Exogenes Melatonin führt zur Modifikation der zellulären Stressantwort in der Leber nach polymikrobieller Sepsis in der Maus

Die Sepsis ist aufgrund ihrer Häufigkeit und hohen Mortalität ein Krankheitsbild mit herausragender klinischer Bedeutung. Neben der Sanierung des Infektfokus und einer antibiotischen Therapie beschränken sich die aktuell verfügbaren Therapiemöglichkeiten auf eine Stabilisierung des Patienten und die Behandlung der sich entwickelnden Organfehlfunktionen. Eine spezifische supportive Therapie konnte bisher, trotz vielfacher wissenschaftlicher Bemühungen, noch nicht etabliert werden. Die Komplexität der pathophysiologischen Zusammenhänge des Krankheitsbildes erschwert die Identifizierung von Therapiemechanismen. Einen möglichen Ansatzpunkt stellt oxidativer Stress dar. In vorangegangenen experimentellen und vereinzelten klinischen Untersuchungen konnte ein positiver Effekt von Melatonin auf das Redoxgleichgewicht belegt werden. Unserer Arbeitsgruppe war es zudem möglich eine dosisabhängige Lebensverlängerung während einer polymikrobiellen Sepsis in der Maus durch Melatonin zu zeigen. Wie dieser Effekt vermittelt wird, ist bisher nicht abschließend geklärt. Weitere Bereiche der zellulären Stressantwort müssen in Betracht gezogen werden. Hierzu gehören die Mechanismen der Zelle als Reaktion auf den vermehrten Anfall fehlgefalteter Proteine im Endoplasmatischen Retikulum, welche als Unfolded Protein Response bezeichnet werden. Verbindungen zur Sepsis sind beschrieben, der Einfluss von Melatonin ist jedoch weitgehend unklar. Ziel der vorliegenden Arbeit war es, die Auswirkungen von Melatonin auf Marker für oxidativen Stress und Unfolded Protein Response zu evaluieren und mögliche Verbindungen aufzudecken. Zu diesem Zweck wurden männliche C3H / HeN Mäuse einer Scheinoperation unterzogen oder durch Coecum Ligation und Inzision eine polymikrobielle Sepsis induziert. Es wurde Melatonin in einer Dosis von 1 mg / kg / Körpergewicht oder Vehikellösung injiziert und nach 5 Stunden in Narkose die Organe der Tiere entnommen. Der Gehalt an Superoxid in Aorta, Leber und Milz wurde mittels Elektronenspinresonanz-Spektroskopie bestimmt. Protein- und mRNA-Expression verschiedener Marker der zellulären Stressantwort in der Leber wurden respektive mit Western Blot und quantitativer Echtzeit-Polymerasekettenreaktion bestimmt. Die vorliegenden Ergebnisse zeigen, dass die Sepsis zu einem durch Melatonin reversiblen Anstieg der Superoxidkonzentration in Leber und Aorta führt, während sich die in der Milz bereits basal erhöhten Konzentrationen unbeeinflusst zeigten. Die hepatische Expression der Superoxiddismutase korrelierte nicht mit den veränderten Konzentrationen an reaktiven Sauerstoffspezies. Melatonin hatte keine Wirkung auf den Expressionsanstieg der Adhäsionsmoleküle vaskuläres Zelladhäsionsmolekül-1 und intrazelluläres Adhäsionsmolekül-1 in der Sepsis. Ein ähnliches Verhalten der Phosphorylierung von extracellular-signal regulated kinases 1 / 2 zu den Adhäsionsmolekülen lässt eine Beteiligung an deren Regulation möglich erscheinen. Ein generell induzierender Effekt der Sepsis auf die Unfolded Protein Response blieb entgegen früherer Beobachtungen aus. Als Erklärung für die heterogene Datenlag kommen abweichende Sepsismodelle und die Untersuchung unterschiedlicher Organe bzw. Zelllinien in Betracht. Melatonin führte im angewandten Versuchsaufbau in der Leber septischer Mäuse zu einer Aktivierung der protein kinase ribonucleic acid-like endoplasmic reticulum kinase und des nachgeschalteten CCAAT / enhancer-binding-protein homologous protein. Dieser Signalweg stellt über den Verbrauch von Redoxäquivalenten und die Endoplasmatisches Retikulum Oxidase 1 eine mögliche Verbindung zwischen Unfolded Protein Response und oxidativem Stress dar. In der vorliegenden Arbeit konnten Erkenntnisse über die Vermittlung des protektiven Effekts von Melatonin in der Sepsis gewonnen werden. Zudem wurden Anhaltsatzpunkte für weitere Studien generiert und Faktoren identifiziert die hierbei besonderer Berücksichtigung bedürfen.Sepsis is due to its prevalence and high mortality a disorder with exceptional clinical significance. Apart from removal of the focus of infection and antibiotic treatment therapeutic options are currently limited to stabilizing the patient and compensating the developing organ dysfunction. So far, a specific supportive therapy could not be established despite extensive scientific effort. The complexity of underlying pathophysiology of the disease has hindered identification of therapeutic targets. Oxidative stress poses a possible area of interest in this regard. Previous experimental and a limited number of clinical studies have shown promising results concerning the positive effect of melatonin on redox balance. Our working group was able to show a dose dependent prolongation of survival by melatonin in mice in polymicrobial sepsis. How this was mediated remains to be clarified but other areas of cellular stress response have to be considered apart from oxidative stress. This includes cells mechanisms in coping with an increasing amount of misfolded protein in the endoplasmic reticulum which are summarized under the term unfolded protein response. Relevance of this process in sepsis has been noted but the role of melatonin remains largely unclear. In this study we aimed to elicit the effects of melatonin on common markers of oxidative Stress and the unfolded protein response and identify possible connections. For this male C3H / HeN mice were submitted to sham operation or underwent cecal ligation and incision to induce sepsis under anesthesia. 1 mg / kg bodyweight of melatonin or vehicle solution were administered and after 5 hours the animals’ organs were removed. The concentration of superoxide in aorta, liver and spleen was measured with electron spin resonance. Protein and mRNA expression levels were determined by western blot analysis and quantitative real-time polymerase chain reaction respectively. The results indicate a rise in the superoxide concentration in liver and aorta of septic animals reversible by application of melatonin whereas already initially elevated concentrations in the spleen remained unchanged. No correlation between hepatic expression of superoxide dismutase and concentration on reactive oxygen species was seen. Melatonin did not influence the rise in expression of adhesion molecules vascular cell adhesion molecule-1 and intracellular cellular adhesion molecule-1caused by sepsis. A similar behavior of the phosphorylation of extracellular-signal regulated kinases 1 / 2 to changes in protein expression lets involvement in regulation of these adhesion molecules seem possible. An inducing effect of sepsis on the unfolded protein response in general could not be shown contrary to previous observations. The Zusammenfassung/Summary 6 heterogenicity of data might be caused by varying sepsis models and differences in examined cell lines or organs. Melatonin in this experimental set up led to activation of protein kinase ribonucleic acid-like endoplasmic reticulum kinase and the downstream CCAAT / enhancer-binding-protein homologous protein in the liver of septic mice. This signaling pathway poses a possible connection between oxidative stress and unfolded protein response by reduction in consumption of redox equivalents and involvement of endoplasmic reticulum oxidase 1. The presented study was able to gather evidence on the mediation of the protective effects of melatonin in sepsis. Further objectives for subsequent studies were generated along with factors which thereby demand special consideration

Childhood adversity and chronicity of mood disorders

To evaluate the potential impact of early childhood problems on the chronicity of mood disorders. A representative cohort from the population was prospectively studied from ages 19/20 to 39/40. Unipolar (UP) and bipolar disorders (BP) were operationally defined applying broad Zurich criteria for bipolarity. Chronicity required the presence of symptoms for more days than not over 2years prior to an interview, or almost daily occurrence for 1year. A family history and a history of childhood problems were taken at ages 27/28 and 29/30. Data include the first of multiple self-assessments with the Symptom-Checklist-90 R at age 19/20, and mastery and self-esteem assessed 1year later. A factor analysis of childhood problems yielded two factors: family problems and conduct problems. Sexual trauma, which did not load on either factor, and conduct problems were unrelated to chronicity of UP or BP or both together. In contrast, childhood family problems increased the risk of chronicity by a factor of 1.7. An anxious personality in childhood and low self-esteem and mastery in early adulthood were also associated with chronicity. Childhood family problems are strong risk factors for the chronicity of mood disorders (UP and BP). The risk may be mediated partly by anxious personality traits, poor coping and low self-estee

Linking unfounded beliefs to genetic dopamine availability

Unfounded convictions involving beliefs in the paranormal, grandiosity ideas or suspicious thoughts are endorsed at varying degrees among the general population. Here, we investigated the neurobiopsychological basis of the observed inter-individual variability in the propensity toward unfounded beliefs. One hundred two healthy individuals were genotyped for four polymorphisms in the COMT gene (rs6269, rs4633, rs4818, and rs4680, also known as val158met) that define common functional haplotypes with substantial impact on synaptic dopamine degradation, completed a questionnaire measuring unfounded beliefs, and took part in a behavioral experiment assessing perceptual inference. We found that greater dopamine availability was associated with a stronger propensity toward unfounded beliefs, and that this effect was statistically mediated by an enhanced influence of expectations on perceptual inference. Our results indicate that genetic differences in dopaminergic neurotransmission account for inter-individual differences in perceptual inference linked to the formation and maintenance of unfounded beliefs. Thus, dopamine might be critically involved in the processes underlying one's interpretation of the relationship between the self and the world

Marked Increase in Avidity of SARS-CoV-2 Antibodies 7-8 Months After Infection Is Not Diminished in Old Age

The kinetics of immunoglobulin G (IgG) avidity maturation during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection obtained from 217 participants of the Ischgl cohort, Austria, was studied 0.5-1.5 months (baseline) and 7-8 months (follow-up) after infection. The IgG avidity assay, using a modified IgG enzyme-linked immunosorbent assay (ELISA) and 5.5 M urea, revealed that old age does not diminish the increase in avidity, detected in all participants positive at both time points, from 18% to 42%. High avidity was associated with a marked residual neutralization capacity in 97.2.% of participants (211/217), which was even higher in the older age group, revealing an important role of avidity assays as easy and cheap surrogate tests for assessing the maturation of the immune system conveying potential protection against further SARS-CoV-2 infections without necessitating expensive and laborious neutralization assays

Assessing We-Disease Appraisals of Health Problems: Development and Validation of the We-Disease Questionnaire

In couples dealing with health problems, we-disease appraisals can influence dyadic coping strategies to alleviate distress. This study describes the development and validation of a self-report scale to assess we-disease appraisals of health problems. The newly developed We-Disease Questionnaire (WDQ) was administered in three samples: parents of children with type 1 diabetes (n = 240) or cancer (n = 125) and individuals with visual impairment and their partners (n = 216). Reliability was measured by coefficient omega. To assess construct validity, correlations with other measures of individual and dyadic adjustment were examined. Descriptive statistics across all samples were compared. A 4-item version of the WDQ demonstrated good reliability and validity and showed meaningful associations with established scales. We-disease appraisals were highest among parents of children with cancer and lowest among couples with visual impairment. The WDQ is a reliable and valid measure that can be used across different health problems

A narrative review on endopancreatic interventions: an innovative access to the pancreas

The natural connection between the duodenum and the pancreatic duct enables a minimally invasive access to the pancreas. Endoscopically this access is already regularly used, mainly for diagnostic and even for certain therapeutic purposes. With per-oral pancreatoscopy the endopancreatic approach allows the direct visualization of the pancreatic duct system potentially improving the diagnostic work-up of pancreatic cystic neoplasms, intrapancreatic strictures and removal of pancreatic duct stones. However, the endopancreatic access can equally be applied for surgical interventions. The objective of this review is to summarize endoscopic and surgical interventions using the endopancreatic access. Endopancreatic surgery stands for a further development of the endoscopic technique: a rigid endoscope is transabdominally introduced over the duodenum and the papilla to enable resections of strictures and inflamed tissue from inside the pancreas under visual control. While the orientation and localization of target structures using this minimally invasive approach is difficult, the development of an accurate image guidance system will play a key role for the clinical implementation and widespread use of endoscopic and surgical endopancreatic interventions

Schneditz D. Reactive hyperemia in the human liver

We tested whether hepatic blood flow is altered following central hypovolemia caused by simulated orthostatic stress. After 30 min of supine rest, hemodynamic, plasma density, and indocyanine green (ICG) clearance responses were determined during and after release of a 15-min 40 mmHg lower body negative pressure (LBNP) stimulus. Plasma density shifts and the time course of plasma ICG concentration were used to assess intravascular volume and hepatic perfusion changes. Plasma volume decreased during LBNP (Ϫ10%) as did cardiac output (Ϫ15%), whereas heart rate (ϩ14%) and peripheral resistance (ϩ17%) increased, as expected. On the basis of ICG elimination, hepatic perfusion decreased from 1.67 Ϯ 0.32 (pre-LBNP control) to 1.29 Ϯ 0.26 l/min (Ϫ22%) during LBNP. Immediately after LBNP release, we found hepatic perfusion 25% above control levels (to 2.08 Ϯ 0.48 l/min, P ϭ 0.0001). Hepatic vascular conductance after LBNP was also significantly higher than during pre-LBNP control (21.4 Ϯ 5.4 vs. 17.1 Ϯ 3.1 ml ⅐ min Ϫ1 ⅐ mmHg Ϫ1 , P Ͻ 0.0001). This indicates autoregulatory vasodilatation in response to relative ischemia during a stimulus that has cardiovascular effects similar to normal orthostasis. We present evidence for physiological post-LBNP reactive hyperemia in the human liver. Further studies are needed to quantify the intensity of this response in relation to stimulus duration and magnitude, and clarify its mechanism. hepatic; indocyanine green; orthostasis; splanchnic blood flow; autoregulation; lower body negative pressure CENTRAL HYPOVOLEMIA, AS CAUSED by blood redistribution (e.g., orthostasis) or blood loss (e.g., trauma) can be simulated by application of negative pressure to the body from the iliac crest downward (lower body "negative" pressure, LBNP), as this leads to peripheral blood pooling while avoiding additional hydrostatic effects of upright posture (14). Driven by decreased load on cardiopulmonary and eventually arterial baroreceptors, neurohumoral readjustments occur. The splanchnic vascular bed is a major regulatory target because it represents a large regional vascular conductance and constitutes the primary blood reserve in cardiovascular "emergency" situations (11) Even low (Յ20 mmHg) levels of LBNP suffice to induce sympathetic activation and reduce splanchnic perfusion (17), whereas higher stimulus levels (e.g., 50 mmHg) lower splanchnic vascular conductance as well, by as much as Ϸ30% (6, 33). Reduced perfusion has local metabolic consequences. Vascular "escape" from sympathetic influence (9, 34) and the general concept of "reactive hyperemia" (20, 31) and autoregulation (38) are well established, but hepatic reactive hyperemia as such has not yet been reported. Splanchnic ischemia is connected to hypotensive episodes especially under prolonged hypovolemic stress such as hemodialysis and ultrafiltration of excess body fluid (12, 36). We speculated whether a much shorter perturbation such as standard LBNP would also induce ischemia. We measured hepatic clearance of ICG as a surrogate for splanchnic perfusion before, during, and after LBNP and hypothesized that after LBNP-induced vasoconstriction, hepatic perfusion would not only return to but also actually exceed pre-LBNP control levels, owing to local effects of relative hypoperfusion induced metabolite accumulation that occurred during LBNP. METHODS The study was done in 14 healthy, male volunteers of moderate physical fitness, free from cardiovascular, renal, hepatic, and pulmonary diseases and not on any medication. The subjects abstained from use of tobacco, caffeine, alcohol, and heavy exercise for at least 48 h preceding each investigation and the subjects were their own controls. The Graz Medical University Research Ethics Committee approved the study protocol, and written, informed consent was obtained from each subject. Before the study, LBNP sham runs without blood sampling were carried out for familiarization to the study (24). Protocols were conducted between 9 and 12 AM to minimize circadian influences on hemodynamic variables (29). The subjects were fasting and emptied the bladder before each study. An antecubital vein was cannulated, for blood sampling and administration of ICG. Experiments were carried out in a semidark, quiet room maintained at 24°C and humidity at 55%. A padded pair of tightly connected chains was used to stabilize and maintain an exact sealing position at the exact level of the iliac crest within the LBNP box (14). The box was equipped with a footrest that was individually adjusted before LBNP was commenced. A pillow supported the head to avoid stimulation of the otolith organs, which has been reported to increase muscle sympathetic nerve activity and calf vascular resistance (21). Baseline data were collected for 30 min in the supine position, with the seal in place, before LBNP to allow for reequilibration of gravityrelated fluid shifts (16). Pressure within the box was lowered electronically by a pump within 10 s and monitored by an electronic gauge (24). LBNP (Ϫ40 mmHg) lasted for 15 min because any longer period affects LBNP tolerance (15). During LBNP the subjects were instructed to avoid movements of the lower limbs and to breathe normally. The post-LBNP observation period lasted another 15 min. The time course of the experimental protocol is shown in Blood volume and hepatic perfusion. ICG (25 mg) was injected at two times, 20 min before and 7 min into LBNP, with sufficient time between injections for ICG to be completely cleared from the blood stream. Whereas the ICG disappearance following the first injectio

Giant magnetochiral anisotropy from quantum-confined surface states of topological insulator nanowires

Wireless technology relies on the conversion of alternating electromagnetic fields into direct currents, a process known as rectification. Although rectifiers are normally based on semiconductor diodes, quantum mechanical non-reciprocal transport effects that enable a highly controllable rectification were recently discovered1,2,3,4,5,6,7,8,9. One such effect is magnetochiral anisotropy (MCA)6,7,8,9, in which the resistance of a material or a device depends on both the direction of the current flow and an applied magnetic field. However, the size of rectification possible due to MCA is usually extremely small because MCA relies on inversion symmetry breaking that leads to the manifestation of spin–orbit coupling, which is a relativistic effect6,7,8. In typical materials, the rectification coefficient γ due to MCA is usually ∣γ∣ ≲ 1 A−1 T−1 (refs. 8,9,10,11,12) and the maximum values reported so far are ∣γ∣ ≈ 100 A−1 T−1 in carbon nanotubes13 and ZrTe5 (ref. 14). Here, to overcome this limitation, we artificially break the inversion symmetry via an applied gate voltage in thin topological insulator (TI) nanowire heterostructures and theoretically predict that such a symmetry breaking can lead to a giant MCA effect. Our prediction is confirmed via experiments on thin bulk-insulating (Bi1−xSbx)2Te3 (BST) TI nanowires, in which we observe an MCA consistent with theory and ∣γ∣ ≈ 100,000 A−1 T−1, a very large MCA rectification coefficient in a normal conductor

Gadoxetic acid uptake as a molecular imaging biomarker for sorafenib resistance in patients with hepatocellular carcinoma: a post hoc analysis of the SORAMIC trial

PURPOSE Gadoxetic acid uptake on hepatobiliary phase MRI has been shown to correlate with ß-catenin mutation in patients with HCC, which is associated with resistance to certain therapies. This study aimed to evaluate the prognostic value of gadoxetic acid uptake on hepatobiliary phase MRI in patients with advanced HCC receiving sorafenib. METHODS 312 patients with available baseline hepatobiliary phase MRI images received sorafenib alone or following selective internal radiation therapy (SIRT) within SORAMIC trial. The signal intensity of index tumor and normal liver parenchyma were measured on the native and hepatobiliary phase MRI images, and relative tumor enhancement higher than relative liver enhancement were accepted as high gadoxetic acid uptake, and its prognostic value was assessed using univariate and multivariate Cox proportional hazard models. RESULTS The median OS of the study population was 13.4 (11.8-14.5) months. High gadoxetic acid uptake was seen in 51 (16.3%) patients, and none of the baseline characteristics was associated with high uptake. In univariate analysis, high gadoxetic acid uptake was significantly associated with shorter overall survival (10.7 vs. 14.0~months, p = 0.005). Multivariate analysis confirmed independent prognostic value of high gadoxetic acid uptake (HR, 1.7 1.21-2.3, p = 0.002), as well as Child-Pugh class (p = 0.033), tumor diameter (p = 0.002), and ALBI grade (p = 0.015). CONCLUSION In advanced HCC patients receiving sorafenib (alone or combined with SIRT), high gadoxetic acid uptake of the tumor on pretreatment MRI, a surrogate of ß-catenin mutation, correlates with shorter survival. Gadoxetic acid uptake status might serve in treatment decision-making process

Persistence of immunity to SARS-CoV-2 over time in the ski resort Ischgl

Background In early March 2020, a SARS-CoV-2 outbreak in the ski resort Ischgl in Austria triggered the spread of SARS-CoV-2 throughout Austria and Northern Europe. In a previous study, we found that the seroprevalence in the adult population of Ischgl had reached 45% by the end of April, representing an exceptionally high level of local seropositivity in Europe. We performed a follow-up study in Ischgl, which is the first to show persistence of immunity and protection against SARS-CoV-2 and some of its variants at a community level. Methods Of the 1259 adults that participated in the baseline study, 801 have been included in the follow-up in November 2020. The study involved the analysis of binding and neutralizing antibodies and T cell responses. In addition, the incidence of SARS-CoV-2 and its variants in Ischgl was compared to the incidence in similar municipalities in Tyrol until April 2021. Findings For the 801 individuals that participated in both studies, the seroprevalence declined from 51.4% (95% confidence interval (CI) 47.9-54.9) to 45.4% (95% CI 42.0-49.0). Median antibody concentrations dropped considerably (5.345, 95% CI 4.833 - 6.123 to 2.298, 95% CI 2.141 - 2.527) but antibody avidity increased (17.02, 95% CI 16.49 - 17.94 to 42.46, 95% CI 41.06 - 46.26). Only one person had lost detectable antibodies and T cell responses. In parallel to this persistent immunity, we observed that Ischgl was relatively spared, compared to similar municipalities, from the prominent second COVID-19 wave that hit Austria in November 2020. In addition, we used sequencing data to show that the local immunity acquired from wild-type infections also helped to curb infections from variants of SARS-CoV-2 which spread in Austria since January 2021. Interpretation The relatively high level of seroprevalence (40-45%) in Ischgl persisted and might have been associated with the observed protection of Ischgl residents against virus infection during the second COVID-19 wave as well as against variant spread in 2021. Funding Funding was provided by the government of Tyrol and the FWF Austrian Science Fund