Sebastian Meyer

Nucleotide recognition by the cytoplasmic domain of the human chloride transporter ClC-5

The ubiquitous CBS domains, which are found as part of cytoplasmic domains in the ClC family of chloride channels and transporters, have previously been identified as building blocks for regulatory nucleotide-binding sites. Here we report the structures of the cytoplasmic domain of the human transporter ClC-5 in complex with ATP and ADP. The nucleotides bind to a specific site in the protein. As determined by equilibrium dialysis, the affinities for ATP, ADP and AMP are in the high micromolar range. Point mutations that interfere with nucleotide binding change the transport behavior of a ClC-5 mutant expressed in Xenopus laevis oocytes. Our results establish the structural and energetic basis for the interaction of ClC-5 with nucleotides and provide a framework for future investigations.

Predictors of Relapse in the Year After Hospital Discharge Among Patients With Schizophrenia

OBJECTIVE Relapse and its predictors were examined among patients with schizophrenia in the year after hospital discharge. METHODS The sample included 200 patients with schizophrenia participating in a German multicenter study. Relapse was defined as a worsening of psychopathological symptoms or rehospitalization in the year after hospital discharge. Predictors examined were variables related to course of illness and to response and remission at discharge. RESULTS Fifty-two percent of participants had a relapse. Patients whose symptoms were not in remission at discharge were more likely to have a relapse, as were those who had more severe symptoms and more side effects at discharge. Those who experienced a relapse were less likely to be taking a second-generation antipsychotic at discharge, less likely to have a positive attitude toward treatment adherence, and less likely to be employed. CONCLUSIONS The high rate of relapse among patients with schizophrenia highlights the need to improve current treatment strategies.

Predictors of response and remission in the acute treatment of first-episode schizophrenia patients — Is it all about early response?

BACKGROUND To evaluate the predictive validity of early response compared to other well-known predictor variables in acutely ill first-episode patients. METHODS 112 patients were treated with a mean dosage of 4.14 mg (±1.70) haloperidol and 112 patients with a mean dosage of 4.17 mg (±1.55) risperidone for a mean inpatient treatment duration of 42.92 days (±16.85) within a double-blind, randomized controlled trial. Early response was defined as a ≥ 30% improvement in the PANSS total score by week 2, response as a ≥ 50% reduction in the PANSS total score from admission to discharge and remission according to the consensus criteria. Univariate tests and logistic regression models were applied to identify significant predictors of response and remission. RESULTS 52% of the patients were responders and 59% remitters at discharge. Non-remitters at discharge were hindered from becoming remitters mainly by the presence of negative symptoms. Univariate tests revealed several significant differences between responders/non-responders and remitters/non-remitters such as age, severity of baseline psychopathology as well as the frequency of early response. Both early response (p<0.0001) and a higher PANSS positive subscore at admission (p=0.0002) were identified as significant predictors of response at discharge, whereas a shorter duration of untreated psychosis (p=0.0167), a lower PANSS general psychopathology subscore (p<0.0001), and early treatment response (p=0.0002) were identified as significant predictors of remission. CONCLUSION Together with the finding that early response is a significant predictor of response and remission, the relevance and predictive validity of negative and depressive symptoms for outcome is also highlighted.

A Space–Time Conditional Intensity Model for Invasive Meningococcal Disease Occurrence

A novel point process model continuous in space-time is proposed for quantifying the transmission dynamics of the two most common meningococcal antigenic sequence types observed in Germany 2002-2008. Modeling is based on the conditional intensity function (CIF), which is described by a superposition of additive and multiplicative components. As an epidemiological interesting finding, spread behavior was shown to depend on type in addition to age: basic reproduction numbers were 0.25 (95% CI 0.19-0.34) and 0.11 (95% CI 0.07-0.17) for types B:P1.7-2,4:F1-5 and C:P1.5,2:F3-3, respectively. Altogether, the proposed methodology represents a comprehensive and universal regression framework for the modeling, simulation, and inference of self-exciting spatiotemporal point processes based on the CIF. Usability of the modeling in biometric practice is promoted by an implementation in the R package surveillance.

Oxytocin and vasopressin levels are decreased in the plasma of male schizophrenia patients

Objective Impaired social functioning and autistic symptoms are characteristics of schizophrenia. The social hormones oxytocin (OT) and arginine-vasopressin (AVP) both modulate social interaction and therefore may be involved in the pathogenesis of schizophrenia. We investigated whether men with schizophrenia show altered OT and AVP levels compared with healthy controls (HC) and whether autism symptoms are associated with OT levels. Methods Forty-one men with non-acute schizophrenia and 45 matched HC were enroled. Schizophrenia was assessed with the Positive and Negative Syndrome Scale (PANSS). Blood samples were collected on 2 days, and plasma OT and AVP levels were measured by ELISA immunoassay. Results The schizophrenia patients had significantly lower plasma OT levels than the HC; a similar trend was found for AVP. Plasma OT levels were associated with severe life events, fewer important attached persons, and a higher score on the PANSS negative scale; the most dominant PANSS items were ‘preoccupation’, ‘emotional withdrawal’, and ‘passive/apathetic social withdrawal’. Conclusion These findings support an association between the social hormones OT and AVP and schizophrenia. We suggest that OT metabolism may be altered in schizophrenia, but other possible causes for decreased plasma OT levels in schizophrenia patients include decreased OT synthesis, mRNA expression, and translation. Especially the ‘autistic’ symptoms of schizophrenia seem to be closely linked to an altered metabolism of OT, the ‘attachment’ hormone.

Comparative cross-sectional study of empathy among first year and final year medical students in Jimma University, Ethiopia: Steady state of the heart and opening of the eyes

BackgroundThere is general consent that empathy is crucial for the physician-patient relationship and thus an important issue in medical education. This comparative study was designed to examine the differences in empathy between first year and final year medical students in Jimma University, Ethiopia.MethodsA comparative cross-sectional study among 131 first year and 106 final year medical students was conducted in Jimma University, Ethiopia on academic year 2010/11. The study subjects were selected using simple random sampling technique from the list of the students. Study participation was voluntary. The Balanced Emotional Empathy Scale (BEES) was used for the detection of “heart-reading”, i.e. emotional empathy and the Reading the Mind in the Eyes test (RME-R test) to evaluate “mind-reading”, i.e. cognitive empathy. We performed t-test to compare the mean difference in empathy and RME-R scores between the two groups of students. A linear regression was computed to identify potential factors influencing the BEES and RME-R.ResultsOut of the total 237 students, 207 (87.3%) were males. The mean age of first year and final year students was 19.3 ± 1.1 and 24.0 ± 1.4 years respectively. First year students have scored 40.6 ± 23.8 while final year students scored 41.5 ± 20.8 mean in the BEES measuring emotional empathy score. However, this difference was not statistically significant (t = −0.30, df = 231, P-value >0.05). Final year students had significantly higher mean cognitive empathy score (17.8 ± 4.5) than first year students (14.4 ± 4.8) [β = 2.7, 95%CI (1.20, 4.13)]. Males had scored lower cognitive [β = −2.5, 95%CI (−4.37, −0.66)] and emotional empathy [β = −12.0, 95%CI (−21.66, −5.46)].ConclusionsLow emotional (BEES) and cognitive empathy sores were found in first year and final year students of Jimma University could have implications on the medical education curricula. Medical education targeted at enhancing emotional empathy and increasing cognitive empathy is required by segmenting with gender for effective physician-patient interaction. The influence of empathy on clinical competence should be studied using more rigorous design.

Spatio-Temporal Analysis of Epidemic Phenomena Using the R Package surveillance

The availability of geocoded health data and the inherent temporal structure of communicable diseases have led to an increased interest in statistical models and software for spatio-temporal data with epidemic features. The open source R package surveillance can handle various levels of aggregation at which infective events have been recorded: individual-level time-stamped geo-referenced data (case reports) in either continuous space or discrete space, as well as counts aggregated by period and region. For each of these data types, the surveillance package implements tools for visualization, likelihoood inference and simulation from recently developed statistical regression frameworks capturing endemic and epidemic dynamics. Altogether, this paper is a guide to the spatio-temporal modeling of epidemic phenomena, exemplified by analyses of public health surveillance data on measles and invasive meningococcal disease.

Power-law models for infectious disease spread

Short-time human travel behaviour can be described by a power law with respect to distance. We incorporate this information in space–time models for infectious disease surveillance data to better capture the dynamics of disease spread. Two previously established model classes are extended, which both decompose disease risk additively into endemic and epidemic components: a spatio-temporal point process model for individual-level data and a multivariate time-series model for aggregated count data. In both frameworks, a power-law decay of spatial interaction is embedded into the epidemic component and estimated jointly with all other unknown parameters using (penalised) likelihood inference. Whereas the power law can be based on Euclidean distance in the point process model, a novel formulation is proposed for count data where the power law depends on the order of the neighbourhood of discrete spatial units. The performance of the new approach is investigated by a reanalysis of individual cases of invasive meningococcal disease in Germany (2002–2008) and count data on influenza in 140 administrative districts of Southern Germany (2001–2008). In both applications, the power law substantially improves model fit and predictions, and is reasonably close to alternative qualitative formulations, where distance and order of neighbourhood, respectively, are treated as a factor. Implementation in the R package surveillance allows the approach to be applied in other settings.

The validity of self-rated psychotic symptoms in depressed inpatients ☆

BACKGROUND Self-ratings of psychotic experiences might be biased by depressive symptoms. METHOD Data from a large naturalistic multicentre trial on depressed inpatients (n=488) who were assessed on a biweekly basis until discharge were analyzed. Self-rated psychotic symptoms as assessed with the 90-Item Symptom Checklist (SCL-90) were correlated with the SCL-90 total score, the SCL-90 depression score, the Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale 21 item (HAMD-21) total score, the Montgomery Åsberg Depression Rating Scale (MADRS) total score and the clinician-rated paranoid-hallucinatory score of the Association for Methodology and Documentation in Psychiatry (AMDP) scale. RESULTS At discharge the SCL-90 psychosis score correlated highest with the SCL-90 depression score (0.78, P<0.001) and with the BDI total score (0.64, P<0.001). Moderate correlations were found for the MADRS (0.34, P<0.001), HAMD (0.37, P<0.001) and AMDP depression score (0.33, P<0.001). Only a weak correlation was found between the SCL-90 psychosis score and the AMDP paranoid-hallucinatory syndrome score (0.15, P<0.001). Linear regression showed that change in self-rated psychotic symptoms over the treatment course was best explained by a change in the SCL-90 depression score (P<0.001). The change in clinician-rated AMDP paranoid-hallucinatory score had lesser influence (P=0.02). CONCLUSIONS In depressed patients self-rated psychotic symptoms correlate poorly with clinician-rated psychotic symptoms. Caution is warranted when interpreting results from epidemiological surveys using self-rated psychotic symptom questionnaires as indicators of psychotic symptoms. Depressive symptoms which are highly prevalent in the general population might influence such self-ratings.

Genetics of emergent suicidality during antidepressive treatment—Data from a naturalistic study on a large sample of inpatients with a major depressive episode

Factors contributing to treatment-emergent suicidal ideation (TESI) using antidepressants have been in the focus of recent research strategies. We investigated previously established clinical predictors of TESI and combined these with several polymorphisms of candidate genes in patients with major depressive disorder. Common polymorphisms involved in the tryptophan hydroxylase 1 (TPH1) and 2 (TPH2), serotonin transporter, monoamine oxidase A (MAOA) and brain-derived neurotrophic factor (BDNF) were investigated in a naturalistic inpatient study of the German research network on depression. We compared patients showing TESI with non-TESI suicidal patients and with non-suicidal patients using univariate tests to detect relevant factors, which were further tested in logistic regression and CART (Classification and Regression Trees) analyses. Of the 269 patients, TESI occurred in 22 patients (17 female), 117 patients were defined as non-TESI suicidal patients, and 130 patients were classified as non-suicidal. When comparing cases with both control groups we found the TPH2 rs1386494 (C/T) polymorphism to be moderately associated with TESI (Univariate tests: TESI vs. non-suicidality: p=0.005; adjusted: p=0.09; TESI vs. non-TESI suicidal patients: p=0.0024; adjusted: p=0.086). This polymorphism remained the only significant genetic factor in addition to clinical predictors in logistic regression and CART analyses. CART analyses suggested interactions with several clinical predictors. Haplotype analyses further supported a contribution of this polymorphism in TESI. The TPH2 rs1386494 (C/T) polymorphism might contribute to the genetic background of TESI. This polymorphism has been previously associated with committed suicide and major depressive disorder. The small number of cases warrants replication in larger patient samples. Lack of a placebo control group hampers definite conclusions on an association with antidepressive treatment.