Utveckling av lymfocytär thyreodit hos hund med fokus på immunologiska mekanismer

Lymfocytär thyreodit är en av de vanligaste endokrina sjukdomarna hos hund och uppkommer på grund av en autoimmun reaktion mot thyroidea. Det resulterar i att körteln bryts ned och nivåerna av thyroideahormoner i kroppen minskar. Detta får i värsta fall fatala konsekvenser för djuret då thyroideahormonerna påverkar många av kroppens organsystem. Dock är den exakta patogenesen bakom sjukdomsutvecklingen okänd men karaktäriseras av både ett cellulärt och humoralt immunsvar. Framförallt autoreaktiva T-hjälparceller samt cytotoxiska Tlymfocyter bidrar till den cellulära nedbrytningen och den humorala immunresponsen utgörs utav autoantikroppar riktade mot thyroglobulin, thyroideahormonerna och thyroperoxidas. Dessutom finns spekulationer om att regulatoriska T-celler (Tregs) hos sjuka individer är nedreglerade vilket ger en nedsatt perifer immunosuppression. På grund av den multifaktoriella och komplexa bakgrunden till sjukdomsutvecklingen syftar denna litteraturstudie till att försöka sammanfatta de olika immunologiska mekanismerna som ger upphov till lymfocytär thyreodit hos hund. Immunresponsen vid lymfocytär thyreodit verkar främst vara ett cellmedierat immunsvar som karaktäriseras av en ökad mängd cytotoxiska T-lymfocyter och en ökad mängd cytokiner från T-hjälparceller typ 1. Polymorfier i cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), som uttrycks på cellytan på både aktiverade T-lymfocyter och regulatoriska T-celler, förefaller spela en stor roll vid lymfocytär thyreodit. CTLA-4 verkar i normala fall nedreglerande på immunsvaret vilket gör att defekter i molekylens struktur eller regleringen av dess uttryck kan påverka utvecklingen av autoimmuna tillstånd. Det medför att Tregs immunosuppressiva förmåga minskar men också till att autoreaktiva T-hjälparceller inte hämmas. Vidare verkar även dog leukocyte antigen (DLA) klass II på antigenpresenterande celler vara inblandad eftersom antigen som presenteras på denna molekyl kan initiera ett immunsvar. Detta gör att defekter i DLA som tillåter att autoantigen plockas upp och presenteras på DLA II kan leda till en autoimmun reaktion mot autoantigenet, vilket vid lymfocytär thyreodit är peptider producerade i thyroidea. Utöver det påträffas även autoantikroppar ofta vid sjukdomstillståndet. Autoantikroppar riktade mot thyroglobulin är vanligast och tros uppkomma genom att vissa predisponerade hundar har thyroglobulin med en annorlunda molekylstruktur som gör att immunförsvaret reagerar på det. Autoantikropparna tycks verka framförallt via antibody-dependent cell-mediated cytotoxicity (ADCC). Ytterligare mekanismer som tros vara inblandade i sjukdomsutvecklingen är andra faktorer som leder till nedreglering av regulatoriska T-celler. En sådan komponent är plastiska regulatoriska T-celler som får T-hjälparcell typ 1-egenskaper och på det viset förlorar en del av sin immunosuppressiva förmåga. En annan möjlig mekanism är epigenetiska modifieringar i FoxP3-genen. FoxP3 är kopplat till T-cellsreceptorsignalering och vissa modifieringar tros påverka den regulatoriska T-cellens immunosuppressiva funktion.Lymphocytic thyroiditis is one of the most common endocrine disorders in dogs and arises from an autoimmune response against the thyroid. This results in the gland being degraded and the levels of thyroid hormones in the body decreasing. In the worst case, this will have fatal consequences for the animal as the thyroid hormones affect many of the organ systems in the body. However, the pathogenesis behind the development of the disease is unknown but it is characterized by a cellular and humoral immune response. The cellular immune response mainly consists of autoreactive T-helper cells as well as cytotoxic T-lymphocytes and the humoral immune response consists of autoantibodies against thyroglobulin, thyroid hormones and thyroperoxidase. In addition, there are speculations that regulatory T cells in diseased animals are down-regulated, which results in decreased peripheral immune suppression (tolerance). Due to the multifactorial background to the pathogenesis, this literature study aims to summarize the various immunological mechanisms that may lead to lymphocytic thyroiditis in dogs. The immune response in lymphocytic thyroiditis appears to be primarily cell-mediated characterized by an increased number of cytotoxic T-lymphocytes and by T-helper type 1 cytokines. Polymorphisms in the cytotoxic T-lymphocyte antigen-4, which is expressed on the cell surface of both activated T-lymphocytes and regulatory T-cells, appear to play a major role in lymphocytic thyroiditis. Cytotoxic T-lymphocyte antigen-4 functions to down-regulate the immune response and defects in its molecular structure or its upregulation can be a primal cause for the development of autoimmune conditions. Such defects would reduce the immunosuppressive capacity of regulatory T cells, but also prevent inhibition of autoreactive T-helper cells. Likewise, dog leukocyte antigen class II on antigen presenting cells is also likely to be involved since antigen presented on this molecule may initiate an immune response. Defects in dog leukocyte antigen that would allow autoantigen to be picked up could possibly lead to an autoimmune response against the autoantigen, which in lymphocytic thyroiditis are molecules of the thyroid. In addition, autoantibodies also occur frequently within the disease. Autoantibodies directed against thyroglobulin are most common. Their formation is believed to originate from thyroglobulin with an abnormal molecule structure in some predisposed dogs, which causes the immune system to react against it. The autoantibodies seem to work primarily through antibodydependent cell-mediated cytotoxicity. Additional mechanisms hypothesized to be involved in the development of lymphocytic thyroiditis are other factors that cause down-regulation of regulatory T cells. One such factor is plastic regulatory T cells that receive properties of type 1 T-helper cells and thus lose some of their immunosuppressive ability. Another possible mechanism is epigenetic modifications in the FoxP3 gene. FoxP3 is linked to T-cell receptor signaling and some modifications are believed to affect the immunosuppressive function in regulatory T-cells

Sensitivity to Angular and Radial Source Movements as a Function of Acoustic Complexity in Normal and Impaired Hearing

In contrast to static sounds, spatially dynamic sounds have received little attention in psychoacoustic research so far. This holds true especially for acoustically complex (reverberant, multisource) conditions and impaired hearing. The current study therefore investigated the influence of reverberation and the number of concurrent sound sources on source movement detection in young normal-hearing (YNH) and elderly hearing-impaired (EHI) listeners. A listening environment based on natural environmental sounds was simulated using virtual acoustics and rendered over headphones. Both near-far (‘radial’) and left-right (‘angular’) movements of a frontal target source were considered. The acoustic complexity was varied by adding static lateral distractor sound sources as well as reverberation. Acoustic analyses confirmed the expected changes in stimulus features that are thought to underlie radial and angular source movements under anechoic conditions and suggested a special role of monaural spectral changes under reverberant conditions. Analyses of the detection thresholds showed that, with the exception of the single-source scenarios, the EHI group was less sensitive to source movements than the YNH group, despite adequate stimulus audibility. Adding static sound sources clearly impaired the detectability of angular source movements for the EHI (but not the YNH) group. Reverberation, on the other hand, clearly impaired radial source movement detection for the EHI (but not the YNH) listeners. These results illustrate the feasibility of studying factors related to auditory movement perception with the help of the developed test setup

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Pressure study on the interplay between magnetic order and valence-change crossover in EuPd2_2(Si1−x_{1-x}Gex_x)2_2

We present results of the magnetic susceptibility on high-quality single crystals of EuPd$_2$(Si$_{1-x}$Ge$_x$)$_2$ for Ge concentrations 0 $\leq x \leq$ 0.105 performed under varying hydrostatic (He-gas) pressure 0 $\leq p \leq$ 0.5 GPa. The work extends on recent studies at ambient pressure demonstrating the drastic change in the magnetic response from valence-change-crossover behavior for $x$ = 0 and 0.058, to long-range antiferromagnetic (afm) order below $T_{\text{N}}$ = 47 K for $x$ = 0.105. The valence-change-crossover temperature $T'_{\text{V}}$ shows an extraordinarily strong pressure dependence of d$T'_{\text{V}}$/d$p$ = +(80 $\pm$ 10) K/GPa. In contrast, a very small pressure dependence of d$T_{\text{N}}$/d$p \leq$ +(1 $\pm$ 0.5) K/GPa is found for the afm order upon pressurizing the $x$ = 0.105 crystal from $p$ = 0 to 0.05 GPa. Remarkably, by further increasing the pressure to 0.1 GPa, a drastic change in the ground state from afm order to valence-change-crossover behavior is observed. Estimates of the electronic entropy, derived from analyzing susceptibility data at varying pressures, indicate that the boundary between afm order and valence-change crossover represents a first-order phase transition. Our results suggest a particular type of second-order critical endpoint of the first-order transition for $x$ = 0.105 at $p_{\text{cr}} \approx$ 0.06 GPa and $T_{\text{cr}} \approx$ 45 K where intriguing strong-coupling effects between fluctuating charge-, spin- and lattice degrees of freedom can be expected

Kontinentale spændinger - matematiske modeller leverer ny viden

Indtil nu har geologer antaget, at hævningsfaserne i de sedimentære bassiner var ledsaget af en samtidig øget tektonisk aktivitet ved pladeranden, men nye computersimulationer har nu vist, at bassinerne også hæves, når den tektoniske aktivitet er på retur

FFAR4 (GPR120) signaling is not required for anti-inflammatory and insulin-sensitizing effects of omega-3 fatty acids

Free fatty acid receptor-4 (FFAR4), also known as GPR120, has been reported to mediate the beneficial effects of omega-3 polyunsaturated fatty acids (ω3-PUFAs) by inducing an anti-inflammatory immune response. Thus, activation of FFAR4 has been reported to ameliorate chronic low-grade inflammation and insulin resistance accompanying obesity. However, conflicting reports on the role of FFAR4 in mediating the effects of ω3-PUFAs are emerging, suggesting that FFAR4 may not be the sole effector. Hence analyses of the importance of this receptor in relation to other signaling pathways and prominent effects of ω3-PUFAs remain to be elucidated. In the present study, we used Ffar4 knockouts (KO) and heterozygous (HET) mice fed either low fat, low sucrose reference diet; high fat, high sucrose ω3-PUFA; or high fat, high sucrose ω6-PUFA diet for 36 weeks. We demonstrate that both KO and HET mice fed ω3-PUFAs were protected against obesity, hepatic triacylglycerol accumulation, and whole-body insulin resistance. Moreover, ω3-PUFA fed mice had increased circulating protein levels of the anti-inflammatory adipokine, adiponectin, decreased fasting insulin levels, and decreased mRNA expression of several proinflammatory molecules within visceral adipose tissue. In conclusion, we find that FFAR4 signaling is not required for the reported anti-inflammatory and insulin-sensitizing effects mediated by ω3-PUFAs

Interactions between metabolic, reward and cognitive processes in appetite control:Implications for novel weight management therapies

Traditional models of appetite control have emphasised the role of parallel homeostatic and hedonic systems, but more recently the distinction between independent homeostatic and hedonic systems has been abandoned in favour of a framework that emphasises the cross talk between the neurochemical substrates of the two systems. In addition, evidence has emerged more recently, that higher level cognitive functions such as learning, memory and attention play an important role in everyday appetite control and that homeostatic signals also play a role in cognition. Here, we review this evidence and present a comprehensive model of the control of appetite that integrates cognitive, homeostatic and reward mechanisms. We discuss the implications of this model for understanding the factors that may contribute to disordered patterns of eating and suggest opportunities for developing more effective treatment approaches for eating disorders and weight management