The LDAEP as a potential biomarker for central serotonergic activity: challenges to overcome

Biological indicators for neurotransmitter activity are of great interest for a better understanding of the pathophysiology of psychiatric disorders. The monoaminergic neurotransmitter serotonin, in particular, plays an important role in the aetiology of many mental disorders. Serotonin has homeostatic effects on brain functioning by regulating the general excitability of neurons, and thus plays a role in modulating perception and behaviour. The loudness dependence of auditory evoked potentials (LDAEP) is a measure of the excitability of neurons in the auditory cortex during the processing of tones of different intensities. Due to a strong serotonergic innervation of the primary auditory cortex it is assumed that serotonin has modulatory effects on these brain areas. A strong LDAEP is thought to reflect a weak serotonergic activity and vice versa. The LDAEP has been successfully applied in several fields of research. One of its most promising applications is the prediction of treatment responses. However, the LDAEPs validity has been challenged. Particularly, research on some clinical diagnoses is constrained by an inherent heterogeneous symptom constellation within clinical diagnoses based on ICD-10 or DSM-V. It is therefore necessary to assess the symptoms with dimensional measures in order to give evidence to the underlying biological abnormalities. On the other hand, no standardized protocols exist for the application and analysis of the LDAEP. Basically, in order to measure the electrophysiological response of the auditory cortex, dipole source analysis, distributed imaging methods (LORETA) and single electrode estimation have been applied. However, results obtained with different approaches show major inconsistencies. The aim of the present thesis was to progress in the search of biomarkers suitable for a daily clinical use. So far, findings in schizophrenia research using LDAEP are inconsistent and lack comparability due to the above-mentioned methodological issues. Study I conducted within this thesis investigated patients with schizophrenia by means of LDAEP taking dimensional measures of the symptoms into account. Patients showed higher LDAEP values compared to healthy controls, indicating a lower serotonergic activity. Moreover, predominant negative symptoms were associated with the LDAEP. These findings are in line with other studies, which showed a dysfunctional serotonergic neurotransmission in the genesis of negative symptoms. Study II examined the underlying neural generators during loudness processing using magnetoencephalography (MEG). Magnetic field tomography analysis revealed additional activation of brain regions outside of the auditory cortex. Time course analysis further specified that tones with high intensities were processed within hundreds of milliseconds from the primary auditory cortex as well as the primary somatosensory cortex via the posterior cingulate cortex into the premotor cortex. These findings have strong implications on the comparability of the different analysis approaches. In summary, in search of clinical biomarkers it is important to shed light on possible influences of methodological factors in order to improve their reliability and validity. Their application in daily clinical practice would lead to more precise diagnoses and improve treatment strategies by enabling a better prediction of therapeutic outcome. In der psychiatrischen Forschung sind biologische Indikatoren für die Neurotransmitter-Aktivität im Gehirn von grossem Interesse. Insbesondere Serotonin, ein monoaminer Neurotransmitter, spielt in der Ätiologie vieler psychischer Erkrankungen eine wichtige Rolle. Serotonin wird eine regulierende Funktion im Gehirn zugeschrieben, indem es das Erregungsniveau von Nervenzellen mit der Wahrnehmung und dem Verhalten des Organismus abstimmt. Die Lautstärkeabhängigkeit Akustisch Evozierter Potentiale (LAAEP) ist ein Mass für die Reagibilität der Neurone im auditorischen Kortex bei der Verarbeitung unterschiedlich lauter Töne. Angesichts einer starken serotonergen Innervation des primären auditorischen Kortex wird vermutet, dass Serotonin einen modulierenden Einfluss auf die Aktivität dieses Kortexareals hat. Es wird angenommen, dass eine starke LAAEP eine schwache serotonerge Aktivität wiederspiegelt und vice versa. Trotz eines beachtlichen Erfolges der LAAEP in verschiedenen Bereichen der neurowissenschaftli- chen Forschung in der Psychiatrie, ist dieser Indikator noch nicht genügend validiert, um im klinischen Alltag verwendet werden zu können. Ausserdem sind derartige Biomarker bei Untersuchungen an psychiatrischen Stichproben mit heterogenen Symptomkonstellationen nicht uneingeschränkt anwendbar. Symptome, die unter derselben klinischen Diagnose subsumiert sind, unterliegen möglicherweise unterschiedlichen biologischen Ursachen. Im Kontext solcher Forschung ist es daher erforderlich, dimensionale Beschreibungen der Symptome zu berücksichtigen und mit der LAAEP zu assoziieren. Zum anderen existieren bis anhin keine standardisierten Protokolle für die Applikati- on und Auswertung der LAAEP. Um Potentialveränderungen im auditorischen Kortex zu erfassen, wurden einerseits Dipolquellenmodelle sowie verteilte Quellenmodelle (LORETA) und andererseits Ableitungen an einzelnen Elektroden vorgenommen. Untersuchungen zeigen, dass die Ergebnisse zwischen diesen Auswertungsansätzen inkohärent sind. Ziel der vorliegenden Arbeit war es, diesen Limitationen Rechnung zu tragen um die Etablierung der LAAEP voranzubringen. Erkenntnisse zur LAAEP bei schizophrenen Patienten sind uneinheitlich und aus methodischen Gründen schwer miteinander zu vergleichen. In der Studie I wurden Patienten mit Schizophrenie mittels LAAEP und unter Berücksichtigung des Schweregrads unterschiedlicher Symptomcluster, namentlich Negativ- und Positivsymptome, untersucht. Patienten zeigten eine signifikant höhere LAAEP im Vergleich zur gesunden Kontrollgruppe, beziehungsweise eine erniedrigte serotonerge Aktivität. Darüberhinaus war die Ausprägung der Negativsymptomatik stark mit der LAAEP assoziiert. Dies ist in Übereinstimmung mit früherer Literatur, die eine Dysfunktion des serotonergen Systems in der Genese von Negativsymptomen hypothetisierte. In der Studie II wurden die der LAAEP zugrundeliegenden Generatoren im Gehirn näher untersucht. Mithilfe von Magnetoencephalographie (MEG) und eines verteilten Imaging Verfahrens wurde ermittelt, dass nebst dem auditorischen Kortex auch andere Hirnregionen involviert sind. Eine Analyse der Zeitverläufe ergab eine sequenzielle Verarbeitung von den sensorischen Arealen über den posterioren cingulären Cortex zum Prämotor-Cortex im Millisekundenbereich. Diese zusätzlichen Aktivierungen dürften eine Auswirkung auf die Vergleichbarkeit der unterschiedlichen Auswertungsmethoden haben. Zusammenfassend ist es von grosser Bedeutung, den Einfluss möglicher methodologischer Faktoren auf die LAAEP zu untersuchen um die Reliabilität und Validität dieses klinischen Biomarkers zu verbessern. Der Einsatz im klinischen Alltag würde eine präzisere Diagnostik und eine bessere Therapieprädiktion begünstigen und so die Behandlung von Patienten massgeblich verbessern. i

The bumpy road of purinergic inhibitors to clinical application in immune-mediated diseases

Purinergic signaling plays important roles throughout the body in the regulation of organ functions during and following the disruption of homeostasis. This is also reflected by the widespread expression of two families of purinergic receptors (P1 and P2) with numerous subtypes. In the last few decades, there has been increasing evidence that purinergic signaling plays an important role in the regulation of immune functions. Mainly, signals mediated by P2 receptors have been shown to contribute to immune system-mediated pathologies. Thus, interference with P2 receptors may be a promising strategy for the modulation of immune responses. Although only a few clinical studies have been conducted in isolated entities with limited success, preclinical work suggests that the use of P2 receptor inhibitors may bear some promise in various autoimmune diseases. Despite the association of P2 receptors with several disorders from this field, the use of P2 receptor antagonists in clinical therapy is still very scarce. In this narrative review, we briefly review the involvement of the purinergic system in immunological responses and clinical studies on the effect of purinergic inhibition on autoimmune processes. We then open the aperture a bit and show some preclinical studies demonstrating a potential effect of purinergic blockade on autoimmune events. Using suramin, a non-specific purinergic inhibitor, as an example, we further show that off-target effects could be responsible for observed effects in immunological settings, which may have interesting implications. Overall, we believe that it is worthwhile to further investigate this hitherto underexplored area

Avant-propos

Avec un clin d’œil à la mouvance surréaliste, nous serions tentées d’évoquer une situation de « hasard objectif » en prenant acte de la constellation de titres et d’événements touchant à « l’Afrique aujourd’hui » surgis dans le panorama francophone depuis 2016. Le panel scientifique à l’origine de notre publication n’a en effet pas songé prolonger le colloque organisé au Collège de France en mai 2016 par Alain Mabanckou, « Penser et écrire l’Afrique aujourd’hui », publié depuis aux Éditions d..

Managerial capacity among district health managers and its association with district performance: a comparative descriptive study of six districts in the Eastern Region of Ghana

District health managers play a pivotal role in the delivery of basic health services in many countries, including Ghana, as they are responsible for converting inputs and resources such as, staff, supplies and equipment into effective services that are responsive to population needs. Weak management capacity among local health managers has been suggested as a major obstacle for responsive health service delivery. However, evidence on district health managers' competencies and its association with health system performance is scarce.; To examine managerial capacity among district health managers and its association with health system performance in six districts in the Eastern Region of Ghana.; Fifty-nine district health managers' in six different performing districts in the Eastern Region of Ghana completed a self-administered questionnaire measuring their management competencies and skills. In addition, the participants provided information on their socio-demographic background; previous management experience and training; the extent of available management support systems, and the dynamics within their district health management teams. A non-parametric one-way analysis was applied to test the association between management capacity and district performance, which was measured by 17 health indicators.; Shortcomings within different aspects of district management were identified, however there were no significant differences observed in the availability of support systems, characteristics and qualifications of district health managers across the different performing districts. Overall management capacity among district health managers were significantly higher in high performing districts compared with lower performing districts (p = 0.02). Furthermore, district health managers in better performing districts reported a higher extent of teamwork (p = 0.02), communication within their teams (p<0.01) and organizational commitment (p<0.01) compared with lower performing districts.; The findings demonstrate individual and institutional capacity needs, and highlights the importance of developing management competencies and skills as well as positive team dynamics among health managers at district level

How does district health management emerge within a complex health system? Insights for capacity strengthening in Ghana

Introduction:; District health managers (DHMs) play a pivotal role in the operation of district health systems in low-and middle income countries, including Ghana. Their capacity is determined by their competencies, but also by the organization and system in which they are embedded. The objective of this paper is to explore how district health management emerges from contextual, organizational, and individual factors in order to demonstrate that capacity strengthening efforts at district level need to transcend individual competencies to take on more systemic approaches.; Methods:; Semi-structured interviews (; n; = 21) were conducted to gain insight into aspects that affect district health management in the Eastern Region of Ghana. Interviews were conducted with DHMs (; n; = 15) from six different districts, as well as with their superiors at the regional level (; n; = 4) and peers from non-governmental organizations (; n; = 2). A thematic analysis was conducted by using an analytical approach based on systems theory.; Results:; Contextual aspects, such as priorities among elected officials, poor infrastructure and working conditions, centralized decision-making, delayed disbursement of funds and staff shortages, affect organizational processes and the way DHMs carry out their role. Enabling organizational aspects that provide DHMs with direction and a clear perception of their role, include positive team dynamics, good relations with supervisors, job descriptions, appraisals, information systems, policies and guidelines. Meanwhile, hierarchical organizational structures, agendas driven by vertical programs and limited opportunities for professional development provide DHMs with limited authority to make decisions and dampens their motivation. The DHMs ability to carry out their role effectively depends on their perception of their role and the effort they expend, in addition to their competencies. In regards to competencies, a need for more general management and leadership skills were called for by DHMs as well as by their superiors and peers.; Conclusion:; Systemic approaches are called for in order to strengthen district health management capacity. This study can provide national policy-makers, donors and researchers with a deeper understanding of factors that should be taken into consideration when developing, planning, implementing, and assessing capacity-building strategies targeted at strengthening district health management

TRIMAGE: A dedicated trimodality (PET/MR/EEG) imaging tool for schizophrenia

Simultaneous PET/MR/EEG (Positron Emission Tomography - Magnetic Resonance - Electroencephalography), a new tool for the investigation of neuronal networks in the human brain, is presented here within the framework of the European Union Project TRIMAGE. The trimodal, cost-effective PET/MR/EEG imaging tool makes use of cutting edge technology both in PET and in MR fields. A novel type of magnet (1.5T, non-cryogenic) has been built together with a PET scanner that makes use of the most advanced photodetectors (i.e., SiPM matrices), scintillators matrices (LYSO) and digital electronics. The combined PET/MR/EEG system is dedicated to brain imaging and has an inner diameter of 260 mm and an axial Field-of-View of 160 mm. It enables the acquisition and assessment of molecular metabolic information with high spatial and temporal resolution in a given brain simultaneously. The dopaminergic system and the glutamatergic system in schizophrenic patients are investigated via PET, the same physiological/pathophysiological conditions with regard to functional connectivity, via fMRI, and its electrophysiological signature via EEG. In addition to basic neuroscience questions addressing neurovascular-metabolic coupling, this new methodology lays the foundation for individual physiological and pathological fingerprints for a wide research field addressing healthy aging, gender effects, plasticity and different psychiatric and neurological diseases. The preliminary performances of two components of the imaging tool (PET and MR) are discussed. Initial results of the search of possible candidates for suitable schizophrenia biomarkers are also presented as obtained with PET/MR systems available to the collaboration

Effects of whole-body vibration on proxies of muscle strength in old adults: a systematic review and meta-analysis on the role of physical capacity level

Forest plot overview of Classification No-Go, outcome: all strength outcomes (IMVC, DS, Power, RFD, FS). (PPTX 75 kb

Early-Life Farm Exposures and Eczema Among Adults in the Agricultural Lung Health Study

Background Several studies conducted in Europe have suggested a protective association between early-life farming exposure and childhood eczema or atopic dermatitis; however, few studies have examined associations in adults. Objectives We investigated associations between early-life exposures and eczema among 3217 adult farmers and farm spouses (mean age, 62.8 years) in a case–control study nested within an US agricultural cohort. Methods We used sampling-weighted logistic regression to estimate odds ratios and 95% confidence intervals for associations between early-life exposures and self-reported doctor-diagnosed eczema (273 cases) and polytomous logistic regression to estimate odds ratios (95% confidence intervals) for a 4-level outcome combining information on eczema and atopy (specific IgE ≥ 0.35). Additionally, we explored genetic and gene–environment associations with eczema. Results Although early-life farming exposures were not associated with eczema overall, several early-life exposures were associated with a reduced risk of having both eczema and atopy. Notably, results suggest stronger protective associations among individuals with both eczema and atopy than among those with either alone. For example, odds ratios (95% confidence intervals) for having a mother who did farm work while pregnant were 1.01 (0.60, 1.69) for eczema alone and 0.80 (0.65, 0.99) for atopy alone, but 0.54 (0.33, 0.80) for having both. A genetic risk score based on previously identified atopic dermatitis variants was strongly positively associated with eczema, and interaction testing suggested protective effects of several early-life farming exposures only in individuals at lower genetic risk. Conclusions In utero and childhood farming exposures are associated with decreased odds of having eczema with atopy in adults

Interaction between Genetic Risk Scores for Reduced Pulmonary Function and Smoking, Asthma and Endotoxin

Rationale Genome-wide association studies (GWASs) have identified numerous loci associated with lower pulmonary function. Pulmonary function is strongly related to smoking and has also been associated with asthma and dust endotoxin. At the individual SNP level, genome-wide analyses of pulmonary function have not identified appreciable evidence for gene by environment interactions. Genetic Risk Scores (GRSs) may enhance power to identify gene–environment interactions, but studies are few. Methods We analysed 2844 individuals of European ancestry with 1000 Genomes imputed GWAS data from a case–control study of adult asthma nested within a US agricultural cohort. Pulmonary function traits were FEV1, FVC and FEV1/FVC. Using data from a recent large meta-analysis of GWAS, we constructed a weighted GRS for each trait by combining the top (p value\u3c5×10−9) genetic variants, after clumping based on distance (±250 kb) and linkage disequilibrium (r2=0.5). We used linear regression, adjusting for relevant covariates, to estimate associations of each trait with its GRS and to assess interactions. Results Each trait was highly significantly associated with its GRS (all three p values\u3c8.9×10−8). The inverse association of the GRS with FEV1/FVC was stronger for current smokers (pinteraction=0.017) or former smokers (pinteraction=0.064) when compared with never smokers and among asthmatics compared with non-asthmatics (pinteraction=0.053). No significant interactions were observed between any GRS and house dust endotoxin. Conclusions Evaluation of interactions using GRSs supports a greater impact of increased genetic susceptibility on reduced pulmonary function in the presence of smoking or asthma