Using diffusion imaging to explore the anatomical nature of early course schizophrenia

Schizophrenia (SCZ) is a serious brain disorder that affects around 1% of the world population. Despite a long history of research in diagnosis and treatment of SCZ, we are still far from being able to explain the origin of the disease and the interindividual differences in the trajectory of the disease. The neurodevelopmental hypothesis states that SCZ is caused by early maturational abnormalities, which interact with later brain development. Neuroimaging provides a noninvasive opportunity to study this theory in vivo. Traditionally, Magnetic resonance imaging (MRI) has been used to examine macrostructural gray matter features such as gray matter volume or cortical thickness and SCZ has been established as a brain disorder hereinafter. Diffusion tensor imaging (DTI) allows to investigate the microstructure of brain tissue. It measures the magnitude and direction of water molecule`s diffusion and is highly sensitive to alterations of gray and white matter organization. Gray matter contains the neurons and the white matter contains myelinated axons and provides long and middle range connectivity between cortical neurons. White matter alterations observed in SCZ, therefore, support the disconnection theory stating that SCZ is a brain disorder with disrupted integration of different brain systems. Finally, while early imaging research focused on chronic states of SCZ a shift of the field towards studying early stages can be observed in more recent years. Understanding early course SCZ raises the hope to improve diagnosis and subsequently prevention and intervention. In line with this research the aim of the presented studies is to characterize microstructural white and gray matter alterations in early course SCZ using diffusion MRI combined with advanced post-processing techniques, which are sufficiently sensitive to detect subtle brain conspicuities. Implications of and associations with neuropsychological and clinical symptoms and diagnosis of SCZ will be discussed subsequently. Paper 1 The purpose of the first project is to characterize white matter organization in patients with early course SCZ. To my knowledge this is the first study investigating five main intra-hemispheric corti-cocortical white matter tracts using manual guided tractography in early course SCZ. The tracts were selected based on previous findings: uncinate fasciculus (UF), cingulum bundle (CB), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF) and arcuate fasciculus (AF). Diffusion parameters (fractional anisotropy [FA], trace, axial diffusivity [AD] and radial diffusivity [RD]) were computed for each tract and compared between patients with early course SCZ (number [n]=30) and healthy controls (HC) (n=30). The association of the diffusion parameters of the tracts with clinical symptoms, memory performance, and processing speed was examined afterwards. A significant group effect, represented by reduced FA and increased RD and trace in the patients’ group compared to HC was observed for the right AF (FA [F=5.94, df=1, p=.016]; RD [F=5.60, df=1, p=.020]), CB (FA [F=9.35, df=1, p=.003]; RD [F=11.55, df=1, p=.0010] and ILF (FA [F=14.77, df=1, p=.004]; RD [F=13.25, df=1, p<.0001]). The pattern of lower FA and higher RD is indicative for myelin abnormalities. Structural alterations were correlated with positive symptoms (ILF, AF), and cognitive performance (CB), which points to the clinical relevance of the observed white matter conspicuities. Paper 2 In the past, DTI has mainly been used to study white mater, because technical challenges limited the use of DTI for the characterization of gray matter organization. However, as an extension of the classical disconnection theory one would not only expect dysconnectivity in white matter, but also a disruption of gray matter organization. The aim of this study therefore is to use novel DTI method- heterogeneity- to study the microstructural gray matter organization over the course of SCZ. In comparison to traditional diffusion indices, which focus on intra-voxel diffusion properties, heterogeneity captures the microstructural organization of a larger cortical area. After applying a free water correc-tion to control for partial volume effects, T1 and diffusion images were registered to each other and the variability (=heterogeneity) of diffusion parameters within the four brain lobes defined by auto-matic parcellation method was calculated. Patients with chronic SCZ (n=27) did not show differences of cortical organization when compared to HC (n=22). However, patients with early course SCZ (n=19) showed increased heterogeneity in the frontal lobe when compared to HC (n=15) (F=10.68, df=1, p<.0030). This indicates a lower grade of cortical organization in patients than in HC. It is suggested that this can be explained by neurodevelopmental abnormalities, plausibly caused by abnormal synaptic reorganization and pruning during adolescence and early adulthood in SCZ

Infektion mit Plasmodium falciparum in der Schwangerschaft: Pathogenese, Immunologie und Impfstoffentwicklung

Eine Infektion mit Plasmodium falciparum während der Schwangerschaft stellt in (sub)tropischen Gebieten noch immer eine besondere medizinische Herausforderung dar. Schwere Anämie der Mutter und erniedrigtes Geburtsgewicht beim Kind sind häufige Komplikationen, die jährlich allein in der Sub- Sahara Region zu 10.000 mütterlichen und 200.000 perinatalen Todesfällen führen. Methoden: Eine Literaturrecherche zu den Schwerpunktbereichen Pathogenese, Immunologie und Impfstoffentwicklung wurde mit PubMed als Hauptliteraturquelle durchgeführt. Ergebnisse: Plazentare P. falciparum-Stämme exprimieren das sog. VAR2CSA-Antigen auf der Oberfläche infizierter Erythrozyten, welches spezifisch an Chondroitinsulfat A im intervillösen Raum der Plazenta bindet. Die Adhäsion infizierter Erythrozyten führt zu einer lokalen Entzündungsreaktion, die das immunprotektive Milieu beeinträchtigt. Mit zunehmender Schwangerschaftsanzahl entwickeln Frauen in Endemiegebieten Antikörpern gegen VAR2CSA-tragende Parasitenstämme. Diese sind mit verminderten Infektions- und Komplikationsraten assoziiert. Allerdings verhindern Größe und Polymorphismus von VAR2CSA seine Verwendung als Impfstoffantigen. Daher steht die Identifizierung kleinerer VAR2CSA-Abschnitte, die eine effektive Immunantwort hervorrufen, im Zentrum der Impfstoffforschung. Die minimale CSA-Bindungsregion konnte in N-terminalen Multidomänen von VAR2CSA lokalisiert werden. Bei Labortieren können Antikörper gegen die DBL4 Domäne sowie gegen N-terminale Multidomänen die CSA-Bindung in vitro hemmen. Diskussion: N- terminale Multidomänen von VAR2CSA, wie DBL1-2 und ID1-ID2a, haben sich in präklinischen Studien bewährt und sind Bestandteil zweier Impfstoffe in Phase I der klinischen Prüfung. Sollte die Wirkung der Impfstoffe nicht hinreichend sein, könnten die N-terminalen Bereiche mit weiteren Domänen, wie DBL4, kombiniert, aus mehreren Genotypen zusammengesetzt oder an potentere Träger, wie virusartige Partikel, gebunden werden

Modulation of μ‐opioid receptor activation by acidic pH is dependent on ligand structure and an ionizable amino acid residue

Background and Purpose: Adverse side effects of conventional opioids can be avoided if ligands selectively activate peripheral opioid receptors in injured tissue. Injury and inflammation are typically accompanied by acidification. In this study, we examined influences of low pH and mutation of the ionizable amino acid residue H297(6.52) on mu-opioid receptor binding and signalling induced by the mu-opioid receptor ligands fentanyl, DAMGO, and naloxone. Experimental Approach: HEK 293 cells stably transfected with mu-opioid receptors were used to study opioid ligand binding, [S-35]-GTP gamma S binding, and cAMP reduction at physiological and acidic pH. We used mu-opioid receptors mutated at H297(6.52) to A (MOR-H297(6.52)A) to delineate ligand-specific interactions with H297(6.52). Key Results: Low pH and the mutant receptor MOR-H297(6.52)A impaired naloxone binding and antagonism of cAMP reduction. In addition, DAMGO binding and G-protein activation were decreased under these conditions. Fentanyl-induced signalling was not influenced by pH and largely independent of H297(6.52). Conclusions and Implications: Our investigations indicate that low pH selectively impairs mu-opioid receptor signalling modulated by ligands capable of forming hydrogen bonds with H297(6.52). We propose that protonation of H297(6.52) at acidic pH reduces binding and subsequent signalling of such ligands. Novel agonists targeting opioid receptors in injured tissue might benefit from lack of hydrogen bond formation with H297(6.52)

Definitions and Epidemiology of Coronary Functional Abnormalities

Coronary functional abnormalities are frequent causes of angina pectoris, particularly in patients with unobstructed coronary arteries. There is a spectrum of endotypes of functional coronary abnormalities with different mechanisms of pathology including enhanced vasoconstriction (i.e. coronary artery spasm) or impaired vasodilatation, such as impaired coronary flow reserve or increased microvascular resistance. These vasomotor abnormalities can affect various compartments of the coronary circulation such as the epicardial conduit arteries and/or the coronary microcirculation. Unequivocal categorisation and nomenclature of the broad spectrum of disease endotypes is crucial both in clinical practice as well as in clinical trials. This article describes the definitions of coronary functional abnormalities with currently accepted cut-off values, as well as diagnostic methods to identify and distinguish endotypes. The authors also provide a summary of contemporary data on the prevalence of the different endotypes of coronary functional abnormalities and their coexistence

Changes in Alcoholic Beverage Choice and Risky Drinking among Adolescents in Europe 1999–2019

This paper explores trends in beverage preference in adolescents, identifies related regional differences, and examines cluster differences in key drinking measures. Data were obtained from the European School Survey Project on Alcohol and Other Drugs (ESPAD), covering 24 European countries between 1999 and 2019. Trends in the distribution of alcoholic beverages on the participants’ most recent drinking occasion were analysed by sex and country using fractional multinomial logit regression. Clusters of countries based on trends and predicted beverage proportions were compared regarding the prevalence of drinkers, mean alcohol volume and prevalence of heavy drinking. Four distinct clusters each among girls and boys emerged. Among girls, there was not one type of beverage that was preferred across clusters, but the proportion of cider/alcopops strongly increased over time in most clusters. Among boys, the proportion of beer decreased, but was dominant across time in all clusters. Only northern European countries formed a geographically defined region with the highest prevalence of heavy drinking and average alcohol volume in both genders. Adolescent beverage preferences are associated with mean alcohol volume and heavy drinking at a country-level. Future approaches to drinking cultures need to take subpopulations such as adolescents into account

Molecular Principles of Intrauterine Growth Restriction in Plasmodium Falciparum Infection

Malaria in pregnancy still constitutes a particular medical challenge in tropical and subtropical regions. Of the five Plasmodium species that are pathogenic to humans, infection with Plasmodium falciparum leads to fulminant progression of the disease with massive impact on pregnancy. Severe anemia of the mother, miscarriage, stillbirth, preterm delivery and intrauterine growth restriction (IUGR) with reduced birth weight are frequent complications that lead to more than 10,000 maternal and 200,000 perinatal deaths annually in sub-Saharan Africa alone. P. falciparum can adhere to the placenta via the expression of the surface antigen VAR2CSA, which leads to sequestration of infected erythrocytes in the intervillous space. This process induces a placental inflammation with involvement of immune cells and humoral factors. Especially, monocytes get activated and change the release of soluble mediators, including a variety of cytokines. This proinflammatory environment contributes to disorders of angiogenesis, blood flow, autophagy, and nutrient transport in the placenta and erythropoiesis. Collectively, they impair placental functions and, consequently, fetal growth. The discovery that women in endemic regions develop a certain immunity against VAR2CSA-expressing parasites with increasing number of pregnancies has redefined the understanding of malaria in pregnancy and offers strategies for the development of vaccines. The following review gives an overview of molecular processes in P. falciparum infection in pregnancy which may be involved in the development of IUGR

Invasive Diagnosis of Coronary Functional Disorders Causing Angina Pectoris

Coronary vasomotion disorders represent a frequent cause of angina and/or dyspnoea in patients with non-obstructed coronary arteries. The highly sophisticated interplay of vasodilatation and vasoconstriction can be assessed in an interventional diagnostic procedure. Established parameters characterising adequate vasodilatation are coronary blood flow at rest, and, after drug-induced vasodilation, coronary flow reserve, and microvascular resistance (hyperaemic microvascular resistance, index of microcirculatory resistance). An increased vasoconstrictive potential is diagnosed by provocation testing with acetylcholine or ergonovine. This enables a diagnosis of coronary epicardial and/or microvascular spasm. Ischaemia associated with microvascular spasm can be confirmed by ischaemic ECG changes and the measurement of lactate concentrations in the coronary sinus. Although interventional diagnostic procedures are helpful for determining the mechanism of the angina, which may be the key to successful medical treatment, they are still neither widely accepted nor applied in many medical centres. This article summarises currently well-established invasive methods for the diagnosis of coronary functional disorders causing angina pectoris