Long term impact of systemic bacterial infection on the cerebral vasculature and microglia

Background: Systemic infection leads to generation of inflammatory mediators that result in metabolic and behavioural changes. Repeated or chronic systemic inflammation leads to a state of innate immune tolerance: a protective mechanism against over-activity of the immune system. In this study we investigated the immune adaptation of microglia and brain vascular endothelial cells in response to systemic inflammation or bacterial infection. Methods: Mice were given repeated doses of lipopolysaccharide (LPS) or a single injection of live Salmonella typhimurium. Inflammatory cytokines were measured in serum, spleen and brain, and microglial phenotype studied by immunohistochemistry.mice were infected with Salmonella typhimurium and subsequently challenged with a focal unilateral, intracerebral injection of LPS. Results: Repeated systemic LPS challenges resulted in increased brain IL-1?, TNF? and IL-12 levels, despite attenuated systemic cytokine production. Each LPS challenge induced significant changes in burrowing behaviour. In contrast, brain IL-1? and IL-12 levels in Salmonella typhimurium infected mice increased over three weeks, with high interferon-? levels in the circulation. Behavioural changes were only observed during the acute phase of the infection. Microglia and cerebral vasculature display an activated phenotype, and focal intracerebral injection of LPS 4 weeks after infection results in an exaggerated local inflammatory response when compared to non-infected mice. Conclusions: These studies reveal that the innate immune cells in the brain do not become tolerant to systemic infection, but are primed instead. This may lead to prolonged and damaging cytokine production that may have aprofound effect on the onset and/ or progression of pre-existing neurodegenerative disease.Humans and animals are regularly exposed to bacterial and viral pathogens that can have a considerable impact on our day-to-day living [1]. Upon infection, a set of immune, physiological, metabolic, and behavioural responses is initiated, representing a highly organized strategy of the organism to fight infection. Pro-inflammatory mediators generated in peripheral tissue communicate with the brain to modify behaviour [2], which aids our ability to fight and eliminate the pathogen. The communication pathways from the site of inflammation to the brain have been investigated in animal models and systemic challenge with lipopolysaccharide (LPS) or double stranded RNA (poly I:C) have been widely used to mimic aspects of bacterial and viral infection respectively [3, 4]. These studies have provided evidence that systemically generated inflammatory mediators signal to the brain via both neural and humoral routes, the latter signalling via the circumventricular organs or across the blood-brain barrier (BBB). Signalling into the brain via these routes evokes a response in the perivascular macrophages (PVMs) and microglia, which in turn synthesise diverse inflammatory mediators including cytokines, prostaglandins and nitric oxide [2, 5, 6]. Immune-to-brain communication also occurs in humans who show changes in mood and cognition following systemic inflammation or infection, which are associated with changes in activity in particular regions of the CNS [7-9]. While these changes are part of our normal homeostasis, it is increasingly evident that systemic inflammation has a detrimental effect in animals and also humans, that suffer from chronic neurodegeneration [10, 11]. We, and others, have shown that microglia become primed by on-going neuropathology in the brain, which increases their response towards subsequent inflammatory stimuli, including systemic inflammation [12, 13] Similar findings have been made in aged rodents [14, 15], where it has been shown that there is an exaggerated behavioural and innate immune response in the brainto systemic bacterial and viral infections, but the molecular mechanisms underlying the microglial priming under these conditions is far from understood.Humans and animals are rarely exposed to a single acute systemic inflammatory event: they rather encounter infectious pathogens that replicate in vivo or are exposed to low concentrations of LPS over a prolonged period of time. There is limited information on the impact of non-neurotrophic bacterial infections on the CNS and whether prolonged systemic inflammation will give rise to either a hyper-(priming) or hypo-(tolerance) innate immune response in the brain in response to a subsequent inflammatory stimulus.In this study we measured the levels of cytokines in the serum, spleen and brain as well as assessing sickness behaviour following a systemic bacterial infection using attenuated Salmonella typhimurium SL3261: we compared the effect to that of repeated LPS injections. We show that Salmonella typhimurium caused acute, transient behavioural changes and a robust peripheral immune response that peaks at day 7. Systemic inflammation resulted in a delayed increase in cytokine production in the brain and priming of microglia, which persisted up to four weeks post infection. These effects were not mimicked by repeated LPS challenges. It is well recognised that systemic bacterial and viral infections are significant contributors to morbidity in the elderly [16], and it has been suggested that primed microglia play a role in the increased clinical symptoms seen in patients with Alzheimer’s disease who have systemic inflammation or infections [11, 17]. We show here that systemic infection leads to prolonged cytokine synthesis in the brain and also priming of brain innate immune cells to a subsequent focal inflammatory challenge in the brain parenchyma

Zidovudine plus lamivudine in Human T-Lymphotropic Virus type-I-associated myelopathy: a randomised trial

BACKGROUND: No therapies have been proven to persistently improve the outcome of HTLV-I-associated myelopathy. Clinical benefit has been reported with zidovudine and with lamivudine in observational studies. We therefore conducted a randomised, double blind, placebo controlled study of six months combination therapy with these nucleoside analogues in sixteen patients. RESULTS: Primary outcomes were change in HTLV-I proviral load in PBMCs and clinical measures. Secondary endpoints were changes in T-cell subsets and markers of activation and proliferation. Six patients discontinued zidovudine. No significant changes in pain, bladder function, disability score, gait, proviral load or markers of T-cell activation or proliferation were seen between the two arms. Active therapy was associated with an unexplained decrease in CD8 and non-T lymphocyte counts. CONCLUSION: Failure to detect clinical improvement may have been due irreversible nerve damage in these patients with a long clinical history and future studies should target patients presenting earlier. The lack of virological effect but may reflect a lack of activity of these nucleoside analogues against HTLV-I RT in vivo, inadequate intracellular concentrations of the active moiety or the contribution of new cell infection to maintaining proviral load at this stage of infection may be relatively small masking the effects of RT inhibition

Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP

Over a decade ago Polymerase δ interacting protein of 38 kDa (PDIP38) was proposed to play a role in DNA repair. Since this time, both the physiological function and subcellular location of PDIP38 has remained ambiguous and our present understanding of PDIP38 function has been hampered by a lack of detailed biochemical and structural studies. Here we show, that human PDIP38 is directed to the mitochondrion in a membrane potential dependent manner, where it resides in the matrix compartment, together with its partner protein CLPX. Our structural analysis revealed that PDIP38 is composed of two conserved domains separated by an α/β linker region. The N-terminal (YccV-like) domain of PDIP38 forms an SH3-like β-barrel, which interacts specifically with CLPX, via the adaptor docking loop within the N-terminal Zinc binding domain of CLPX. In contrast, the C-terminal (DUF525) domain forms an immunoglobin-like β-sandwich fold, which contains a highly conserved putative substrate binding pocket. Importantly, PDIP38 modulates the substrate specificity of CLPX and protects CLPX from LONM-mediated degradation, which stabilises the cellular levels of CLPX. Collectively, our findings shed new light on the mechanism and function of mitochondrial PDIP38, demonstrating that PDIP38 is a bona fide adaptor protein for the mitochondrial protease, CLPXP

In Search of HPA Axis Dysregulation in Child and Adolescent Depression

Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis in adults with major depressive disorder is among the most consistent and robust biological findings in psychiatry. Given the importance of the adolescent transition to the development and recurrence of depressive phenomena over the lifespan, it is important to have an integrative perspective on research investigating the various components of HPA axis functioning among depressed young people. The present narrative review synthesizes evidence from the following five categories of studies conducted with children and adolescents: (1) those examining the HPA system’s response to the dexamethasone suppression test (DST); (2) those assessing basal HPA axis functioning; (3) those administering corticotropin-releasing hormone (CRH) challenge; (4) those incorporating psychological probes of the HPA axis; and (5) those examining HPA axis functioning in children of depressed mothers. Evidence is generally consistent with models of developmental psychopathology that hypothesize that atypical HPA axis functioning precedes the emergence of clinical levels of depression and that the HPA axis becomes increasingly dysregulated from child to adult manifestations of depression. Multidisciplinary approaches and longitudinal research designs that extend across development are needed to more clearly and usefully elucidate the role of the HPA axis in depression

Patterns of HIV testing practices among young gay and bisexual men living in Scotland: a qualitative study

Abstract Background Increasing overall rates, and frequency, of HIV testing in populations at risk is a key public health objective and a critical dimension of HIV prevention efforts. In the UK, men who have sex with men (MSM) remain one of the communities most at risk of HIV and, within this, young gay men are a key risk group. Understanding HIV testing practices is important in the development of interventions to promote testing among young gay and bisexual men. Methods Qualitative interviews were conducted with thirty young gay and bisexual men (aged 18–29) in Scotland. Thematic analysis of men’s accounts of their approach to HIV testing identified three overarching patterns of testing: ‘habitual’, ‘reactive’ and ‘ ad hoc’. Results This qualitative study, the first to explore patterns of HIV testing practices among young gay and bisexual men in the UK, contributes novel findings around the role of social support and ‘community’ in shaping young men’s approaches to HIV testing. The findings suggest that social support can play an important role in encouraging and facilitating HIV testing among young gay men, however, social norms of non-testing also have the potential to act as a barrier to development of a regular routine. Men with habitual testing practices framed HIV testing as both a personal and ‘community’ responsibility, and more effective than testing in response to risk events or emergent symptoms. Men who reported reactive testing practices described testing for HIV primarily in response to perceived exposure to sexual risk, along with ‘transitional moments’ such as starting, ending or changes to a relationship. Among young men who reported testing on an ad hoc basis, inconvenience and disruptions to HIV testing practices, particularly where men lacked social support, acted as a barrier to developing a routine of regular testing. Conclusions Our findings suggest that interventions which seek to increase rates of HIV testing and testing frequency among young gay and bisexual men should include a specific focus on promoting and supporting positive testing practices within young men’s friendship groups and wider gay communities

Measurement and interpretation of same-sign W boson pair production in association with two jets in pp collisions at s = 13 TeV with the ATLAS detector

This paper presents the measurement of fducial and diferential cross sections for both the inclusive and electroweak production of a same-sign W-boson pair in association with two jets (W±W±jj) using 139 fb−1 of proton-proton collision data recorded at a centre-of-mass energy of √s = 13 TeV by the ATLAS detector at the Large Hadron Collider. The analysis is performed by selecting two same-charge leptons, electron or muon, and at least two jets with large invariant mass and a large rapidity diference. The measured fducial cross sections for electroweak and inclusive W±W±jj production are 2.92 ± 0.22 (stat.) ± 0.19 (syst.)fb and 3.38±0.22 (stat.)±0.19 (syst.)fb, respectively, in agreement with Standard Model predictions. The measurements are used to constrain anomalous quartic gauge couplings by extracting 95% confdence level intervals on dimension-8 operators. A search for doubly charged Higgs bosons H±± that are produced in vector-boson fusion processes and decay into a same-sign W boson pair is performed. The largest deviation from the Standard Model occurs for an H±± mass near 450 GeV, with a global signifcance of 2.5 standard deviations

Combination of searches for heavy spin-1 resonances using 139 fb−1 of proton-proton collision data at s = 13 TeV with the ATLAS detector

A combination of searches for new heavy spin-1 resonances decaying into different pairings of W, Z, or Higgs bosons, as well as directly into leptons or quarks, is presented. The data sample used corresponds to 139 fb−1 of proton-proton collisions at = 13 TeV collected during 2015–2018 with the ATLAS detector at the CERN Large Hadron Collider. Analyses selecting quark pairs (qq, bb, , and tb) or third-generation leptons (τν and ττ) are included in this kind of combination for the first time. A simplified model predicting a spin-1 heavy vector-boson triplet is used. Cross-section limits are set at the 95% confidence level and are compared with predictions for the benchmark model. These limits are also expressed in terms of constraints on couplings of the heavy vector-boson triplet to quarks, leptons, and the Higgs boson. The complementarity of the various analyses increases the sensitivity to new physics, and the resulting constraints are stronger than those from any individual analysis considered. The data exclude a heavy vector-boson triplet with mass below 5.8 TeV in a weakly coupled scenario, below 4.4 TeV in a strongly coupled scenario, and up to 1.5 TeV in the case of production via vector-boson fusion