[Psychiatric aspects of terrorism]. / Terrorismus aus psychiatrischer Sicht.

BACKGROUND: Terrorism belongs to the extreme forms of violence that have so far received little attention in psychiatric research and are rarely mentioned in textbooks of psychiatry. After terror attacks, however, the question regularly arises whether terrorists suffer from mental disorders. OBJECTIVE AND METHODS: The aim of this review is to summarize the multidimensional causes of terrorism with special emphasis on psychopathological aspects of the perpetrators. In addition to a brief summary of the historical background and recent developments in terrorism, a literature search was performed using PubMed, SCOPUS, PsychInfo and PsychARTICLES. RESULTS: From a psychiatric point of view, a differentiation between lone terrorists and group terrorists is essential. Lone terrorists have a much higher prevalence of psychiatric disorders, such as psychotic, paranoid and affective symptoms. The majority of terrorists acting in groups rarely suffer from such mental disorders. For these perpetrators biographic aspects and socialization, group dynamics and ideological personality profiles with narcissistic, histrionic, fanatic and antisocial components are more relevant. The phenomenon of terrorism predominantly being a male domain is discussed. CONCLUSION: The manifold manifestations of terrorism are caused by complex patterns of interacting biographic, sociological, ideological and psychopathological components that differ between lone acting and group terrorists. The real causes for acts of terrorism are not various ideologies permitting violence but consist more of a pre-existing violence-oriented mentality of the perpetrators looking for such ideologies to justify their acts. The possibilities of psychiatry in prevention and early recognition are limited. Some recently developed scales for risk assessment of extreme violence are mentioned.

The Patient in Your Alzheimer's Disease Study May be in Another: Duplication and Deception in Clinical Trials of Alzheimer's Disease.

Duplicate and deceptive subjects, a significant issue in CNS studies, are not often considered in Alzheimer's Disease (AD) clinical trials. However, AD patients and their study partners may be motivated to take advantage of different mechanisms of action, increase odds of receiving active treatment, and/or obtain financial compensation, which may lead them to participate in multiple studies. CTSdatabase reviewed memory loss subjects (n=1087) from January 2017 through May 2019 to determine how many attempted to screen at multiple sites. 117 subjects (10.8%) visited more than one site within two years. When these potential AD subjects went to additional sites, it was predominantly for non-memory indications (often MDD or schizophrenia). For those that participated in studies, the rate of duplication approached 4% of screened AD subjects. This data indicates that significant numbers of AD subjects attempt to enroll at multiple sites, which confounds efficacy and safety signals in clinical trials.

Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression.

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.

Opioid Analgesic Prescribing Practices of Dental Professionals in the United States.

The prescription of opioid analgesics by dental professionals is widespread in the United States. Policy makers, government agencies, and professional organizations consider this phenomenon a growing public health concern. This study examined trends in the prescription of opioid analgesics for adults by dental professionals and associated factors in the United States. Data from the Medical Expenditure Panel Survey (1996-2013) were analyzed. Descriptive statistics were calculated separately for each year. Logistic regression analyses were conducted to estimate the overall trend during the period with and without adjusting for dental procedures and personal characteristics. Survey weights were incorporated to handle the sampling design. The prescription of opioid analgesics following dental care increased over time. After adjusting for sociodemographic factors, source of payment, and type of dental procedure, the odds ratio (OR) of prescribing opioid analgesics following a dental visit per each decade difference was 1.28 (95% confidence interval [CI], 1.19-1.38). Surgical, root canal, and implant procedures had the highest rates of opioid prescriptions and the greatest increases in rates over the study period. After adjusting for personal characteristics and type of dental procedure, the OR of receiving a prescription for opioids comparing blacks, Asians, and Hispanics to whites was 1.29 (95% CI, 1.17-1.41), 0.57 (95% CI, 0.47-0.70), and 0.84 (95% CI, 0.75-0.95), respectively. Opioid analgesic prescriptions following dental visits increased over time after adjusting for personal characteristics and type of dental procedure. The odds of receiving a prescription for opioids were higher for certain racial/ethnic minority groups. Knowledge Transfer Statement: This study highlights dental professionals prescribing practices of opioid analgesics by following dental treatments in the United States. With this knowledge, appropriate guidelines, protocols, and policies can be developed and implemented to address any inappropriate prescribing practices of opioid analgesics. In addition, this information could lead to an improvement in the prescribing practices of dental professionals and to evidence-based therapeutic decision making.

MRI artefacts after Bonebridge implantation.

The new transcutaneous bone conduction implant (BCI) Bonebridge (BB, MED-EL) allows the skin to remain intact and therefore overcomes some issues related to percutaneous systems, such as skin reaction around the external screw and cosmetic complaints. According to manufacturer, BB is MRI conditional up to 1,5 Tesla (T). The artefact of the neurocranium after BB implantation is extensive as shown in the present report. This has to be taken into account when patients suffering conductive, mixed or single-sided hearing loss with candidacy for a BCI are counselled. In patients with comorbid intracranial tumour or other diseases of the brain that require imaging control scans with MRI percutaneous, BCI should be the implant of choice considering the very small artefact of the percutaneous screw in MRI.

Melatonin induces transcriptional regulation of Bim by FoxO3a in HepG2 cells.

BACKGROUND: Melatonin induces apoptosis in many different cancer cell lines, including hepatocellular carcinoma cells. However, the responsible pathways have not been clearly elucidated. A member of the forkhead transcription factors' family, FoxO3a, has been implicated in the expression of the proapoptotic protein Bim (a Bcl-2-interacting mediator of cell death). In this study, we used human HepG2 liver cancer cells as an in vitro model to investigate whether melatonin treatment induces Bim through regulation by the transcription factor FoxO3a. METHODS: Cytotoxicity of melatonin was compared in HepG2 hepatoblastoma cells and primary human hepatocytes. Proapoptotic Bim expression was analysed by reverse transcriptase-polymerase chain reaction and western blot. Reporter gene assays and chromatin immunoprecipitation assays were performed to analyse whether FoxO3a transactivates the Bim promoter. Small interfering RNA (siRNA) was used to study the role of FoxO3a in Bim expression. Immunofluorescence was performed to analyse FoxO3a localisation in HepG2 cells. RESULTS: Melatonin treatment induces apoptosis in HepG2 cells, but not in primary human hepatocytes. The proapoptotic effect was mediated by increased expression of the BH3-only protein Bim. During melatonin treatment, we observed increased transcriptional activity of the forkhead-responsive element and could demonstrate that FoxO3a binds to a specific sequence within the Bim promoter. Furthermore, melatonin reduced phosphorylation of FoxO3a at Thr(32) and Ser(253), and induced its increased nuclear localisation. Moreover, silencing experiments with FoxO3a siRNA prevented Bim upregulation. CONCLUSION: This study shows that melatonin can induce apoptosis in HepG2 hepatocarcinoma cells through the upregulation of proapoptotic Bim mediated by nuclear translocation and activation of the transcription factor FoxO3a.

Increasing association between a neuropeptide Y promoter polymorphism and body mass index during the course of development.

OBJECTIVE: To investigate the association of the neuropeptide Y (NPY) promoter polymorphism rs16147 with body mass index (BMI) during the course of development from infancy to adulthood. DESIGN: Longitudinal, prospective study of a German community sample. SUBJECTS: n = 306 young adults (139 males, 167 females). MEASUREMENTS: Participants' body weight and height were assessed at the ages of 3 months and 2, 4.5, 8, 11, 15 and 19 years. NPY rs16147 was genotyped. RESULTS: Controlling for a number of possible confounders, homozygote carriers of the rs16147 C allele exhibited significantly lower BMI scores when compared with individuals carrying the T allele. In addition, a significant genotype by age interaction emerged, indicating that the genotype effect increased during the course of development. CONCLUSIONS: This is the first longitudinal study to report an association between rs16147 and BMI during childhood and adolescence. The finding that this effect increased during the course of development may either be due to age-dependent alterations in gene expression or to maturation processes within the weight regulation circuits of the central nervous system.

[Appendicitis necessitatis: appendicitis perforating the abdominal wall]. / Appendicitis necessitatis: Durch die Bauchwand perforierte Appendizitis.

Perforation of the appendix through the anterior abdominal wall is a rare complication of a frequent disorder. We report on a 37-year old patient presenting with purulent secretion from the right lower abdomen. The CT scan of the abdomen revealed a perityphlitic abscess with perforation of the anterior abdominal wall. The patient underwent laparotomy with appendectomy and subsequent revision of the abdominal wall. Appendicocutaneous fistula due to perforation through the abdominal wall is a rarity. In analogy to empyema necessitatis, which would require the pleural empyema to penetrate the thoracic wall, the entity was denoted appendicitis necessitatis.

Regional variations in the glial influence on synapse development in the mouse CNS.

There is increasing evidence that synapse function depends on interactions with glial cells, namely astrocytes. Studies on specific neurons of the central nervous system (CNS) indicated that glial signals also control synapse development, but it remained unclear whether this is a general principle that applies to other neuronal cell types. To address this question, we developed new methods to immunoisolate neurons from different brain regions of postnatal mice and to culture them in a chemically defined medium. Electrophysiological recordings and immunocytochemical staining revealed vigorous synaptogenesis in hippocampal and cerebellar neurons, but not in retinal ganglion cells (RGCs) in the absence of glial cells. Co-culture with glia promoted synapse formation in RGCs as indicated by a strong increase in the incidence and frequency of action potential-independent miniature synaptic currents, but showed no such effects in hippocampal or cerebellar neurons. On the other hand, glial signals promoted the efficacy of excitatory synapses in all regions as indicated by an increase in the size of spontaneous synaptic events in cerebellar cultures and of miniature synaptic currents in hippocampal neurons and RGCs. Inhibitory synaptic currents remained largely unaffected by glia. Our results indicate that in the mammalian CNS, the way that glial signals promote the development of excitatory synapses depends on the type of neuron.

A new approach to sample size calculation for reference interval studies.

A new criterion is proposed for determining the sample size required for a study performed for the purpose of establishing reference intervals. The basic idea behind the criterion is to compare the empirical coverage (i.e. the probability content) of the reference region obtained from the sample with its target value (e.g. 95 per cent) and to set suitable limits delta1, delta2 to the difference between both quantities which must not be exceeded with sufficiently large probability beta (e.g. beta=90 per cent). For the most frequently used parametric and distribution-free methods of estimating univariate reference limits, implicit formulae are derived relating the sample size to the design parameters delta1, delta2 and beta. For symmetric specification of (delta1, delta2), explicit approximation formulae for the computation of n are given. Exact values obtained by means of suitable numerical techniques are presented in a set of tables covering specifications of delta1, delta2 and beta which can be recommended for real applications. The tables can be used both for one- and two-sided reference intervals.

[How effective are interventions in children and adolescents with antisocial behavior? A utilization study]. / Wie effektiv sind Interventionen bei Kindern und Jugendlichen mit Störungen des Sozialverhaltens? eine Inanspruchnahmestudie.

OBJECTIVE: Anti-social behavior in childhood and adolescence represents a frequent behavior disorder in this age group and its prognosis is predominantly unfavourable. The purpose of this study was to analyze the outcome and predictors of outpatients and inpatients with conduct disorders and internalizing disorders. METHOD: We compared a 10 year follow-up history of in- and outpatients with conduct disorders and internalizing disorders. The sample of patients with conduct disorders was divided into three groups ("I": F90.1; "E": F91.2, F92; "D": F91.1, F91.3). The outcome was defined as an improvement of psychosocial functioning (SGKJ). Statistical analysis consisted of Fisher exact test and logistical regression. RESULTS: Our findings showed the best results in patients with the ICD 10 diagnosis F90.1. Inpatient treatment was superior to outpatient treatment. Cooperation of parents and children, severeness of disease, psychosocial risk factors and pharmacotherapy were found to be the most important predictors. CONCLUSIONS: Effectiveness of an outpatient treatment of children and adolescents with conduct disorders can be increased by training of parents, home treatment or pharmacotherapy.

Differential regulation of synaptic vesicle proteins by antidepressant drugs.

Synaptic vesicle proteins (SVP) play a critical role in neurotransmitter release and neural plasticity, and have been implicated in the pathophysiology of psychiatric disorders such as depression. Antidepressant drugs not only alter the level of neurotransmitters, but also modulate de novo gene transcription and synthesis of proteins involved in neural plasticity. In order to investigate the effects of antidepressant compounds on SVP-mRNA levels, the expressions of synaptophysin, synaptotagmin, VAMP, and synapsin-I were analysed by in situ hybridization in rats which had been treated with desipramine, fluoxetine, tranylcypromine, or saline. The results demonstrate that chronic treatment with fluoxetine and tranylcypromine leads to an increased expression of synaptophysin, but decreased expression of synaptotagmin and VAMP in the hippocampus and cerebral cortex. Additionally, synapsin I-mRNA levels in the hippocampus and cerebral cortex are significantly reduced in tranylcypromine-treated animals. This identifies SVP genes as target genes of antidepressant treatment.

Epidemiology and prognosis of specific disorders of language and scholastic skills.

Data from a prospective longitudinal study on the development of children born at biological and psychosocial risk were utilised to examine language and learning abilities of 320 children at ages 4.5 and 8 years. Following the research criteria of the ICD-10, specific developmental disorders of speech and language and specific developmental disorders of scholastic skills were diagnosed. Data were also provided for a clinical and general low achievement group according to less stringent criteria. Frequencies in the risk population were low for specific disorders (ICD-10) (0.6%-3.7% depending on age and type of disorder). Higher frequencies were found when a clinical definition (0.6%-13.6%) or overall low achievement score (0.6%-18.6%) was chosen. The impact of well-documented organic and psychosocial risks was analysed. Organic risk affected language abilities at 4.5 years of age but neither language nor learning abilities at 8 years of age. Psychosocial aspects of a child's environment proved to be associated with both specific language and learning abilities. Stability of language disorders, association between language and reading/spelling disorders as well as gender effects were investigated.

Tissue inhibitors of metalloproteinases in liver and serum/plasma in chronic active hepatitis C and HCV-induced cirrhosis.

BACKGROUND/AIMS: The development of liver cirrhosis can be described as a process of tissue remodeling, which involves increased matrix turnover. In order to determine whether the expression of tissue inhibitors of metalloproteinases (TIMPs) reflects these changes and can be used as a marker for the activity of ongoing fibrosis, we studied TIMP-1, 2 and -3 in liver and serum/plasma of patients with chronic hepatitis C, hepatitis C virus-induced cirrhosis and healthy controls. METHODOLOGY: Northern and Western blot analysis, reverse transcriptase polymerase chain reaction and ELISA measurements were performed. RESULTS: Reverse transcriptase polymerase chain reaction showed transcripts of all 3 TIMPs in liver tissue. TIMP-1 and -2 were also detectable in lymphocytes and granulocytes, which did not contain any TIMP-3. mRNA for TIMP-1 and -3, but not for TIMP-2, was detectable by Northern blot in normal human liver and increased in fibrosis and cirrhosis. Western blotting demonstrated the presence of all 3 TIMP proteins in healthy liver. TIMP-1 and TIMP-2 levels increased, but TIMP-3 was unchanged in cirrhosis compared to normal tissue. ELISA studies showed that the increase of TIMP-1 occurred only in advanced cirrhosis, while levels did not elevate in chronic hepatitis with or without fibrosis. In plasma, some of the cirrhotic patients had very high TIMP-1 values, while mean circulating TIMP-1 levels were not significantly different between controls, hepatitis C and cirrhotic patients. Serum TIMP-2 levels were higher in chronic hepatitis and cirrhosis than in controls, but did not differ between patients with or without histologic fibrosis. CONCLUSIONS: In normal human liver there is expression of all 3 TIMPs studied. The amount of hepatic TIMP-1 protein increases late in the fibrotic process, and there is a weak correlation between the activity of fibroproliferation and hepatic or circulating amounts of TIMP-1. Currently there is no evidence that measurement of TIMP-2 and TIMP-3 in liver or blood improves diagnosis of fibroproliferation in chronic hepatitis C.

Induction of DNA double-strand breaks in mammalian cells and yeast.

Induction of DNA double-strand breaks (dsb) and their distribution are dependent on the energy deposition pattern within the cell nucleus (physical structure) and the ultrastructure of the chromosomes and its variation by the cell cycle and gene activities (biological structure). For electron radiation very similar RBE-values are observed for mammalian and yeast cells (AlK, 1.5 keV, 15 keV/micrometer: 2.6 in mammalian cells and 2.2 in yeast; CK 0.278 keV, 23 keV/micrometer: approx. 2.5 in mammalian cells and 3.8 in yeast). In contrast, the RBE-values for the induction of dsb of 4He2+ and light ions in the LET range from about 100 keV/micrometer up to 1000 keV/micrometer are significantly higher for yeast cells compared to mammalian cells. For example, the RBE-value of alpha-particles (120 keV/micrometer) is about 1.2 for mammalian cells whereas for yeast the RBE-value is about 2.5. The yeast chromatin has less condensed fibres compared with mammalian cells. Since a single CK photoelectron can induce only one dsb, the different condensation of the mammalian and yeast chromatin has no influence. However, particles may induce more than one dsb when traversing a chromatin fibre. The probability for the induction of closely neighboured dsb is higher the more condensed the chromatin fibres are. Since small DNA fragments (50 bp up to several kbp) are lost by standard methods of lysis, the underestimation of dsb yields increases with fibre condensation, which is in accordance with the observes dsb yields in mammalian cells and yeast. In order to obtain relevant yields of dsb (and corresponding RBE-values) the measurement of all DNA fragments down to about 50 bp are needed.

Induction of DNA double-strand breaks by 1H and 4He lons in primary human skin fibroblasts in the LET range of 8 to 124 keV/microm.

Yields of DNA double-strand breaks were determined in primary human skin fibroblasts exposed to 1H and 4He ions at various linear energy transfers (LETs) and to 15 MeV electrons as the reference radiation. The values obtained for the relative biological effectiveness (RBE) were 2.03, 1.45 and 1.36 for 1H ions at LETs of 35, 23 and 7.9 keV/microm, respectively, and 1.2, 1.18, 1.38 and 1.31 for 4He ions at LETs of 124, 76, 35 and 27 keV/microm, respectively. The data were obtained using pulsed-field gel electrophoresis of DNA released from cells using the chromosomes of the yeast Saccharomyces cerevisiae as length markers and fitting the experimental mass distributions of fragmented DNA to those obtained by computer simulation of the random breakage of human chromosomes. The RBE values for induction of DSBs in mammalian cells cannot be fitted to a common RBE-LET relationship for electrons and 1H, 4He and light ions. Comparison of the RBEs for mammalian cells with the corresponding RBEs obtained for yeast cells shows similar RBEs of electrons for yeast and mammalian cells; however, for 4He and light ions in the LET range of 100 to 1000 keV/microm, the RBEs for yeast are significantly higher compared with mammalian cells. These characteristics of the RBE-LET relationships for yeast and mammalian cells are attributed to the fraction of small DNA fragments induced by particles when traversing the higher-order chromatin structures which are different to some extent in these two cell types.

At risk for language disorders? Correlates and course of language disorders in preschool children born at risk.

The language abilities of 324 children of an at-risk population were investigated at age 2 and 4.5 y. Modified research criteria of the ICD-10 for specific developmental disorders of speech and language were applied. Frequencies between 4% and 7%, depending on age and type of disorder, were diagnosed among children whose performance on the language measure was only 1 instead of ICD-10's 2 SD below group mean, but the discrepancy measure of 1 SD between non-verbal language score and language measure was retained. Psychosocial aspects of a child's environment proved to be better predictors of later language disorders than obstetric complications. Stability of specific language disorders was on the whole fairly low, but children who perform below age level on language measures remained at risk. Gender differences are almost compensated by the age 4.5 y.

Structure of mitochondrial aldehyde dehydrogenase: the genetic component of ethanol aversion.

BACKGROUND: The single genetic factor most strongly correlated with reduced alcohol consumption and incidence of alcoholism is a naturally occurring variant of mitochondrial aldehyde dehydrogenase (ALDH2). This variant contains a glutamate to lysine substitution at position 487 (E487K). The E487K variant of ALDH2 is found in approximately 50% of the Asian population, and is associated with a phenotypic loss of ALDH2 activity in both heterozygotes and homozygotes. ALDH2-deficient individuals exhibit an averse response to ethanol consumption, which is probably caused by elevated levels of blood acetaldehyde. The structure of ALDH2 is important for the elucidation of its catalytic mechanism, to gain a clear understanding of the contribution of ALDH2 to the genetic component of alcoholism and for the development of specific ALDH2 inhibitors as potential drugs for use in the treatment of alcoholism. RESULTS: The X-ray structure of bovine ALDH2 has been solved to 2.65 A in its free form and to 2.75 A in a complex with NAD+. The enzyme structure contains three domains; two dinucleotide-binding domains and a small three-stranded beta-sheet domain, which is involved in subunit interactions in this tetrameric enzyme. The E487K mutation occurs in this small oligomerization domain and is located at a key interface between subunits immediately below the active site of another monomer. The active site of ALDH2 is divided into two halves by the nicotinamide ring of NAD+. Adjacent to the A-side (Pro-R) of the nicotinamide ring is a cluster of three cysteines (Cys301, Cys302 and Cys303) and adjacent to the B-side (Pro-S) are Thr244, Glu268, Glu476 and an ordered water molecule bound to Thr244 and Glu476. CONCLUSIONS: Although there is a recognizable Rossmann-type fold, the coenzyme-binding region of ALDH2 binds NAD+ in a manner not seen in other NAD+-binding enzymes. The positions of the residues near the nicotinamide ring of NAD+ suggest a chemical mechanism whereby Glu268 functions as a general base through a bound water molecule. The sidechain amide nitrogen of Asn169 and the peptide nitrogen of Cys302 are in position to stabilize the oxyanion present in the tetrahedral transition state prior to hydride transfer. The functional importance of residue Glu487 now appears to be due to indirect interactions of this residue with the substrate-binding site via Arg264 and Arg475.