98 research outputs found
Sonographic Monitoring of Midline Shift in Space-Occupying Stroke
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Background and Purpose
—Transcranial color-coded duplex sonography (TCCS) allows bedside imaging of intracranial hemodynamics and parenchymal structures. It provides reliable information regarding midline shift (MLS) in space-occupying hemispheric stroke. We studied the value of MLS measurement to predict fatal outcome at different time points after stroke onset.
Methods
—Forty-two patients with acute, severe hemispheric stroke were enrolled. Cranial computed tomography (CCT) and extracranial duplex sonography were performed on admission. TCCS was carried out 8±3, 16±3, 24±3, 32±3, and 40±3 hours after stroke onset. Lesion size was determined from follow-up CCT.
Results
—Twelve patients died as the result of cerebral herniation (group 1); 28 survived (group 2). Two patients received decompressive hemicraniectomy and were therefore excluded from further evaluation. MLS was significantly higher in group 1 as early as 16 hours after onset of stroke. Specificity and positive predictive values for death caused by cerebral herniation of MLS ≥2.5, 3.5, 4.0, and 5.0 mm after 16, 24, 32, and 40 hours were 1.0.
Conclusions
—TCCS helps to estimate outcome as early as 16 hours after stroke onset and thus facilitates identification of patients who are unlikely to survive without decompressive craniectomy. Because of its noninvasive character and bedside suitability, sonographic monitoring of MLS might be a useful tool in management of critically ill patients who cannot undergo repeated CCT scans.
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Glucose Metabolism in CD4+ T cell Subsets Modulates Inflammation and Autoimmunity
No full textUnderstanding the mechanisms that control T cell function and differentiation is crucial to develop new strategies to modulate immune function and prevent autoimmune and inflammatory disease. The balance between effector (Teff; Th1, Th2 and Th17) and regulatory (Treg) T cells is critical to provide an appropriate, but not excessive, immune response and therapies to induce Treg or inhibit Teff are likely promising treatment strategies. It has recently become clear that T cell metabolism is important in both T cell activation and differentiation. T cells undergo a metabolic reprogramming upon activation and not all differentiated T cell subsets utilize the same metabolic fuels or programs.These metabolic differences are not trivial, as T cell metabolism is tightlyregulated and dysregulation can lead to cell death or reduced immunity. Anunderstanding of the metabolic differences between Teff and Treg may lead to a new direction for treating inflammatory diseases by modulating the Teff:Treg balance through metabolic inhibition. Previous studies have shown that Teff express higher levels of the glucose transporter Glut1 than Treg, however the role of Glut1, and importantly, the cell-intrinsic role of glucose metabolism in T cell differentiation and inflammation was not previously examined. The work presented here examines the role of Glut1 in T cell differentiation. We show that effector CD4 T cells were dependent on Glut1 for proliferation and function both in vitro and in vivo. In contrast, Treg were Glut1-independent and capable of suppressing colitis in the absence of Glut1 expression.Additionally, previous studies have shown broad metabolic differences between Teff and Treg, however the specific metabolic profiles of Teff and Treg are poorly understood. Here, Teff and Treg metabolism is examined to test if dependence on distinct metabolic pathways will allow selective targeting of different T cell populations. We show that pyruvate dehydrogenase kinase 1 (PDHK1) is differentially expressed in the T cell subsets and inhibition of PDHK1 selectively suppresses Th17 and promotes Treg differentiation and function. Because Teff and Treg have distinct metabolic profiles, we hypothesized that the Treg-specific transcription factor FoxP3 may drive the Treg oxidative metabolic program. We therefore examined the role of FoxP3 in T cell metabolism and determined that FoxP3 promotes glucose and lipid oxidation and suppresses glycolytic metabolism. Importantly, we show that promoting glycolysis with transgenic expression of Glut1 inhibits Treg suppressive capacity. Together, these data suggest that FoxP3 drives an oxidative metabolic program that is critical to Treg function. Overall, this work examines the metabolic phenotypes and regulation of Teff and Treg and potential metabolic targets that could be used to treat autoimmune and inflammatory disease.</p
Role of T cells in malnutrition and obesity.
No full textNutritional status is critically important for immune cell function. While obesity is characterized by inflammation that promotes metabolic syndrome including cardiovascular disease and insulin resistance, malnutrition can result in immune cell defects and increased risk of mortality from infectious diseases. T cells play an important role in the immune adaptation to both obesity and malnutrition. T cells in obesity have been shown to have an early and critical role in inducing inflammation, accompanying the accumulation of inflammatory macrophages in obese adipose tissue, which are known to promote insulin resistance. How T cells are recruited to adipose tissue and activated in obesity is a topic of considerable interest. Conversely, T cell number is decreased in malnourished individuals, and T cells in the setting of malnutrition have decreased effector function and proliferative capacity. The adipokine leptin, which is secreted in proportion to adipocyte mass, may have a key role in mediating adipocyte-T cell interactions in both obesity and malnutrition, and has been shown to promote effector T cell function and metabolism while inhibiting regulatory T cell proliferation. Additionally, key molecular signals are involved in T cell metabolic adaptation during nutrient stress; among them, the metabolic regulator AMP kinase and the mammalian target of rapamycin have critical roles in regulating T cell number, function, and metabolism. In summary, understanding how T cell number and function are altered in obesity and malnutrition will lead to better understanding of and treatment for diseases where nutritional status determines clinical outcome
Adenosine-mono-phosphate-activated protein kinase-independent effects of metformin in T cells
No full textThe anti-diabetic drug metformin regulates T-cell responses to immune activation and is proposed to function by regulating the energy-stress-sensing adenosine-monophosphate-activated protein kinase (AMPK). However, the molecular details of how metformin controls T cell immune responses have not been studied nor is there any direct evidence that metformin acts on T cells via AMPK. Here, we report that metformin regulates cell growth and proliferation of antigen-activated T cells by modulating the metabolic reprogramming that is required for effector T cell differentiation. Metformin thus inhibits the mammalian target of rapamycin complex I signalling pathway and prevents the expression of the transcription factors c-Myc and hypoxia-inducible factor 1 alpha. However, the inhibitory effects of metformin on T cells did not depend on the expression of AMPK in T cells. Accordingly, experiments with metformin inform about the importance of metabolic reprogramming for T cell immune responses but do not inform about the importance of AMPK
Feasibility and validity of transcranial duplex sonography in patients with acute stroke
No full textObjectives: To evaluate in a prospective multicentre setting the feasibility of transcranial colour coded duplex sonography (TCCS) for examination of the middle cerebral artery (MCA) in patients with acute hemispheric stroke, and to assess the validity of sonographic findings in a subgroup of patients who also had a correlative angiographic examination. Methods: TCCS was performed in 58 consecutive patients within six hours of the onset of a moderate to severe hemispheric stroke. Ultrasound contrast agent (Levovist) was applied if necessary. Thirty two patients also had computed tomography angiography (n = 13), magnetic resonance angiography (n = 18), or digital subtraction angiography (n = 1). In 14 of these patients, both the sonographic and corresponding angiographic examination were performed within six hours of stroke onset (mean time difference between TCCS and angiography 0.8 hours). Eighteen patients, in whom angiography was carried out more than 24 hours after stroke onset, had a follow up TCCS for method comparison (mean time difference 6.1 hours). Results: Initial unenhanced TCCS performed 3.4 (SD 1.2) hours after the onset of symptoms depicted the symptomatic MCA mainstem in 32 patients (55%) (13 occlusions, one stenosis, 18 patent arteries). After signal enhancement, MCA status could be determined in 54 patients (93%) (p < 0.05), showing an occlusion in 25, a stenosis in two, and a patent artery in 27 patients. In 3 1 of the 32 patients who had correlative angiography, TCCS and angiography produced the same diagnosis of the symptomatic MCA (10 occlusions, three stenoses, 18 patent arteries); TCCS was inconclusive in the remaining one. Conclusion: TCCS is a feasible, fast, and valid non-invasive bedside method for evaluating the MCA in an acute stroke setting, particularly when contrast enhancement is applied. It may be a valuable and cost effective alternative to computed tomography and magnetic resonance angiography in future stroke trials
Comparison of edoxaban and enoxaparin in a rat model of AlCl3-induced thrombosis of the superior sagittal sinus
No full textCerebral sinus venous thrombosis (CSVT) is an uncommon disease that is usually treated with anticoagulation (heparin, low-molecular heparin, or vitamin K-antagonists). We compared treatment with edoxaban, an oral factor Xa-antagonist, that has not been approved in patients with CSVT, with enoxaparin, a well-established therapy, in a rat model of CSVT. Fifty male Wistar rats were randomized into 5 groups (10 animals each) and subjected to aluminum chloride (AlCl3)-induced thrombosis of the superior sagittal sinus (SSS) or sham procedure. Animals with thrombosis of the SSS were treated with edoxaban, enoxaparin, or placebo. Diagnostic workup included neurological examination, MRI imaging, MR-flow measurements of the SSS, and immunohistochemical staining. Neurological examination revealed no differences between treatment groups. Seven days after initial thrombosis, flow in the SSS was lower in the active treatment group as compared to sham-operated animals (p 0.05). Immunohistochemical staining showed no differences in the actively treated animals. Edoxaban proved to be similar to enoxaparin in a model of experimental AlCl3-induced CSVT
Editorial: The metabolic challenges of immune cells in health and disease
No full textCopyright: © 2015 Frezza and Mauro. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.CM is supported by the British Heart Foundation Fellowship FS/12/38/29640. CF is funded by the UK Medical Research Council
Human memory CD8+ T-cells exhibit an intrinsic metabolic advantage as reflected by increased mitochondrial functionality and high glycolytic potential
No full textIntrinsic differences between na•ve and memory CD8+ T-cells affect both quality and quantity of cognate antigen response. Cellular immune function and metabolic pathways are closely linked. The metabolic repertoire of na•ve and memory T-cells remains largely unknown. Here we assessed key metabolic features of human na•ve and effector-memory CD8+ T-cells under basal, metabolic stress, and activating conditions. Basal mitochondrial respiration was similar in both subsets. Memory cells, however, possessed more complex, tubular mitochondria, and displayed greater respiratory capacity and enhanced fatty acid oxidation. Basal glycolysis was also comparable in both subsets. Memory cells, however, showed an exclusive capacity to rapidly upregulate glycolysis after mitochondrial respiration blockage. In line with this finding, effector memory CD8+ T-cells expressed more cytoplasmic GAPDH levels with enhanced activity compared to na•ve CD8+ T-cells.
Protective immunologic memory depends on antigen-experienced T-cells that are able to: (a) rapidly acquire effector function and (b) expand as secondary effector cells (Masopust and Picker, 2012). The clonal re-expansion of memory cells requires aerobic glycolysis (Warburg effect) in order to meet added biosynthetic and energetic demands (Vander Heiden et al., 2009). The metabolic requirements of rapidly responding effector memory CD8+ T-cells are unknown. Here we show that human effector memory CD8+ T-cells possess the intrinsic ability to upregulate aerobic glycolysis with unexpected rapid dynamics. In contrast to prototypical aerobic switch in activated T-cells, this early phase is insensitive to blockage of mTORC1, a known regulator of glucose metabolism in proliferating T-cells (Finlay et al., 2012; Fox et al., 2005). CD28 signaling via mTORC2 and AKT is required to sustain this early increased glycolyis. Importantly, preventing this early glycolytic phase by either blocking AKT activity or glucose deprivation, led to an impairment of IFN-gamma secretion.
Therefore, increased metabolic capacities in effector memory CD8+ T-cells promote a primed state to immediately support high glycolytic activity upon activation. This early glycolytic phase is prerequisite for immediate effector function and therefore linking metabolic features with CD8+ T-cells recall functionality.
Our findings established differential metabolic repertoires between na•ve and effector-memory CD8+ T-cells, with implications for strategies aiming to therapeutically manipulate CD8+ T-cell memory
Leptin metabolically licenses T cells for activation to link nutrition and immunity.
No full textImmune responses are highly energy-dependent processes. Activated T cells increase glucose uptake and aerobic glycolysis to survive and function. Malnutrition and starvation limit nutrients and are associated with immune deficiency and increased susceptibility to infection. Although it is clear that immunity is suppressed in times of nutrient stress, mechanisms that link systemic nutrition to T cell function are poorly understood. We show in this study that fasting leads to persistent defects in T cell activation and metabolism, as T cells from fasted animals had low glucose uptake and decreased ability to produce inflammatory cytokines, even when stimulated in nutrient-rich media. To explore the mechanism of this long-lasting T cell metabolic defect, we examined leptin, an adipokine reduced in fasting that regulates systemic metabolism and promotes effector T cell function. We show that leptin is essential for activated T cells to upregulate glucose uptake and metabolism. This effect was cell intrinsic and specific to activated effector T cells, as naive T cells and regulatory T cells did not require leptin for metabolic regulation. Importantly, either leptin addition to cultured T cells from fasted animals or leptin injections to fasting animals was sufficient to rescue both T cell metabolic and functional defects. Leptin-mediated metabolic regulation was critical, as transgenic expression of the glucose transporter Glut1 rescued cytokine production of T cells from fasted mice. Together, these data demonstrate that induction of T cell metabolism upon activation is dependent on systemic nutritional status, and leptin links adipocytes to metabolically license activated T cells in states of nutritional sufficiency
Hope and Deception in Conception Bay: Marchant-Settler Relations in Newfoundland, 1785–1855. By Sean T. Cadigan. Toronto: University of Toronto Press, 1995. Pp. xiv, 242. 1895, paper.
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