychological interviews should be included in any infertility investigation as a matter of routine and that therapeutic procedures should take into account both the clinical and psychological diagnosis to prevent unsuccessful situations.     

Ionic liquid phase microextraction combined with fluorescence spectrometry for preconcentration and quantitation of carvedilol in pharmaceutical preparations and biological media

Background

Carvedilol belongs to a group of medicines termed non-selective beta-adrenergic blocking agents. In the presented approach, a practical and environmentally friendly microextraction method based on the application of ionic liquids (ILs) was followed by fluorescence spectrometry for trace determination of carvedilol in pharmaceutical and biological media.

Methods

A rapid and simple ionic liquid phase microextraction was utilized for preconcentration and extraction of carvedilol. A hydrophobic ionic liquid (IL) was applied as a microextraction solvent. In order to disperse the IL through the aqueous media and extract the analyte of interest, IL was injected into the sample solution and a proper temperature was applied and then for aggregating the IL-phase, the sample was cooled in an ice water-bath. The aqueous media was centrifuged and IL-phase collected at the bottom of the test tube was introduced to the micro-cell of spectrofluorimeter, in order to determine the concentration of the enriched analyte.

Results

Main parameters affecting the accuracy and precision of the proposed approach were investigated and optimized values were obtained. A linear response range of 10–250 μg l⁻¹ and a limit of detection (LOD) of 1.7 μg l⁻¹ were obtained.

Conclusion

Finally, the presented method was utilized for trace determination of carvedilol in commercial pharmaceutical preparations and biological media.     

Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis

As an alternative pathway of controlled cell death, necroptosis can be triggered by tumor necrosis factor via the kinases RIPK1/RIPK3 and the effector protein mixed-lineage kinase domain-like protein (MLKL). Upon activation, MLKL oligomerizes and integrates into the plasma membrane via its executioner domain. Here, we present the X-ray and NMR costructures of the human MLKL executioner domain covalently bound via Cys86 to a xanthine class inhibitor. The structures reveal that the compound stabilizes the interaction between the auto-inhibitory brace helix α6 and the four-helix bundle by stacking to Phe148. An NMR-based functional assay observing the conformation of this helix showed that the F148A mutant is unresponsive to the compound, providing further evidence for the importance of this interaction. Real-time and diffusion NMR studies demonstrate that xanthine derivatives inhibit MLKL oligomerization. Finally, we show that the other well-known MLKL inhibitor Necrosulfonamide, which also covalently modifies Cys86, must employ a different mode of action.

Controlled cell death is essential for tissue homeostasis. Besides the well-studied controlled cell-death mechanism apoptosis, other pathways of controlled cell death exist. One of the best-studied alternative mechanisms is Tumor Necrosis Factor (TNF)-induced necroptosis, which depends on TNF receptor 1, Receptor-Interacting Protein Kinase 1 (RIPK1), RIPK3, and the mixed-lineage kinase domain-like protein (MLKL) (1). TNF induces necroptosis when caspase activity is reduced (2). In contrast to apoptosis, necroptosis leads to the massive release of damage-associated molecular patterns, some of which have proinflammatory activity (3). Consequently, necroptosis has been associated with several inflammatory diseases, including amyotrophic lateral sclerosis (4), chronic intestinal inflammation (5), and skin inflammation (6). Therefore, all three proteins involved in the canonical necroptosis signaling and execution cascade (RIPK1, RIPK3, and MLKL) are attractive molecular targets for therapeutic small-molecule intervention (7).MLKL, the effector in the necroptosis signal chain, consists of two domains connected by two so-called brace helices, as described by Murphy et al. (8) for the mouse full-length protein. Structural information on human full-length MLKL is not available. However, individual domains could be characterized. The structure of the C-terminal domain of human MLKL was solved by X-ray crystallography (9) and reveals a catalytically inactive pseudokinase domain. Upon phosphorylation of the pseudokinase domain (Thr356 and Ser357) by RIPK3 (10), the activation signal is relayed to the N-terminal executioner domain. The solution structure of the latter has been solved by NMR spectroscopy by two laboratories (11, 12) and consists of a four-helix bundle (α1, α2, α3, and α5) as well as two additional α-helices (α4 and α6). The first brace helix (α6) plays an important role in the proposed plug-release mechanism (11). It postulates that phosphorylation of MLKL destabilizes the packing of the auto-inhibitory α-helix 6 to the four-helix bundle and, thereby, promotes the detachment of α-helix 6 from the four-helix bundle. The MLKL four-helix bundle is now able to oligomerize and integrates into the plasma membrane (13), which leads to permeabilization of the membrane and the breakdown of the cellular structure.Inhibition of MLKL-induced pore formation can be achieved by different modes of action. First reports of successfully targeting the nucleotide-binding site of the pseudokinase domain (14) could not be confirmed as a specific MLKL-mediated effect due to additional effective inhibition of RIPK1 and RIPK3, which is most likely responsible for the observed antinecroptotic effect of that compound (15). Furthermore, compounds that are more selective for the MLKL pseudokinase nucleotide-binding site show no impact on necroptosis (15). In a cellular high-throughput screen (HTS) comprising ∼200,000 compounds, two different chemical series of necroptosis inhibitors targeting the N-terminal four-helix bundle were discovered (10). The first inhibitor, Necrosulfonamide (NSA), binds covalently to Cys86 located in α-helix 4 of MLKL. Its optimization turned out to be challenging, due to steep structure–activity relationships (SARs) (10, 16). However, NSA is a widely used chemical probe. Compounds of the second class identified in the same HTS, the xanthines, also covalently modify Cys86. They show tractable SARs with the most potent compound revealing a half-maximal inhibitory concentration (IC₅₀) of 2 nM in a cellular necroptosis assay (17).Here, we present the high-resolution structures of the human MLKL executioner domain in complex with a covalent inhibitor of the xanthine class solved by X-ray crystallography and in solution by NMR spectroscopy. Both complex structures revealed a π–π stacking interaction between Phe148 and the xanthine core, which turned out to be the essential element of its inhibitory mode of action. Mutational analysis and an in vitro NMR functional assay were employed to investigate the inhibitory effects of the different small molecules supporting the finding that the xanthine class and NSA act via distinct mechanisms.