19,761 research outputs found

    The Influence of Neuroendocrine and Genetic Markers of Stress on Cognitive Processing and Intrusive Symptoms

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    This body of research investigated the influence of neuroendocrine and genetic elements of arousal on cognitive processes in the development of intrusive memories and flash-forward intrusions as related to Post-Traumatic Stress Disorder. Specifically, this thesis investigated various mechanisms that may underlie intrusive symptoms as postulated by prevalent theories of PTSD. Study 1 examined the distinctive relationship between peritraumatic dissociation and subsequent re-experiencing symptoms. Network analyses revealed strong positive edges between peritraumatic dissociation and subsequent amnesia, as well as the re-experiencing symptoms of physical reactivity to reminders, flashbacks, intrusions, and dreams, and to a lesser extent emotional numbness and hypervigilance. The finding that peritraumatic dissociation is related to subsequent re-experiencing symptoms is consistent with cognitive models that emphasize the role of dissociative experiences during a traumatic event in the etiology of PTSD re-experiencing symptoms. Study 2 aimed to determine whether peri-traumatic stress, as measured via salivary cortisol and salivary alpha-amylase, as well as pre-existing genetic polymorphisms on the FKBP5 gene increased dissociation and data-driven processing, and subsequently impacted intrusive memories related to a trauma film. The findings revealed that greater noradrenergic arousal predicted less intrusive memory distress in individuals who scored higher on data-driven processing and trait dissociation, and in FKBP5 low-risk carriers. For individuals who reported less data-driven processing and trait dissociation, and in FKBP5 high-risk carriers, as noradrenergic arousal increased, intrusive memory distress increased. This study also showed no association between data-driven processing with memory fragmentation, and fragmentation with intrusive memories. Whilst these findings support some aspect of cognitive models of PTSD as they indicate a role for data-driven processing and dissociation in intrusive symptoms, they highlight a threshold at which these variables stop moderating the relationship between arousal and intrusive memories and suggest that memory fragmentation is not related to intrusive memories. Study 3 examined the role of cognitive control in flash-forward intrusions in the context of an enduring stressor, the COVID-19 pandemic. In line with expectations, results showed that as cognitive control worsened, FKBP5 high-risk carriers reported more flash-forward distress, and low-risk carriers reported less distress. These findings are considered in the context of hippocampal changes and are consistent with emerging theories of PTSD. Lastly, study 4 sought to investigate the role of two neurological processes, pattern separation and pattern completion in intrusive memories in individuals with PTSD compared to trauma exposed controls. Consistent with existing literature, the data indicate that individuals with PTSD reported more data-driven processing, more intrusive symptoms, and demonstrated better behavioural pattern completion than trauma-exposed controls. These findings are in line with current cognitive models of PTSD, as they again indicate a role for data-driven processing in PTSD. However, study 4 found no support for the postulate that deficient pattern separation is a feature of PTSD and found an opposite effect for the role of pattern completion. Whilst these findings are inconsistent with theory, they are in line with existing experimental studies. Overall, the findings from this thesis provide insight into cognitive and biological models of PTSD and shed light on the mechanisms underlying the nature and development of intrusive symptoms

    The macrocyclic lactone oxacyclododecindione reduces fibrosis progression

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    Background: Renal fibrosis is one of the most important triggers of chronic kidney disease (CKD), and only a very limited number of therapeutic options are available to stop fibrosis progression. As fibrosis is characterized by inflammation, myofibroblast activation, and extracellular matrix (ECM) deposition, a drug that can address all these processes might be an interesting therapeutic option.Methods: We tested in vivo in an ischemia–reperfusion (I/R) model in C57BL/6 mice and in kidney tubular epithelial cells (TEC) (HK2 cell line and primary cells) whether the natural product oxacyclododecindione (Oxa) reduces fibrosis progression in kidney disease. This was evaluated by Western blot, mRNA expression, and mass spectrometry secretome analyses, as well as by immunohistochemistry.Results: Indeed, Oxa blocked the expression of epithelial–mesenchymal transition marker proteins and reduced renal damage, immune cell infiltration, and collagen expression and deposition, both in vivo and in vitro. Remarkably, the beneficial effects of Oxa were also detected when the natural product was administered at a time point of established fibrotic changes, a situation close to the clinical situation. Initial in vitro experiments demonstrated that a synthetic Oxa derivative possesses similar features.Conclusion: Although open questions such as possible side effects need to be investigated, our results indicate that the combination of anti-inflammatory and anti-fibrotic effects of Oxa make the substance a promising candidate for a new therapeutic approach in fibrosis treatment, and thus in the prevention of kidney disease progression

    National Koala Disease Risk Analysis Report V 1.2

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    The Koala Disease Risk Analysis (KDRA) identifies the knowledge base, information gaps, risk assessments and critical control points for koala disease hazards. The national focus of the KDRA provides a clear, evidence-based assessment of koala disease which will be of value in evaluating disease risk at all regional levels and for koalas in all management situations (captive, rehabilitation and free-ranging). The KDRA is a key guiding document for actions to achieve a vision of “sustainable, resilient and healthy populations of koalas, living in positive welfare within healthy ecosystems across their range

    Self-diagnosed burnout: an examination of its definition, symptoms, and relationship with clinical depression

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    Burnout is hot topic in public discourse, with members of the general public quick to self-diagnose as suffering from the syndrome. However, there is a lack of consensus among scientists and practitioners as to how burnout should best be conceptualised and whether/how it should be diagnosed. This thesis reports five studies examining self-diagnosed burnout and how it should best be defined, measured and distinguished from clinical depression. The literature review presented in Part I critiques the currently promulgated three-factor conceptualisation of burnout and highlights the inconclusive research findings regarding burnout’s overlap with depression. Part II contains three studies designed to re-define the burnout syndrome. In Study 1, qualitative and quantitative analyses were used to identify key syndromal features of self-diagnosed burnout. In Study 2, a series of bifactor analyses was undertaken to derive a new definitional model and preliminary measure of the syndrome. In Study 3, mixture modelling was used to examine whether the new burnout definition was best modelled dimensionally or categorically. The results of Part II indicated that burnout as experienced by the general population is characterised by several symptoms beyond the traditional triadic symptom model, and that categorical differences in burnout may exist between those with and without a history of mental illness. Part III contains two studies undertaken to evaluate the degree of overlap between burnout and depression. Study 4 assessed for qualitative differences between burnout and depression experienced by participants who reported having experienced both states. Study 5 compared participants with self-diagnosed burnout to participants with clinically-diagnosed depression across several symptom and causal variables. The results of Part III indicated that the new definitional burnout model derived in Part II showed poor differentiation overall between burnout and depression, but that several other phenomenological, symptom and causal differences are likely to exist between the two states. The results of Study 5 also suggested that burnout overlaps more with non-melancholic than melancholic depression. When taken together, as discussed in Part IV, the studies in this thesis extend knowledge of how self-diagnosed burnout should be defined and illuminate how burnout both converges with and diverges from clinical depression

    Pathogenic mechanism of paclitaxel coated balloons and protective effects of dexamethasone

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    Cardiovascular disease (CVD) is the world’s first leading cause of death contributing to 18.8 million global deaths worldwide. Lower extremity peripheral artery disease (PAD) stems from CVD and is the third leading cause of atherosclerotic morbidity. The prevalence of PAD increases significantly with age, and complications can lead to ischemia, non-healing wounds, gangrene, and amputation. Percutaneous transluminal angioplasty (PTA) and stenting are the mainstream techniques used to treat severe PAD. Due to high risk of restenosis within 12 months of the procedure, drug-coated balloons (DCB) and drug eluting-stents (DES) have become the standard of care since the early 2000s. Paclitaxel (PTX) is an extremely potent anti-restenotic agent used to coat balloons and stents to inhibit the assembly of microtubules, thereby inhibiting cell division. A recent systemic review and meta-analysis examined the all-cause of death rates at 1-year, 2-year, and 5-years of PCB and PES in the femoral and/or popliteal arteries versus control. The authors demonstrated a significantly increased risk of death in the PTX arm, which resulted in a warning from the FDA and a halt in the use of PTX devices. The massive release of PTX following balloon or stent application on the vessel wall and into systemic circulation may attribute to delayed systemic toxicity. Dexamethasone (DEX) is a glucocorticoid what may serve as an alternative anti-restenotic agent. In this study, we examined PTX induced toxicity in endothelial cells using cell biological assays and migration assay. This study showed that PTX significantly reduced EC survival, proliferation, and migration. DEX was able to partially rescue the EC functions but was unable to abrogate PTX-induced inhibition of EC migration. RNA sequencing was used to examine differentially expressed genes modulated by PTX and DEX. Protein expression of MCP-1, CKS-2, CD137, and BMF were analyzed with western blots and found that DEX was able to abrogate the PTX induced effects. Overall, this study was the first to examine the potential mechanism(s) of PTX induced systemic toxicity in CVD and may serve as a stepping stone for future investigations to abrogate the adverse effects of PTX mediated devices

    Liver-dependent lung remodeling during systemic inflammation alters responses to secondary infection

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    Systemic duress, like that elicited by sepsis, burns or trauma, predisposes patients to secondary pneumonia, demanding better understanding of host pathways influencing this deleterious connection. These pre-existing circumstances are capable of triggering the hepatic acute phase response (APR), which is essential for limiting susceptibility to secondary lung infections. To identify potential mechanisms underlying protection afforded by the lung-liver axis, our studies aimed to evaluate liver-dependent lung reprogramming when a systemic inflammatory challenge precedes pneumonia. WT mice and APR-deficient littermates lacking hepatocyte STAT3 (hepSTAT3-/-), a transcription factor necessary for full APR initiation, were challenged intraperitoneally with LPS to induce endotoxemia. After 18h, pneumonia was induced by intratracheal E. coli instillation. Endotoxemia alone elicited significant transcriptional alterations in the lungs of WT and hepSTAT3-/- mice as determined by bulk RNAseq, with nearly 2,000 differentially expressed genes between genotypes. The gene signatures revealed exaggerated immune activity in the lungs of hepSTAT3-/- mice, which were compromised in their capacity to launch additional cytokine responses to secondary infection. A separate study performed with single-cell RNASeq revealed a wide range of affected lung cells in hepSTAT3-/- mice, with macrophages/monocytes, neutrophils, fibroblasts, epithelial cells, and endothelial cells all exhibiting remodeled transcriptomes in the absence of an intact liver response. Proteomics revealed substantial liver-dependent modifications in the airspaces of pneumonic mice, implicating a network of dispatched liver-derived mediators influencing lung homeostasis. Coagulation proteins, including several acute phase proteins, were prevalent among these mediators, implying a dysregulation of this immune pathway despite no detectable change in blood clotting capacity in our initial studies. These results indicate that following systemic inflammation, liver acute phase changes dramatically remodel the lungs, resulting in a modified landscape for any stimuli encountered thereafter. Based on the established vulnerability of hepSTAT3-/- mice to secondary lung infections, we believe that intact liver function is critical for maintaining the immunological responsiveness of the lungs

    The association between stress, emotional states, and tinnitus: a mini-review

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    Extensive literature supporting the view of tinnitus induced stress in patients is available. However, limited evidence has been produced studying the opposite, that is, does stress cause tinnitus? The hypothalamus pituitary adrenal axis, one of the main neuroendocrine systems involved in stress response, is commonly disturbed in tinnitus patients. Patients with chronic tinnitus have been shown to develop abnormal responses to psycho-social stress, where the hypothalamus pituitary adrenal axis response is weaker and delayed, suggesting chronic stress contributes to the development of chronic tinnitus. The sympathetic branch of the autonomic nervous system also plays a major role in stress response and its chronic hyperactivity seems to be involved in developing tinnitus. Psycho-social stress has been shown to share the same probability of developing tinnitus as occupational noise and contributes to worsening tinnitus. Additionally, exposure to high stress levels and occupational noise doubles the likelihood of developing tinnitus. Interestingly, short-term stress has been shown to protect the cochlea in animals, but chronic stress exposure has negative consequences. Emotional stress also worsens pre-existing tinnitus and is identified as an important indicator of tinnitus severity. Although there is limited body of literature, stress does seem to play a vital role in the development of tinnitus. This review aims to highlight the association between stress, emotional states, and the development of tinnitus while also addressing the neural and hormonal pathways involved
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