High mobility group box 1 and a network of other biomolecules influence fatigue in patients with Crohn’s disease

Background Fatigue is common in patients with chronic inflammatory and autoimmune diseases, often with a severe impact on the patient’s daily life. From a biological point of view, fatigue can be regarded as an element of the sickness behavior response, a coordinated set of responses induced by pathogens to enhance survival during an infection and immunological danger. The mechanisms are not fully understood but involve activation of the innate immune system, with pro-inflammatory cytokines, in particular interleukin (IL)-1β, acting on cerebral neurons. These mechanisms are also active during chronic inflammatory conditions. High mobility group box 1 (HMGB1) protein has interleukin-1 like properties and is a strong inducer of innate immune responses. Its role in generation of fatigue is not clarified. Emerging evidence indicates that also other biomolecules may influence sickness behavior. We aimed to elucidate how HMGB1 influences fatigue in patients with Crohn’s disease, and how the protein interacts with other candidate biomarkers of fatigue. Methods In 56 patients with newly diagnosed Crohn’s disease, fatigue was evaluated using three different fatigue instruments: the fatigue visual analog scale (fVAS), Fatigue Severity Scale (FSS), and the vitality subscale of Medical Outcomes Study Short-Form Health Survey (SF-36vs). The biochemical markers IL-1 receptor antagonist (RA), soluble IL-1 receptor type 2 (sIL-RII), heat shock protein 90 alpha (HSP90α), HMGB1, anti-fully reduced (fr)HMGB1 antibodies (abs), hemopexin (HPX), and pigment epithelium-derived factor (PEDF) were measured in plasma. Multivariable regression and principal component analyses (PCA) were applied. Results Multivariable regression analyses revealed significant contributions to fatigue severity for HMGB1 in the FSS model, HSP90α in the fVAS model and IL-1RA in the SF-36vs model. Depression and pain scores contributed to all three models. In PCA, two components described 53.3% of the variation. The “inflammation and cellular stress dimension” was dominated by IL-1RA, sIL-1RII, HSP90α, HPX, and PEDF scores, where the “HMGB1 dimension” was dominated by HMGB1, anti-frHMGB1 abs, and fVAS scores. Conclusion This study supports the hypothesis that HMGB1 and a network of other biomolecules influence fatigue severity in chronic inflammatory conditions. The well-known association with depression and pain is also acknowledged.publishedVersio

Interleukin-1-related activity and hypocretin-1 in cerebrospinal fluid contribute to fatigue in primary Sjögren’s syndrome

Background Fatigue is a common and sometimes debilitating phenomenon in primary Sjögren’s syndrome (pSS) and other chronic inflammatory diseases. We aimed to investigate how IL-1 β-related molecules and the neuropeptide hypocretin-1 (Hcrt1), a regulator of wakefulness, influence fatigue. Methods Hcrt1 was measured by radioimmunoassay (RIA) in cerebrospinal fluid (CSF) from 49 patients with pSS. Interleukin-1 receptor antagonist (IL-1Ra), IL-1 receptor type 2 (IL-1RII), IL-6, and S100B protein were measured by enzyme-linked immunosorbent assay (ELISA). Fatigue was rated by the fatigue visual analog scale (fVAS). Results Simple univariate regression and multiple regression analyses with fatigue as a dependent variable revealed that depression, pain, and the biochemical variable IL-1Ra had a significant association with fatigue. In PCA, two significant components were revealed. The first component (PC1) was dominated by variables related to IL-1β activity (IL-1Ra, IL-1RII, and S100B). PC2 showed a negative association between IL-6 and Hcrt1. fVAS was then introduced as an additional variable. This new model demonstrated that fatigue had a higher association with the IL-1β-related PC1 than to PC2. Additionally, a third component (PC3) became significant between low Hcrt1 concentrations and fVAS scores. Conclusions The main findings of this study indicate a functional network in which several IL-1β-related molecules in CSF influence fatigue in addition to the classical clinical factors of depression and pain. The neuropeptide Hcrt1 seems to participate in fatigue generation, but likely not through the IL-1 pathway.publishedVersio

Assessment of risks to wildlife and animal welfare associated with Lodden, Sami traditional hunting of ducks in spring

Source at https://vkm.no/.Spring hunting for ducks (Lodden in Northern Sami) is part of the Sami hunting and trapping culture. In Norway, this traditional hunting has been permitted in Kautokeino Municipality in accordance with the exception provision in the Wildlife Act Section 15, with quotas for males of several duck species. However, hunting in the spring may be in conflict with the Nature Diversity Act's principle for species management, saying (quote from Section 15): “Unnecessary harm and suffering caused to animals occurring in the wild and their nests, lairs and burrows shall be avoided. Likewise, unnecessary pursuing of wildlife shall be avoided.” Furthermore, in accordance with international legislation and agreements, the Wildlife Act (Section 9) states that the hunting season should not be set to the nesting and breeding season for the species in question. The Norwegian Environment Agency (NEA) asked VKM to (1) assess risk and risk-reducing measures on biodiversity and animal welfare when conducting spring hunting of ducks. The terms of reference were additionally clarified by the NEA to include assessments of the risks associated with hunting quotas of up to 150, 300, and 500 male individuals, on the populations of mallard (Anas platyrhynchos), tufted duck (Aythya fuligula), velvet scoter (Melanitta fusca), common scoter (Melanitta nigra), long-tailed duck (Clangula hyemalis), and red-breasted merganser (Mergus serrator). VKM was furthermore asked to (2) point out risk-reducing measures in scenarios with hunting bags corresponding to the mentioned quotas of all the six species. VKM, risk assessment, Norwegian Scientific Committee for Food and Environment, Norwegian Environment Agency, mallard (Anas platyrhynchos), tufted duck (Aythya fuligula), velvet scoter (Melanitta fusca), common scoter (Melanitta nigra), long-tailed duck (Clangula hyemalis), red-breasted merganser (Mergus serrator), spring hunting, LoddenpublishedVersio

Assessment of risks to wildlife and animal welfare associated with Lodden, Sami traditional hunting of ducks in spring

Spring hunting for ducks (Lodden in Northern Sami) is part of the Sami hunting and trapping culture. In Norway, this traditional hunting has been permitted in Kautokeino Municipality in accordance with the exception provision in the Wildlife Act Section 15, with quotas for males of several duck species. However, hunting in the spring may be in conflict with the Nature Diversity Act's principle for species management, saying (quote from Section 15): “Unnecessary harm and suffering caused to animals occurring in the wild and their nests, lairs and burrows shall be avoided. Likewise, unnecessary pursuing of wildlife shall be avoided.” Furthermore, in accordance with international legislation and agreements, the Wildlife Act (Section 9) states that the hunting season should not be set to the nesting and breeding season for the species in question. The Norwegian Environment Agency (NEA) asked VKM to (1) assess risk and risk-reducing measures on biodiversity and animal welfare when conducting spring hunting of ducks. The terms of reference were additionally clarified by the NEA to include assessments of the risks associated with hunting quotas of up to 150, 300, and 500 male individuals, on the populations of mallard (Anas platyrhynchos), tufted duck (Aythya fuligula), velvet scoter (Melanitta fusca), common scoter (Melanitta nigra), long-tailed duck (Clangula hyemalis), and red-breasted merganser (Mergus serrator). VKM was furthermore asked to (2) point out risk-reducing measures in scenarios with hunting bags corresponding to the mentioned quotas of all the six species. VKM, risk assessment, Norwegian Scientific Committee for Food and Environment, Norwegian Environment Agency, mallard (Anas platyrhynchos), tufted duck (Aythya fuligula), velvet scoter (Melanitta fusca), common scoter (Melanitta nigra), long-tailed duck (Clangula hyemalis), red-breasted merganser (Mergus serrator), spring hunting, LoddenpublishedVersio

Assessment of risks to wildlife and animal welfare associated with Lodden, Sami traditional hunting of ducks in spring - Scientific Opinion of the Panel on Biodiversity of the Norwegian Scientific Committee for Food and Environment

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Variant -and individual dependent nature of persistent Anaplasma phagocytophilum infection

<p>Abstract</p> <p>Background</p> <p><it>Anaplasma phagocytophilum </it>is the causative agent of tick-borne fever in ruminants and human granulocytotropic anaplasmosis (HGA). The bacterium is able to survive for several months in immune-competent sheep by modifying important cellular and humoral defence mechanisms. Little is known about how different strains of <it>A. phagocytophilum </it>propagate in their natural hosts during persistent infection.</p> <p>Methods</p> <p>Two groups of five lambs were infected with each of two <it>16S </it>rRNA gene variants of <it>A. phagocytophilum</it>, i.e. <it>16S </it>variant 1 which is identical to GenBank no <ext-link ext-link-id="M73220" ext-link-type="gen">M73220</ext-link> and <it>16S </it>variant 2 which is identical to GenBank no <ext-link ext-link-id="AF336220" ext-link-type="gen">AF336220</ext-link>, respectively. The lambs were infected intravenously and followed by blood sampling for six months. <it>A. phagocytophilum </it>infection in the peripheral blood was detected by absolute quantitative real-time PCR.</p> <p>Results</p> <p>Both <it>16S </it>rRNA gene variants of <it>A. phagocytophilum </it>established persistent infection for at least six months and showed cyclic bacteraemias, but variant 1 introduced more frequent periods of bacteraemia and higher number of organisms than <it>16S </it>rRNA gene variant 2 in the peripheral blood.</p> <p>Conclusion</p> <p>Organisms were available from blood more or less constantly during the persistent infection and there were individual differences in cyclic activity of <it>A. phagocytophilum </it>in the infected animals. Two <it>16S </it>rRNA gene variants of <it>A. phagocytophilum </it>show differences in cyclic activity during persistent infection in lambs.</p

Expression of selected genes isolated from whole blood, liver and obex in lambs with experimental classical scrapie and healthy controls, showing a systemic innate immune response at the clinical end-stage

Abstract Background Incubation period, disease progression, pathology and clinical presentation of classical scrapie in sheep are highly dependent on PRNP genotype, time and route of inoculation and prion strain. Our experimental model with pre-colostrum inoculation of homozygous VRQ lambs has shown to be an effective model with extensive PrPSc dissemination in lymphatic tissue and a short incubation period with severe clinical disease. Serum protein analysis has shown an elevation of acute phase proteins in the clinical stages of this experimental model, and here, we investigate changes in gene expression in whole blood, liver and brain. Results The animals in the scrapie group showed severe signs of illness 22 weeks post inoculation necessitating euthanasia at 23 weeks post inoculation. This severe clinical presentation was accompanied by changes in expression of several genes. The following genes were differentially expressed in whole blood: TLR2, TLR4, C3, IL1B, LF and SAA, in liver tissue, the following genes differentially expressed: TNF-α, SAA, HP, CP, AAT, TTR and TF, and in the brain tissue, the following genes were differentially expressed: HP, CP, ALB and TTR. Conclusions We report a strong and evident transcriptional innate immune response in the terminal stage of classical scrapie in these animals. The PRNP genotype and time of inoculation are believed to contribute to the clinical presentation, including the extensive dissemination of PrPSc throughout the lymphatic tissue

Interleukin-1β, heat shock protein 90α, and hypocretin-1 in chronic fatigue

Background: Fatigue, defined as an overwhelming sense of tiredness, lack of energy, and feeling of exhaustion, is a phenomenon many people have experienced in connection with infections such as influenza, Epstein-Barr virus, etc. Fatigue is also common in cancer, neurological conditions like multiple sclerosis, Parkinson’s disease, and in chronic inflammatory and autoimmune diseases such as rheumatoid arthritis, psoriasis, and others. “Sickness behavior” observed in animals is a conceptual model for understanding fatigue. In this model, infection or tissue damage is followed by behavioral changes like social withdrawal, inactivity, sleepiness, fatigue, and reduced food and water intake. The proinflammatory cytokine interleukin (IL)-1β produced during activation of innate immune cells has a prominent role in mediating this behavior. IL-1β crosses the blood-brain barrier and in the brain IL-1β amplifies its own signaling by inducing microglia to produce IL-1β. In cerebral neurons IL-1β signals through a receptor complex including interleukin-1 receptor I (IL-1RI) and an alternative IL-1 receptor accessory protein that does not mediate inflammation but induce neuronal activation and sickness behavior. The inflammatory response needs to be controlled and is therefore downregulated in a timely manner not to run rampant. In addition, cellular protection mechanisms are activated during inflammation and tissue damage to preserve cellular life from reactive molecules that kill pathogens. Some variants of heat shock proteins (HSPs) released into the extracellular space could represent a defense mechanism of cellular life that also influence fatigue mechanisms. In addition, sleepiness and weariness are closely related to fatigue and part of the sickness behavior response. Inflammation can alter sleep patterns. The master regulator of sleep- and wakefulness, neuropeptide hypocretin-1 (Hcrt1), could therefore have a role in fatigue generation. Objectives: I) Investigate if mechanisms that protect cellular life and homeostasis are involved in the generation of fatigue. II) Develop a non-radioactive, sensitive and selective method for measurement of Hcrt1 in cerebrospinal fluid (CSF). III) Explore how IL-1β and other selected molecules interact in generation of fatigue, and to investigate a possible link between the neuropeptide Hcrt1 and fatigue. Methods: To explore mechanism of fatigue, a cohort of 71 patients with primary Sjögren’s syndrome were investigated. CSF samples where available from 49 patients. A method based on liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was developed for measurements of Hcrt1. Hcrt1 was measured in CSF samples from 22 healthy subjects and 9 patients with narcolepsy type 1. The clinical variables fatigue, depression and pain were scored using the fatigue Visual Analogue Scale (fVAS), Beck Depression Inventory, and the pain item of the Medical Outcome Survey short form 36, respectively. ELISAs were used to measure HSP32, -60, -72, and -90α in plasma, and in CSF to measure concentrations of IL-1Ra, IL-1RII, IL-6, and the calcium binding protein S100B. Hcrt1 in CSF was measured using a radioimmunoassay (RIA) method, in addition to a non-radioactive method based on liquid chromatography coupled with tandem mass spectrometry. Results were analyzed by non-parametric group comparisons, logistic regression, univariate- and multiple regression, and principal component analysis (PCA). Results: Measures of HSP32, -60, -72, and -90α in plasma revealed that the concentrations of HSP90α were significantly higher in pSS patients with high fatigue versus low fatigue. A tendency toward higher concentrations of HSP72 was observed in patients with high fatigue compared to patients with low fatigue. The LC-MS/MS method for Hcrt1 in CSF revealed much lower concentrations in healthy subjects than what has previously been published. Patients with narcolepsy type 1, a sleep disorder characterized by low levels of Hcrt1 in CSF, also had lower levels of Hcrt1 in CSF compared to previous published studies. The LC-MS/MS method was compared to the commonly used RIA method. A Bland-Altman plot showed agreement between the two methods. Analysis of IL-1β related proteins (IL-1Ra, IL-1RII, and S100B), IL-6, and Hcrt1 in CSF demonstrated that IL-1Ra showed significant association with fVAS scores together with the clinical variables BDI scores and pain scores. The relationship of the biochemical variables was explored in PCA, and two significant components appeared: Variables related to IL-1β activity dominated the first component while in the second component there was a negative association between IL-6 and Hcrt1. Fatigue was introduced as an additional variable in a second model. In this PCA, fVAS scores were associated with the first component as was the IL-1β related variables. In addition, the second PCA model revealed a third component that showed a negative relationship between Hcrt1 and fatigue. Conclusions: I) HSP90α and to a lesser degree HSP72 in blood may possibly be parts of a fatigue inducing mechanism. II) The LC-MS/MS method with high selectivity and accuracy revealed considerably lower levels of Hcrt1 in CSF than previously reported. III) IL-1β signaling is a primary driver in fatigue. Several other proteins and molecules interact with IL-1β in a complex network, in which several cell types (neurons, microglia, and astrocytes) probably participate. IV) Hcrt1 also influences fatigue, but probably through another pathway than the IL-1 route

Presence of an acute phase response in sheep with clinical classical scrapie

<p>Abstract</p> <p>Background</p> <p>Work with experimental scrapie in sheep has been performed on-site for many years including studies on PrP^Sc dissemination and histopathology of organs and tissues both at preclinical and clinical stages. In this work serum was sampled at regular intervals from lambs which were infected immediately after birth and from parallel healthy controls, and examined for acute phase proteins. In contrast to earlier experiments, which extensively studied PrP^Sc dissemination and histopathology in peripheral tissues and brain, this experiment is focusing on examination of serum for non-PrP^Sc markers that discriminates the two groups, and give insight into other on-going processes detectable in serum samples.</p> <p>Results</p> <p>There was clear evidence of an acute phase response in sheep with clinical scrapie, both experimental and natural. All the three proteins, ceruloplasmin, haptoglobin and serum amyloid A, were increased at the clinical stage of scrapie.</p> <p>Conclusion</p> <p>There was evidence of a systemic measurable acute phase response at the clinical terminal end-stage of classical scrapie.</p