Assessment of Serotonergic Function by Radioligands and Microdialysis:focus on stress-related behaviour and antidepressant efficacy

Serotonine is een chemische stof die betrokken is bij het doorgeven van signalen in de hersenen en speelt o.a. een rol bij het regelen van de gemoedstoestand, zoals in depressie. De meeste antidepressiva zijn erop gericht om serotonine concentraties in het menselijk brein te verhogen, maar deze geneesmiddelen lijken bij een deel van de patiënten niet erg goed te werken. De reden hiervan is niet duidelijk. Daarom is het van belang om te kunnen meten wat er met de signaaloverdracht door serotonine gebeurt onder invloed van stress en na behandeling met antidepressiva. Een methode om dit op een non-invasieve manier te meten is met positron emissie tomografie (PET). De studies die in dit poefschrift worden beschreven betreffen de validatie van radioactief gemerkte chemische stoffen, of PET tracers, die de aanmaak van serotonine ([11C]5-HTP) en de gevoeligheid van 5-HT2A receptoren voor serotonine ([11C]MDL 100907) in de hersenen kunnen meten. De laatstgenoemde stof bleek zeer geschikt. Hiermee hebben we aangetoond dat 5-HT2A receptoren waarschijnlijk geen essentiële rol spelen bij het omgaan met stress (coping style) en de reactie hierop. Daarnaast hebben we gekeken of de effectiviteit van antidepressiva verbeterd kan worden door aan serotonine heropname remmers (SSRIs) een specifieke 5-HT2C receptor blokker toe te voegen. Door deze geneesmiddelcombinatie lijken de niveaus van zowel serotonine als dopamine, een neurotransmitter betrokken bij motivatie, in de hersenen te kunnen worden verhoogd. PET lijkt een veelbelovende methode om serotonine signaaloverdracht te meten. Toekomstig onderzoek zal moeten uitwijzen of andere onderdelen betrokken bij serotonine signaaloverdracht belangrijk zijn voor stressgerelateerd gedrag. Daarnaast is het van belang om de effecten van antidepressiva op serotonine signaaloverdracht te meten en deze te relateren aan veranderingen in gedrag en gemoedstoestand

Transgenic inhibition of neuronal calcineurin activity in the forebrain facilitates fear conditioning, but inhibits the extinction of contextual fear memories

It is unclear whether protein phosphatases, which counteract the actions of protein kinases, play a beneficial role in the formation and extinction of previously acquired fear memories. In this study, we investigated the role of the calcium/calmodulin dependent phosphatase 2B, also known as calcineurin (CaN) in the formation of contextual fear memory and extinction of previously acquired contextual fear. We used a temporally regulated transgenic approach, that allowed us to selectively inhibit neuronal CaN activity in the forebrain either during conditioning or only during extinction training leaving the conditioning undisturbed. Reducing CaN activity through the expression of a CaN inhibitor facilitated contextual fear conditioning, while it impaired the extinction of previously formed contextual fear memory. These findings give the first genetic evidence that neuronal CaN plays an opposite role in the formation of contextual fear memories and the extinction of previously formed contextual fear memories. (C) 2007 Elsevier Inc. All rights reserved

Molecular imaging of depressive disorders

This chapter summarizes findings of a large number of molecular imaging studies in the field of unipolar and bipolar depression (BD). Brain metabolism in depressed unipolar and bipolar patients is generally hypoactive in the middle frontal gyri, the pregenual and posterior anterior cingulate, the superior temporal gyrus, insula, and the cerebellum, while hyperactivity exists in subcortical (caudate nucleus, thalamus), limbic (amygdala, anterior hippocampus), and medial and inferior frontal regions. Interestingly, after depletion of serotonin or noradrenalin/dopamine in vulnerable (recovered) major depressive disorder (MDD) patients, a similar response pattern in metabolism occurs. Findings on the pre- and postsynaptic dopaminergic system show indications that, at least in subgroups of retarded MDD patients, presynaptic dopaminergic markers may be decreased, while postsynaptic markers may be increased. The findings regarding serotonin synthesis, pre- and postsynaptic imaging can be integrated to a presumable loss of serotonin in MDD, while this remains unclear in BD. This reduction of serotonin and dopamine in MDD was recently summarized in a revised version of the monoamine hypothesis, which focuses more on a dysfunction at the level of the MAO enzyme. This should be addressed further in future studies. Furthermore, future longitudinal molecular imaging studies in the same subjects at different clinical mood states are needed to clarify whether the observed changes in transporters and receptors are compensatory reactions or reflect different, potentially causal mechanisms. Several suggestions for future developments are also provided.</p

De gezonde voedselomgeving:Juridische (on)mogelijkheden voor gemeenten

Overgewicht en obesitas vormen een groeiend probleem voor de volksgezondheid. Met name in de grote steden stijgt het percentage van mensen met overgewicht. Uit onderzoek blijkt dat de inrichting van de leefomgeving hier een belangrijke oorzaak van is, waar in grote mate ongezond voedsel beschikbaar is. Op basis van internationale en nationale doelen zetten gemeenten zich actief in om overgewicht terug te dringen. Het juridisch instrumentarium van gemeenten lijkt echter tekort te schieten, voornamelijk wat betreft het reguleren van de (on)gezonde voedselomgeving. Er worden aanbevelingen gedaan om gemeenten meer juridische handvatten te geve

Measuring serotonin synthesis: from conventional methods to PET tracers and their (pre)clinical implications

The serotonergic system of the brain is complex, with an extensive innervation pattern covering all brain regions and endowed with at least 15 different receptors (each with their particular distribution patterns), specific reuptake mechanisms and synthetic processes. Many aspects of the functioning of the serotonergic system are still unclear, partially because of the difficulty of measuring physiological processes in the living brain. In this review we give an overview of the conventional methods of measuring serotonin synthesis and methods using positron emission tomography (PET) tracers, more specifically with respect to serotonergic function in affective disorders. Conventional methods are invasive and do not directly measure synthesis rates. Although they may give insight into turnover rates, a more direct measurement may be preferred. PET is a noninvasive technique which can trace metabolic processes, like serotonin synthesis. Tracers developed for this purpose are α-[11C]methyltryptophan ([11C]AMT) and 5-hydroxy-L-[β-11C]tryptophan ([11C]5-HTP). Both tracers have advantages and disadvantages. [11C]AMT can enter the kynurenine pathway under inflammatory conditions (and thus provide a false signal), but this tracer has been used in many studies leading to novel insights regarding antidepressant action. [11C]5-HTP is difficult to produce, but trapping of this compound may better represent serotonin synthesis. AMT and 5-HTP kinetics are differently affected by tryptophan depletion and changes of mood. This may indicate that both tracers are associated with different enzymatic processes. In conclusion, PET with radiolabelled substrates for the serotonergic pathway is the only direct way to detect changes of serotonin synthesis in the living brain

Management of Arteriovenous Malformation: A Retrospective Review of 52 Cases

Background and goal of study Arteriovenous malformation (AVM) is relatively uncommon. Its pathogenesis is unknown and it has a variable presentation and clinical course. AVM may cause cosmetic and/or functional impairment that affects the quality of life. Few series are available in the literature on the treatment of AVM. Management of AVM is mainly based on personal philosophy of the treating physician. This study presents our experience in management of AVM. Our ultimate goal is to eradicate AVM by means of complete surgical excision followed by immediate reconstruction to restore the quality of life. The resection defects are reconstructed by selecting optimal techniques from a whole range of available options that replace the missing elements. In cases where complete excision is not possible without mutilating surgery a “palliative” approach is adopted to deal with life threatening situations or impairment of quality of life. Patients and methods All patients referred to our Centre for the Study and Treatment of Birthmarks in the period 1996-2010 were included in the study. Fifty-two consecutive patients with AVM culled from our prospective Vascular Anomalies Database were reviewed retrospectively. Main findings Five patients presented with Schöbinger stage I AVM, 33 patients with a stage II and 14 patients with stage III AVM. 45 patients were managed at our institution. 23 of these 45 patients were treated surgically. 22 of these 23 patients with 23 AVMs were treated surgically with curative intent and in one patient a “palliative” approach was chosen. 11 of the 23 surgically treated patients underwent pre-operative intra-arterial embolisation. 17 defects required one or multiple reconstruction-technique(s) to restore form and function. Two AVMs recurred in two patients, one of whom had two lesions excised. There was no recurrence of the AVM in the remaining 20 patients (mean follow-up of 51 months). The AVM was stable over 4 years in one patient who was surgically treated with a “palliative” approach. The remaining patients were either managed conservatively or treated with alcohol embolisation. Conclusion AVM is a heterogeneous in presentations, symptoms, location and stage. A multidisciplinary approach is vital to achieve optimal outcome. Complete surgical resection with or without pre-operative intra-arterial embolisation is necessary to prevent recurrence of AVM. Reconstruction is an important part of surgical treatment of AVM. Our recurrence rate is favourable as compared to recurrence rates of previous studies.

Positron Emission Tomography (PET) Imaging of Opioid Receptors

The opioid system consists of opioid receptors (which mediate the actions of opium), their endogenous ligands (the enkephalins, endorphins, endomorphins, dynorphin, and nociceptin), and the proteins involved in opioid production, transport, and degradation. PET tracers for the various opioid receptor subtypes are available, and changes in regional opioidergic activity have been assessed during both sensory and affective processing in healthy individuals and in various disease conditions such as chronic pain, neurodegeneration, epilepsy, eating disorders, and substance abuse. It is not always clear whether observed changes of tracer binding refl ect altered release of endogenous opioids or altered opioid receptor expression. Some radioligands for opioid receptors have suboptimal kinetics (i.e., slow dissociation from their target protein) or can induce undesired side effects even at low administered doses (sedation, respiratory arrest). There remains a need for PET tracers with improved properties, which can selectively visualize changes of the apparent density of a single opioid receptor subtype. Yet, PET offers the unique opportunity of quantifying opioid receptor- mediated signaling in the human central nervous system in vivo

Point-of-care troponin T is inferior to high-sensitivity troponin T for ruling out acute myocardial infarction in the emergency department

OBJECTIVE: Point-of-care testing (POCT) cardiac troponin (cTn) measurements are being used increasingly, despite the fact that evidence on the safety of their use is outdated, not taking into account current 'gold standard' high-sensitivity cardiac troponin (hs-cTn) assays. In the present study, we aimed to compare the analytical and diagnostic performance of the AQT90-flex POCT cTnT assay (which is the POCT assay with the lowest reported 99th percentile cutoff currently available) with the laboratory-based Roche Modular E170 hs-cTnT assay. MATERIALS AND METHODS: During a 4-month prospective observational cohort study, laboratory-based hs-cTnT and POCT cTn were measured simultaneously in 261 undifferentiated chest-pain patients presenting to the emergency department (ED) of the Medical Centre Leeuwarden to determine the diagnostic accuracy of both assays in predicting acute myocardial infarction (AMI) at presentation. RESULTS: The POCT cTn assay had a lower sensitivity [68 (49-82) vs. 91 (75-98)] and a lower negative predictive value [95 (91-97) vs. 98 (95-100)%] for the prediction of AMI at presentation compared with the hs-cTnT assay. Furthermore, in three patients, the POCT cTnT assay yielded unexpectedly high results, whereas hs-cTnT results were negative. None of these patients had an AMI, and no possible explanation could be found. CONCLUSION: The AQT90-flex POCT cTnT assay is not yet sensitive and reliable enough to be used to exclude AMI in the ED with a single blood draw at the time of presentation in the ED, and therefore, may have limited applicability in the ED setting