[Social Security Needs Social Medicine: Self-image of Physicians Practicing Social Medicine in Statutory Health Insurances and Social Security Systems]. / Soziale Sicherheit braucht Sozialmedizin Selbstverständnis von Ärztinnen und Ärzten in der sozialmedizinischen Begutachtung und Beratung.

OBJECTIVE: In January, 2014, the division "Social Medicine in Practice and Rehabilitation" of the German Society for Social Medicine and Prevention established a working group on the self-image of the physicians active in the field of social medicine (medical expertise and counseling). METHODS: The result of this work is the contribution presented here after consensus was achieved by specialists of social medicine from different fields and institutions (social security etc.) and in good cooperation with Prof. Dr. Gostomzyk and Prof. Dr. Robra. RESULTS: Based on the importance of an up to date social medicine for claimants and recipients of benefits on the one hand and the social security system on the other, and also on a description of the subjects, objectives and methods the following aspects are presented: · The perspective of social medicine. · Qualification in social medicine, concerning specialist training and continuing medical education. · The fields of duty of experts in social medicine. · The proceedings in social medicine. The working group identified challenges for the specialists in social medicine by a narrowed perception of social medicine by physicians in hospitals and practice, accompanied by an enlarged importance of expertise in social medicine, by the demand for more "patient orientation" and gain of transparency, and concerning the scientific foundation of social medicine. CONCLUSIONS: The working group postulates: · The perspective of social medicine should be spread more widely.. · Confidence in experts of social medicine and their independency should be strengthened.. · The not case-related consulting of the staff and executives should be expanded.. · Social medicine in practice needs support by politics and society, and especially by research and teaching.. · Good cooperation and transfer of experiences of the different branches of social security are essential for the impact of social medicine..

[Evidence-based health services research--a short review and implications]. / Versorgungsforschung--evidenzbasiert Ein Kurzüberblick und Implikationen.

BACKGROUND: Health services research aims to generate knowledge about care processes of people with illnesses who access health-care services. In addition, the consequences of those processes in the care routine concerning the involved persons and the health system are analyzed. CONCEPT OF THE THEORETICAL WORK: In the first part of the manuscript, an overview concerning the current definitions and subsumptions of the concept of health services research is given. The second part of the manuscript focuses on demonstrating how evidence-based health services research can be used to enable optimization of the care system. The concept is called the "circle of care optimization". In the first step the current care situation concerning its deficits and their reasons is analyzed. In the second step a relevant care goal is defined. In the third step an improvement of an existing care process is developed to achieve the defined care goal. In the fourth step, a comparative empirical study with a high-quality study design is carried out, to assess whether the improved care process is superior to the current care as usual. A health economic evaluation will be performed if applicable. If the results show no or only small advantages, the "circle" starts again with step 3. However, if the results show a significant effect in favour of the new care process and are relevant for the delivery of care and efficient in the context of health economics, a fifth step will be performed which involves developing and testing strategies for implementation. Where relevant, the consequences of implementation are investigated in a sixth step. A "best-practice" practical example is demonstrated to illustrate the "circle of care optimization". CONCLUSIONS: conclusions are derived by illustrating future challenges for health services research.

Novel GMP-compatible protocol employing an allogeneic B cell bank for clonal expansion of allospecific natural regulatory T cells.

The adoptive transfer of natural regulatory T cells (nTreg) is a new option to reshape undesired immune reactivity in autoimmunity and transplantation toward "tolerance." The first clinical trials using adoptive transfer of polyclonal nTreg demonstrated safety and hints of efficacy. However, the low frequencies of antigen-specific cells among the pool of polyclonal nTreg and their broad antigen nonspecific suppression are limitations of this approach regarding efficacy and safety. Recently, the isolation and expansion of (allo)antigen-specific nTreg have successfully been achieved by using Treg-specific activation markers but the yield is relatively low. Here, we describe a novel good manufacturing practice (GMP)-compatible expansion protocol of alloantigen-specific nTreg based on the stimulation of nTreg by allogeneic activated B cells. Their functionality and specificity are superior compared to polyclonal nTreg both in vitro and in vivo. Employing an allogeneic B cell bank, designed to cover the majority of HLA types, allows fast GMP-compliant manufacturing for donor-specific nTreg for clinical application in organ and stem cell transplantation. TCR repertoire analyses by next generation sequencing revealed impressive expansion by several log-steps of even very low-abundance alloantigen-specific nTreg clones. This novel method offers a simple approach for expanding antigen-specific nTreg and is characterized by high replicability and easy transferability to full GMP standards.

[Serotonin transporter gene and stress reactivity in unipolar depression. Role of the HPA system as endophenotype of the SLC6A4 gene]. / Serotonintransportergen und Stressreagibilität bei unipolarer Depression. Rolle des HPA-Systems als Endophänotyp des Gens SLC6A4.

BACKGROUND: A length polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) is associated with both depression and hypothalamic-pituitary-adrenal (HPA) system activity. A dysregulation of the HPA system is considered to be a candidate endophenotype of depression. The objective of the present study was an investigation of a possible gene-endophenotype-interaction between 5-HTTLPR and HPA system activity in a sample of inpatients with major depression. MATERIALS AND METHODS: A total of 237 inpatients with major depression were genotyped for 5-HTTLPR and participated in a combined dexamethasone-corticotropin-releasing hormone test (Dex-CRH test) as well as using the Hamilton score (Hamilton rating scale for depression) to determine the severity of the psychopathology. RESULTS: Patients with the ss-genotype showed a significantly higher HPA -system activity in comparison to patients with the lI-genotype, but no association between 5-HTTLPR and the severity of psychopathology could be detected. CONCLUSIONS: The results of the current study demonstrate an influence of 5-HTTLPR on dysregulation of the HPA system in patients with major depression and support the hypothesis that 5-HTTLPR- and HPA-system-interaction constitutes an important component in the pathogenesis of depression.

Estimating the heritability of reporting stressful life events captured by common genetic variants.

BACKGROUND: Although usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies. Method We examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings. RESULTS: A significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This 'heritability' was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10-8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R 2 = 0.08 in SLEs (p = 0.03). CONCLUSIONS: These results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality.

Depression symptom dimensions as predictors of antidepressant treatment outcome: replicable evidence for interest-activity symptoms.

BACKGROUND: Symptom dimensions have not yet been comprehensively tested as predictors of the substantial heterogeneity in outcomes of antidepressant treatment in major depressive disorder. METHOD: We tested nine symptom dimensions derived from a previously published factor analysis of depression rating scales as predictors of outcome in 811 adults with moderate to severe depression treated with flexibly dosed escitalopram or nortriptyline in Genome-based Therapeutic Drugs for Depression (GENDEP). The effects of symptom dimensions were tested in mixed-effect regression models that controlled for overall initial depression severity, age, sex and recruitment centre. Significant results were tested for replicability in 3637 adult out-patients with non-psychotic major depression treated with citalopram in level I of Sequenced Treatment Alternatives to Relieve Depression (STAR*D). RESULTS: The interest-activity symptom dimension (reflecting low interest, reduced activity, indecisiveness and lack of enjoyment) at baseline strongly predicted poor treatment outcome in GENDEP, irrespective of overall depression severity, antidepressant type and outcome measure used. The prediction of poor treatment outcome by the interest-activity dimension was robustly replicated in STAR*D, independent of a comprehensive list of baseline covariates. CONCLUSIONS: Loss of interest, diminished activity and inability to make decisions predict poor outcome of antidepressant treatment even after adjustment for overall depression severity and other clinical covariates. The prominence of such symptoms may require additional treatment strategies and should be accounted for in future investigations of antidepressant response.

Interaction between serotonin transporter gene variants and life events predicts response to antidepressants in the GENDEP project.

There is substantial inter-individual variation in response to antidepressants, and genetic variation may, in part, explain these differences. For example, there is evidence to suggest that variation in the serotonin transporter gene (SLC6A4) predicts response to selective serotonin reuptake inhibitors (SSRIs). Environmental factors such as the occurrence of stressful life events before treatment may also be important. One prior report suggests that both factors interact in predicting response to antidepressants. GENDEP, a prospective part-randomized pharmacogenomics trial, collected longitudinal data on the outcome of 811 patients with major depression undergoing treatment with either an SSRI (escitalopram) or a tricyclic antidepressant (nortriptyline). Life events experienced over 6 months preceding treatment were measured using a List of Threatening Experiences Questionnaire, and several polymorphisms in the serotonin transporter gene (SLC6A4) have been genotyped including the serotonin transporter-linked polymorphic region (5-HTTLPR). Stressful life events were shown to predict a significantly better response to escitalopram but had no effect on response to nortriptyline. Variation in the 5-HTTLPR and another polymorphism in the gene, STin4, significantly modified these effects. Gene-environment interactions including life events may therefore be important not only in the aetiology of depression, but also in predicting response to antidepressant medication.

Trajectories of change in depression severity during treatment with antidepressants.

BACKGROUND: Response and remission defined by cut-off values on the last observed depression severity score are commonly used as outcome criteria in clinical trials, but ignore the time course of symptomatic change and may lead to inefficient analyses. We explore alternative categorization of outcome by naturally occurring trajectories of symptom change. METHOD: Growth mixture models were applied to repeated measurements of depression severity in 807 participants with major depression treated for 12 weeks with escitalopram or nortriptyline in the part-randomized Genome-based Therapeutic Drugs for Depression study. Latent trajectory classes were validated as outcomes in drug efficacy comparison and pharmacogenetic analyses. RESULTS: The final two-piece growth mixture model categorized participants into a majority (75%) following a gradual improvement trajectory and the remainder following a trajectory with rapid initial improvement. The rapid improvement trajectory was over-represented among nortriptyline-treated participants and showed an antidepressant-specific pattern of pharmacogenetic associations. In contrast, conventional response and remission favoured escitalopram and produced chance results in pharmacogenetic analyses. Controlling for drop-out reduced drug differences on response and remission but did not affect latent trajectory results. CONCLUSIONS: Latent trajectory mixture models capture heterogeneity in the development of clinical response after the initiation of antidepressants and provide an outcome that is distinct from traditional endpoint measures. It differentiates between antidepressants with different modes of action and is robust against bias due to differential discontinuation.

Vagus nerve stimulation for depression: efficacy and safety in a European study.

BACKGROUND: Vagus nerve stimulation (VNS) therapy is associated with a decrease in seizure frequency in partial-onset seizure patients. Initial trials suggest that it may be an effective treatment, with few side-effects, for intractable depression. METHOD: An open, uncontrolled European multi-centre study (D03) of VNS therapy was conducted, in addition to stable pharmacotherapy, in 74 patients with treatment-resistant depression (TRD). Treatment remained unchanged for the first 3 months; in the subsequent 9 months, medications and VNS dosing parameters were altered as indicated clinically. RESULTS: The baseline 28-item Hamilton Depression Rating Scale (HAMD-28) score averaged 34. After 3 months of VNS, response rates (> or = 50% reduction in baseline scores) reached 37% and remission rates (HAMD-28 score <10) 17%. Response rates increased to 53% after 1 year of VNS, and remission rates reached 33%. Response was defined as sustained if no relapse occurred during the first year of VNS after response onset; 44% of patients met these criteria. Median time to response was 9 months. Most frequent side-effects were voice alteration (63% at 3 months of stimulation) and coughing (23%). CONCLUSIONS: VNS therapy was effective in reducing severity of depression; efficacy increased over time. Efficacy ratings were in the same range as those previously reported from a USA study using a similar protocol; at 12 months, reduction of symptom severity was significantly higher in the European sample. This might be explained by a small but significant difference in the baseline HAMD-28 score and the lower number of treatments in the current episode in the European study.

Measuring depression: comparison and integration of three scales in the GENDEP study.

BACKGROUND: A number of scales are used to estimate the severity of depression. However, differences between self-report and clinician rating, multi-dimensionality and different weighting of individual symptoms in summed scores may affect the validity of measurement. In this study we examined and integrated the psychometric properties of three commonly used rating scales. METHOD: The 17-item Hamilton Depression Rating Scale (HAMD-17), the Montgomery-Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory (BDI) were administered to 660 adult patients with unipolar depression in a multi-centre pharmacogenetic study. Item response theory (IRT) and factor analysis were used to evaluate their psychometric properties and estimate true depression severity, as well as to group items and derive factor scores. RESULTS: The MADRS and the BDI provide internally consistent but mutually distinct estimates of depression severity. The HAMD-17 is not internally consistent and contains several items less suitable for out-patients. Factor analyses indicated a dominant depression factor. A model comprising three dimensions, namely 'observed mood and anxiety', 'cognitive' and 'neurovegetative', provided a more detailed description of depression severity. CONCLUSIONS: The MADRS and the BDI can be recommended as complementary measures of depression severity. The three factor scores are proposed for external validation.

Relationship between mirtazapine dose, plasma concentration, response, and side effects in clinical practice.

OBJECTIVE: The aim of this study was to evaluate the benefit of mirtazapine plasma concentration monitoring in a typical clinical setting. METHODS: The relationship between mirtazapine plasma concentration, dose, response, and side effects was studied in 65 inpatients presenting with a depressive episode according to ICD-10. Plasma concentrations, the 17-item Hamilton Depression Rating (HAMD), and the UKU side effect rating were performed weekly. A subgroup of 45 patients was evaluated for a concentration-response relationship. RESULTS: We found a low positive correlation between plasma concentration and dose. A low negative correlation between plasma concentration and increased duration of sleep was noted in the first week of mirtazapine treatment, but not during the entire observation time. Responders to mirtazapine treatment presented with higher plasma concentrations than non-responders, revealing a threshold concentration of 30 ng/mL. CONCLUSION: The mirtazapine dose is a weak predictor of mirtazapine plasma concentrations. Plasma concentration measurements may therefore be useful to adjust mirtazapine doses in non-responders with plasma concentrations below 30 ng/mL. Sedative effects appear temporary and require no plasma concentration control when standard doses are administered.

[Endophenotype--a new concept for biological characterization of psychiatric disorders]. / Endophänotypen-ein neues Konzept zur biologischen Charakterisierung psychischer Störungen.

In the field of psychiatric genetics, the concept of endophenotypes is presently receiving high popularity. Current difficulties in the search for susceptibility genes of complex diseases have been attributed to the etiological heterogeneity of the clinical, psychopathologically defined phenotype of the disease. Neurobiological correlates of the disease which are genetically influenced and stable over time are considered to be more promising targets of phenotypes. They are more directly influenced by gene effects and presumably defined by a genetic determination which is less complex than the phenotype of the disorder. The endophenotype strategy has already been successful in complex disorders of other areas in medicine, including alcoholism and late-onset Alzheimer's disease. For schizophrenia, a series of endophenotypes for molecular/genetic investigation has been suggested, but the concept "endophenotype" also provides a basis for biological classification of mental disorders.

High neuroticism and depressive temperament are associated with dysfunctional regulation of the hypothalamic-pituitary-adrenocortical system in healthy volunteers.

OBJECTIVE: Elevated neuroticism, depressive temperament and dysfunctional regulation of the hypothalamic-pituitary-adrenocortical (HPA) system are considered as risk factors for unipolar depression. An interaction of these vulnerability factors was suggested, but controversially discussed. In absence of other informative studies we set out for a replication test and for elucidation of the underlying mechanism. METHOD: Ninety-two subjects recruited in the community-performed assessments of personality and temperament as well as measurement of HPA function with the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. RESULTS: Cortisol levels subsequent to Dex/CRH challenge were associated with neuroticism; high-neuroticism subjects revealed a higher HPA activation. This difference was mainly because of male subjects >/=25 years. A similar relationship was observed for depressive temperament. CONCLUSION: This constellation may propose that HPA dysregulation is the endocrinological basis for neuroticism and depressive temperament; this result supports the view that distinct personality factors and HPA vulnerability interact in mediating depression.

Treatment with the CRH1-receptor-antagonist R121919 improves sleep-EEG in patients with depression.

Well documented changes of sleep electroencephalogram (EEG) in patients with depression include rapid eye movement (REM) sleep disinhibition, decreases of slow-wave-sleep (SWS) and increase in wakefulness. Twenty-seven inpatients with major depression were admitted subsequently to a clinical trial with the CRH(1)-receptor-antagonist R121919 administered in two different dose escalation panels. A random subgroup of 10 patients underwent three sleep-EEG recordings (baseline before treatment, at the end of the first week and at the end of the fourth week of active treatment). SWS time increased significantly compared with baseline after 1 week and after 4 weeks. The number of awakenings and REM density showed a trend toward a decrease during the same time period. Separate evaluation of these changes for both panels showed no significant effect at lower doses, whereas in the higher doses after R121919 REM density decreased and SWS increased significantly between baseline and week 4. Furthermore positive associations between HAMD scores and SWS at the end of active treatment were found. Although these data might indicate that R121919 has a normalizing influence on the sleep EEG, the design of the study does not allow to differentiate genuine drug effects from those of clinical improvement and habituation to the clinical setting.

Genetics of schizophrenia and affective disorders.

The molecular-genetic basis of non-mendelian, genetically influenced disorders (complex disorders) is beginning to be uncovered. Recently, major progress in localization and detection of disposition genes of schizophrenia and bipolar disorder was achieved. We provide a comprehensive overview of recent results of linkage and association studies in schizophrenia and bipolar disorder. Several disposition genes for schizophrenia (DTNBP1, NRG1, G72) were identified, whereas evidence for specific disposition genes in bipolar disorder is more limited. Multiple limitations of current research strategies in the search of disposition genes of complex disorders have to be considered; alternative phenotype definitions, genome-wide association studies and parallel investigation of epigenetic misregulations might overcome these limitations.

Detrimental effects of water extracts from surface and interior of Taxus baccata leaves on the two-spotted spider mite (Tetranychus urticae Koch).

Surface deposits on Taxus baccata needles removed by dipping in water of 96, 60 or 40 degrees C for 5 s caused changes in life history components of mites. Paclitaxel was among other peaks present in the removed fractions in concentrations between 0.017 and 0.170 microg/g of fresh weight (f.w.) increasing with temperature. Long extraction for 60 min at only 40 degrees C did not increase removable paclitaxel, but at 60 degrees C extraction rate was the highest (1.326 microg/g) suggesting that leakage from an interior of needles occurred. Mortality, developmental time, total fecundity, oviposition period and life history parameters of Tetranychus urticae Koch. were detrimentally affected.

State markers of depression in sleep EEG: dependency on drug and gender in patients treated with tianeptine or paroxetine.

Tianeptine enhances while paroxetine inhibits serotonin reuptake into neurons; however, both show an antidepressive action. A subgroup of 38 depressed patients from a drug trial comparing the efficacy of tianeptine with that of paroxetine was studied with regard to their effects on sleep regulation, especially in relation to treatment response. We recorded sleep EEGs at day 7 and day 42 after the start of treatment with either compound, which allows measurement of changes due to the antidepressive medication in relation to the duration of treatment. Spectral analysis of the non-REM sleep EEG revealed a strong decline in the higher sigma frequency range (14-16 Hz) in male treatment responders independent of medication, whereas nonresponders did not show marked changes in this frequency range independent of gender. The patients receiving paroxetine showed less REM sleep and more intermittent wakefulness compared to the patients receiving tianeptine. REM density after 1 week of treatment was a predictor of treatment response in the whole sample. Psychopathological features with regard to the score in single items of the HAMD revealed predictive markers for response, some of which were opposite in the gender groups, especially those related to somatic anxiety. Changes in REM density were inversely correlated to the changes in HAMD in the paroxetine, but not the tianeptine, group. Our data suggest the importance of taking gender into account in the study of the biological effects of drugs. The study further points to the importance of the higher sigma frequency range in the sleep EEG of non-REM sleep and REM density as a marker of treatment response.

[Vagus nerve stimulation. A potential therapy for chronic/recurrent depression?]. / Vagusstimulation. Eine neue Behandlungsoption für chronifizierte depressive Erkrankungen.

Vagus Nerve Stimulation (VNS) is since the 1990 a clinically useful anticonvulsant therapy for treatment-resistant epilepsy. Open acute and longer term data suggest the potential clinical utility of VNS as an antidepressant therapy especially in treatment refractory depression. The vagus nerve has connections to the limbic system and other brain structures which modulate affect. PET studies showed functional changes under VNS in such critical areas, which can explain the mechanisms of action of VMS. Ongoing studies will have to better establish its acute and longer-term efficacy, and specific indications in the treatment of depression.

Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression. a prospective study.

The development and course of depression is causally linked to impairment of central regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. Previous research documented that the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test identifies HPA dysfunction with high sensitivity. We evaluated the predictive validity for medium-term outcome of the cortisol response in the combined DEX/CRH test in 74 remitted patients previously suffering from major depressive disorder. Of the 74 patients, 61 remained in stable remission and 13 relapsed during the first 6 months after discharge from the hospital. Although the cortisol and ACTH responses in the DEX/CRH test did not differ between the two groups of patients on admission, the responses differed significantly just before discharge (P< 0.05). We defined two dichotomous variables as prediction rules indicating (1) the change between admission and discharge in the cortisol response to the DEX/CRH test, and (2) the effect of the CRH infusion on cortisol as compared to the baseline level in the DEX/CRH test prior to discharge only. An elevated cortisol response in the DEX/CRH test was correlated with a four- to six-fold higher risk for relapse than in individuals with a normal cortisol response. The two proposed rules for predicting relapse within the first 6 months after discharge could be optimized by including age and gender. Hence, an exaggerated cortisol response in the combined DEX/CRH test predicts the recurrence of depressive psychopathology. The test performance can be further optimized if gender and age are taken into account.