Light up your skin - light up your life?

Hautaufhellende Kosmetika, respektive Arzneistoffe, werden eingesetzt um dunkle Haut zu bleichen. Da die verschiedenen Produkte in Stoffwechselvorgänge der Haut eingreifen, ist die Bezeichnung "Kosmetikum" nicht ausreichend. Aufgrund der zahlreichen Nebenwirkungen kommt dem kommerziell unterstützten Depigmentieren der Haut eine immense Public Health Relevanz zu, auf die durchgeführte sozialanthropologische Arbeit den Fokus legt.Skin-whitening products are used for bleaching dark skin. The ingredients can react with different layers of the skin and potentially cause a lot of side effects. Nevertheless, a lot of people use skin-whitening products during long periods of time. Therefore, skin-bleaching should be regarded as an important public health issue

Synthese von Precursoren und Referenzsubstanzen neuer MCH-R1, PET-Tracer

Im Laufe der letzten Jahre haben einige Studien nahegelegt, dass das zyklische hypothalamische Peptidhormon MCH (Melanin-Concentrating Hormone) eine wesentliche Rolle bei der Gewichtsregulation durch den Hypothalamus sowie Wasserhaushalt, Energiemetabolismus und psychiatrischen Erkrankungen spielt. Ziel der vorliegenden Arbeit war die Etablierung von Synthesewegen und die Charakterisierung von Precursoren und Referenzstandards für neue MCH-Rezeptor-1 PET-Tracer, da die Positronen-Emissions-Tomographie (PET) als nicht-invasives bildgebendes Verfahren bestens dazu geeignet ist, Stoffwechselprozesse und physiologische Vorgänge auf molekularer Ebene zu erfassen. Auf Basis des selektiven und hochaffinen MCH-R1-Antagonisten racSNAP-7941 mit anxiolytischer, antidepressiver und appetitzügelnder Wirkung wurden die Precursoren und die Referenzverbindungen der entsprechenden PET-Tracer synthetisiert. Insgesamt wurde eine Serie von 17 verschiedenen SNAP-Derivaten und deren Vorstufen hergestellt, spektroskopisch analysiert und zu den Zielverbindungen umgesetzt. Die Precursoren werden im Anschluss an diese Arbeit am AKH Wien zu den Radiotracern umgesetzt, die Biodistributionsstudien und Mikro-PET-Experimenten zugeführt werden, um den MCH-R1 untersuchen zu können und Erkenntnisse über die physiologischen Prozesse rund um MCH zu gewinnen.Reports have suggested that the melanin-concentrating hormone (MCH), a cyclic peptide located predominantly in the hypothalamus, plays a significant role in the hypothalamic regulation of food intake as well as water balance, energy metabolism, and psychiatric disorders. Hence, the present study aims at establishing synthetic pathways and characterization of precursors and reference standards of novel MCH receptor 1 PET tracers. Being a non-invasive imaging technique, positron emission tomography (PET) is optimally capable of capturing metabolic and physiologic processes at the molecular level. Based on the selective, high-affinity MCH-R1 antagonist racSNAP-7941, which has antidepressant, anxiolytic and anorectic effects, different derivatives - precursors as well as reference compounds of the corresponding PET tracers - have been synthesized. In summary, 17 different derivatives of racSNAP-7941 including their corresponding precursors have been synthesized, spectroscopically analyzed, and finally converted into the target compounds. At the Dept. of Nuclear Medicine (General Hospital of Vienna, AKH) these precursors will be used for the radiosyntheses of the potential PET tracers which will be subjected to biodistribution and micro PET experiments. The overall rationale of this project is to further explore physiologic relevance of the MCH-R1

Post-traumatic stress disorder among heart disease patients: a clinical follow-up of individuals with myocardial infarction in the Tromsø Study

Background Myocardial infarction is likely to be experienced as a life-threatening and potentially traumatic event. Approximately one-third of patients with myocardial infarction experience clinically significant symptoms of anxiety/ depression. However, it is unclear how many of these patients experience these symptoms because of post-traumatic stress disorder (PTSD). We conducted a clinical screening of individuals with a confirmed myocardial infarction diagnosis. Our goal was to examine the prevalence of PTSD in myocardial infarction patients and study how PTSD symptoms were associated with exposure to potentially traumatic events. Method This is epidemiological research with a cross-sectional design following up participants from the Tromsø Study with a confirmed diagnosis of myocardial infarction. We sent invitations to participants in the Tromsø Study with clinically significant self-reported anxiety or depression symptoms following myocardial infarction. A cross-sectional sample of N=79 participants (61 men and 18 women) was collected. During an interview, participants completed the Stressful Life Events Screening Questionnaire and the PTSD checklist PCL-5. Results We found nine participants (11.6%) with probable PTSD. This was significantly higher than the postulated population prevalence in Norway (pConclusion PTSD prevalence in myocardial infarction patients was related to lifetime exposure to traumatic events, not the myocardial infarction event alone. More research is required to examine the interaction between myocardial infarction and PTSD. Clinicians should be aware that anxiety or depression symptoms after MI could be secondary symptoms of PTSD

Chemokine CCL9 Is Upregulated Early in Chronic Kidney Disease and Counteracts Kidney Inflammation and Fibrosis

Inflammation and fibrosis play an important pathophysiological role in chronic kidney disease (CKD), with pro-inflammatory mediators and leukocytes promoting organ damage with subsequent fibrosis. Since chemokines are the main regulators of leukocyte chemotaxis and tissue inflammation, we performed systemic chemokine profiling in early CKD in mice. This revealed (C-C motif) ligands 6 and 9 (CCL6 and CCL9) as the most upregulated chemokines, with significantly higher levels of both chemokines in blood (CCL6: 3–4 fold; CCL9: 3–5 fold) as well as kidney as confirmed by Enzyme-linked Immunosorbent Assay (ELISA) in two additional CKD models. Chemokine treatment in a mouse model of early adenine-induced CKD almost completely abolished the CKD-induced infiltration of macrophages and myeloid cells in the kidney without impact on circulating leukocyte numbers. The other way around, especially CCL9-blockade aggravated monocyte and macrophage accumulation in kidney during CKD development, without impact on the ratio of M1-to-M2 macrophages. In parallel, CCL9-blockade raised serum creatinine and urea levels as readouts of kidney dysfunction. It also exacerbated CKD-induced expression of collagen (3.2-fold) and the pro-inflammatory chemokines CCL2 (1.8-fold) and CCL3 (2.1-fold) in kidney. Altogether, this study reveals for the first time that chemokines CCL6 and CCL9 are upregulated early in experimental CKD, with CCL9-blockade during CKD initiation enhancing kidney inflammation and fibrosis

Observation of electron transfer mediated decay in aqueous solution

Photoionization is at the heart of X ray photoelectron spectroscopy XPS , which gives access to important information on a sample s local chemical environment. Local and non local electronic decay after photoionization in which the refilling of core holes results in electron emission from either the initially ionized species or a neighbour, respectively have been well studied. However, electron transfer mediated decay ETMD , which involves the refilling of a core hole by an electron from a neighbouring species, has not yet been observed in condensed phase. Here we report the experimental observation of ETMD in an aqueous LiCl solution by detecting characteristic secondary low energy electrons using liquid microjet soft XPS. Experimental results are interpreted using molecular dynamics and high level ab initio calculations. We show that both solvent molecules and counterions participate in the ETMD processes, and different ion associations have distinctive spectral fingerprints. Furthermore, ETMD spectra are sensitive to coordination numbers, ion solvent distances and solvent arrangemen

Concentration Dependent Ion Selectivity in VDAC: A Molecular Dynamics Simulation Study

The voltage-dependent anion channel (VDAC) forms the major pore in the outer mitochondrial membrane. Its high conducting open state features a moderate anion selectivity. There is some evidence indicating that the electrophysiological properties of VDAC vary with the salt concentration. Using a theoretical approach the molecular basis for this concentration dependence was investigated. Molecular dynamics simulations and continuum electrostatic calculations performed on the mouse VDAC1 isoform clearly demonstrate that the distribution of fixed charges in the channel creates an electric field, which determines the anion preference of VDAC at low salt concentration. Increasing the salt concentration in the bulk results in a higher concentration of ions in the VDAC wide pore. This event induces a large electrostatic screening of the charged residues promoting a less anion selective channel. Residues that are responsible for the electrostatic pattern of the channel were identified using the molecular dynamics trajectories. Some of these residues are found to be conserved suggesting that ion permeation between different VDAC species occurs through a common mechanism. This inference is buttressed by electrophysiological experiments performed on bean VDAC32 protein akin to mouse VDAC

Multimodal Machine Learning Workflows for Prediction of Psychosis in Patients With Clinical High-Risk Syndromes and Recent-Onset Depression

Importance Diverse models have been developed to predict psychosis in patients with clinical high-risk (CHR) states. Whether prediction can be improved by efficiently combining clinical and biological models and by broadening the risk spectrum to young patients with depressive syndromes remains unclear. Objectives To evaluate whether psychosis transition can be predicted in patients with CHR or recent-onset depression (ROD) using multimodal machine learning that optimally integrates clinical and neurocognitive data, structural magnetic resonance imaging (sMRI), and polygenic risk scores (PRS) for schizophrenia; to assess models' geographic generalizability; to test and integrate clinicians' predictions; and to maximize clinical utility by building a sequential prognostic system. Design, Setting, and Participants This multisite, longitudinal prognostic study performed in 7 academic early recognition services in 5 European countries followed up patients with CHR syndromes or ROD and healthy volunteers. The referred sample of 167 patients with CHR syndromes and 167 with ROD was recruited from February 1, 2014, to May 31, 2017, of whom 26 (23 with CHR syndromes and 3 with ROD) developed psychosis. Patients with 18-month follow-up (n = 246) were used for model training and leave-one-site-out cross-validation. The remaining 88 patients with nontransition served as the validation of model specificity. Three hundred thirty-four healthy volunteers provided a normative sample for prognostic signature evaluation. Three independent Swiss projects contributed a further 45 cases with psychosis transition and 600 with nontransition for the external validation of clinical-neurocognitive, sMRI-based, and combined models. Data were analyzed from January 1, 2019, to March 31, 2020. Main Outcomes and Measures Accuracy and generalizability of prognostic systems. Results A total of 668 individuals (334 patients and 334 controls) were included in the analysis (mean [SD] age, 25.1 [5.8] years; 354 [53.0%] female and 314 [47.0%] male). Clinicians attained a balanced accuracy of 73.2% by effectively ruling out (specificity, 84.9%) but ineffectively ruling in (sensitivity, 61.5%) psychosis transition. In contrast, algorithms showed high sensitivity (76.0%-88.0%) but low specificity (53.5%-66.8%). A cybernetic risk calculator combining all algorithmic and human components predicted psychosis with a balanced accuracy of 85.5% (sensitivity, 84.6%; specificity, 86.4%). In comparison, an optimal prognostic workflow produced a balanced accuracy of 85.9% (sensitivity, 84.6%; specificity, 87.3%) at a much lower diagnostic burden by sequentially integrating clinical-neurocognitive, expert-based, PRS-based, and sMRI-based risk estimates as needed for the given patient. Findings were supported by good external validation results. Conclusions and RelevanceThese findings suggest that psychosis transition can be predicted in a broader risk spectrum by sequentially integrating algorithms' and clinicians' risk estimates. For clinical translation, the proposed workflow should undergo large-scale international validation.Question Can a transition to psychosis be predicted in patients with clinical high-risk states or recent-onset depression by optimally integrating clinical, neurocognitive, neuroimaging, and genetic information with clinicians' prognostic estimates? Findings In this prognostic study of 334 patients and 334 control individuals, machine learning models sequentially combining clinical and biological data with clinicians' estimates correctly predicted disease transitions in 85.9% of cases across geographically distinct patient populations. The clinicians' lack of prognostic sensitivity, as measured by a false-negative rate of 38.5%, was reduced to 15.4% by the sequential prognostic model. Meaning These findings suggest that an individualized prognostic workflow integrating artificial and human intelligence may facilitate the personalized prevention of psychosis in young patients with clinical high-risk syndromes or recent-onset depression.</p

Traces of trauma – a multivariate pattern analysis of childhood trauma, brain structure and clinical phenotypes

Background: Childhood trauma (CT) is a major yet elusive psychiatric risk factor, whose multidimensional conceptualization and heterogeneous effects on brain morphology might demand advanced mathematical modeling. Therefore, we present an unsupervised machine learning approach to characterize the clinical and neuroanatomical complexity of CT in a larger, transdiagnostic context. Methods: We used a multicenter European cohort of 1076 female and male individuals (discovery: n = 649; replication: n = 427) comprising young, minimally medicated patients with clinical high-risk states for psychosis; patients with recent-onset depression or psychosis; and healthy volunteers. We employed multivariate sparse partial least squares analysis to detect parsimonious associations between combinations of items from the Childhood Trauma Questionnaire and gray matter volume and tested their generalizability via nested cross-validation as well as via external validation. We investigated the associations of these CT signatures with state (functioning, depressivity, quality of life), trait (personality), and sociodemographic levels. Results: We discovered signatures of age-dependent sexual abuse and sex-dependent physical and sexual abuse, as well as emotional trauma, which projected onto gray matter volume patterns in prefronto-cerebellar, limbic, and sensory networks. These signatures were associated with predominantly impaired clinical state- and trait-level phenotypes, while pointing toward an interaction between sexual abuse, age, urbanicity, and education. We validated the clinical profiles for all three CT signatures in the replication sample. Conclusions: Our results suggest distinct multilayered associations between partially age- and sex-dependent patterns of CT, distributed neuroanatomical networks, and clinical profiles. Hence, our study highlights how machine learning approaches can shape future, more fine-grained CT research

Lack of Histamine H4-Receptor Expression Aggravates TNBS-Induced Acute Colitis Symptoms in Mice

Inflammatory bowel diseases (IBD) are a growing health problem worldwide, severely affecting patients’ life qualities and life expectancies. Therapeutic options, which are rare and focus on symptoms associated with the disease, suffer from increasing numbers of patients refractory to the established strategies. Thus, in order to generate new therapeutic regimens, the detailed understanding of the pathogenic mechanisms causing IBD is necessary. Histamine is an inflammatory mediator associated with IBD. Four histamine receptors are currently known of which the histamine H4-receptor (H4R) has been shown to possess a pro-inflammatory function in several experimental models of inflammatory diseases, including dextran sodium sulfate (DSS)-induced colitis in mice. No single model reflects the complexity of human IBD, but each model provides valuable information on specific aspects of IBD pathogenesis. While DSS-induced colitis mostly relies on innate immune mechanisms, trinitrobenzene sulfonic acid (TNBS)-induced colitis rather reflects T-cell mechanisms. Consequently, an observation made in a single model has to be verified in at least one other model. Therefore, in the present study we investigated the effect of genetic blockade of H4R-signaling in mice subjected to the model of TNBS-induced acute colitis. We analyzed severity and progression of clinical signs of colitis, as well as histopathologic alterations in the colon and local cytokine production. Genetic ablation of H4R expression worsened clinical signs of acute colitis and histological appearance of colon inflammation after TNBS application. Moreover, TNBS instillation enhanced local synthesis of inflammatory mediators associated with a neutrophilic response, i.e., CXCL1, CXCL2, and interleukin-6. Lastly, also myeloperoxidase concentration, indicative for the presence of neutrophils, was elevated in cola of TNBS-treated mice due to the absence of H4R expression. Our results indicate an anti-inflammatory role of histamine via H4R in TNBS-induced acute neutrophilic colitis in mice, thus questioning the strategy of pharmacological H4R blocked as new therapeutic option for patients suffering from IBD