118 research outputs found
Determining predictors of underlying etiology and clinical deterioration in patients with physiologic instability in the emergency department
Thesis (M.A.)--Boston UniversityShock is a critical state defined by inadequate oxygen delivery to tissues. It is well known in the critical care community that early diagnosis and treatment of shock are crucial to improving patient outcomes. However, in many cases, when a state of circulatory shock has been reached, irreversible damage already occurred. In the present study, we broadened our patient cohort from those with shock to those with physiologic instability with the intent of finding predictive factors that allow us to recognize when a patient is at risk for deterioration or when it is already occurring. These patients included patients with pre-shock, shock, and other forms of dysfunction. The purpose of this study was to determine the predictors of underlying etiology of physiologic instability as well as the likelihood of clinical deterioration in these various states, using elements from the physical exam, history, laboratory values, and vital sign measurements.
This study was a prospective observational study of patients, from November 15, 2012 to March 1, 2013, found to have physiologic instability in the
emergency department at an urban, academic tertiary-care hospital with 55,000 annual visits. Physiologic instability was defined as any one of the following abnormalities: heart rate (HR) > 130, respiratory rate (RR>24), shock index (SI) > 1, systolic blood pressure (SBP) 4.0 mmol/L, for a time period of more than five minutes. We identified 540 patients, 74.8% of which were included. Data describing epidemiology, and elements from the patient history and physical exam were abstracted from physician charts and the final etiology of physiologic instability, defined as septic, cardiogenic, hypovolemic, hemorrhagic, or other, was adjudicated by a physician. Blood samples from a subset of our patient group were collected from the hospital hematology laboratory and sent to the Wyss Institute to be analyzed using a novel bacterial detection assay. All of the covariates that data was collected for were analyzed to determine their diagnostic and prognostic value. [TRUNCATED
The reciprocal relationship between smiles and situational contexts
Smiles provide information about a social partnerâs affect and intentions during social interaction. Although always encountered within a specific situation, the influence of contextual information on smile evaluation has not been widely investigated. Moreover, little is known about the reciprocal effect of smiles on evaluations of their accompanying situations. In this research, we assessed how different smile types and situational contexts affected participantsâ social evaluations. In Study 1, 85 participants rated reward, affiliation, and dominance smiles embedded within either enjoyable, polite, or negative (unpleasant) situations. Context had a strong effect on smile ratings, such that smiles in enjoyable situations were rated as more genuine and joyful, as well as indicating less superiority than those in negative situations. In Study 2, 200 participants evaluated the situations that these smiles were perceived within (rather than the smiles themselves). Although situations paired with reward (vs. affiliation) smiles tended to be rated more positively, this effect was absent for negative situations. Ultimately, the findings point toward a reciprocal relationship between smiles and contexts, whereby the face influences evaluations of the situation and vice versa
Functions of the complement components C3 and C5 during sepsis
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154678/1/fsb2fj08110595.pd
Upregulation of Phagocyte-Derived Catecholamines Augments the Acute Inflammatory Response
Following our recent report that phagocytic cells (neutrophils, PMNs, and macrophages) are newly discovered sources of catecholamines, we now show that both epinephrine and norepinephrine directly activate NFÎșB in macrophages, causing enhanced release of proinflammatory cytokines (TNFα, IL-1ÎČ, IL-6). Both adrenal-intact (AD+) and adrenalectomized (ADX) rodents were used, because ADX animals had greatly enhanced catecholamine release from phagocytes, facilitating our efforts to understand the role of catecholamines released from phagocytes. Phagocytes isolated from adrenalectomized rats displayed enhanced expression of tyrosine-hydroxylase and dopamine-ÎČ-hydroxylase, two key enzymes for catecholamine production and exhibited higher baseline secretion of norepinephrine and epinephrine. The effects of upregulation of phagocyte-derived catecholamines were investigated in two models of acute lung injury (ALI). Increased levels of phagocyte-derived catecholamines were associated with intensification of the acute inflammatory response, as assessed by increased plasma leak of albumin, enhanced myeloperoxidase content in lungs, augmented levels of proinflammatory mediators in bronchoalveolar lavage fluids, and elevated expression of pulmonary ICAM-1 and VCAM-1. In adrenalectomized rats, development of ALI was enhanced and related to α2-adrenoceptors engagement but not to involvement of mineralocorticoid or glucocorticoid receptors. Collectively, these data demonstrate that catecholamines are potent inflammatory activators of macrophages, upregulating NFÎșB and further downstream cytokine production of these cells. In adrenalectomized animals, which have been used to further assess the role of catecholamines, there appears to be a compensatory increase in catecholamine generating enzymes and catecholamines in macrophages, resulting in amplification of the acute inflammatory response via engagement of α2-adrenoceptors
Cross-Talk between TLR4 and FcÎłReceptorIII (CD16) Pathways
Pathogen-pattern-recognition by Toll-like receptors (TLRs) and pathogen clearance after immune complex formation via engagement with Fc receptors (FcRs) represent central mechanisms that trigger the immune and inflammatory responses. In the present study, a linkage between TLR4 and FcÎłR was evaluated in vitro and in vivo. Most strikingly, in vitro activation of phagocytes by IgG immune complexes (IgGIC) resulted in an association of TLR4 with FcÎłRIII (CD16) based on co-immunoprecipitation analyses. Neutrophils and macrophages from TLR4 mutant (mut) mice were unresponsive to either lipopolysaccharide (LPS) or IgGIC in vitro, as determined by cytokine production. This phenomenon was accompanied by the inability to phosphorylate tyrosine residues within immunoreceptor tyrosine-based activation motifs (ITAMs) of the FcRÎł-subunit. To transfer these findings in vivo, two different models of acute lung injury (ALI) induced by intratracheal administration of either LPS or IgGIC were employed. As expected, LPS-induced ALI was abolished in TLR4 mut and TLR4â/â mice. Unexpectedly, TLR4 mut and TLR4â/â mice were also resistant to development of ALI following IgGIC deposition in the lungs. In conclusion, our findings suggest that TLR4 and FcÎłRIII pathways are structurally and functionally connected at the receptor level and that TLR4 is indispensable for FcÎłRIII signaling via FcRÎł-subunit activation
Adverse functions of ILâ17A in experimental sepsis
ILâ17A is a proinflammatory cytokine produced by a variety of cells. In the current study, we examined the role of ILâ17A in sepsis induced in mice by cecal ligation and puncture (CLP). ILâ17A levels, which rose timeâdependently in plasma after CLP, were not affected in the absence of αÎČ T cells or neutrophils. In sharp contrast, γΎ T cellâknockout or γΎ T cellâdepleted mice displayed baseline ILâ17A plasma levels after CLP. Neutralization of ILâ17A by two different antibodies improved sepsis (survival from ~10% to nearly 60%). Unexpectedly, antibody treatment was protective, even when administration of antiâILâ17A was delayed for up to 12 h after CLP. These protective effects of ILâ17A blockade were associated with substantially reduced levels of bacteremia together with significant reductions of systemic proinflammatory cytokines and chemokines in plasma. In vitro incubation of mouse peritoneal macrophages with lipopolysaccharide (LPS) in the copresence of ILâ17A substantially increased the production of TNFâα, ILâ1ÎČ, and ILâ6 by these cells. These data suggest that, during experimental sepsis, γΎ T cellâderived ILâ17A promotes high levels of proinflammatory mediators and bacteremia, resulting in enhanced lethality. ILâ17A may be a potential therapeutic target in sepsis.âFlierl, M. A., Rittirsch, D., Gao, H., Hoesel, L. M., Nadeau, B. A., Day, D. E., Zetoune, F. S., Sarma, J. V., HuberâLang, M. S., Ferrara, J. L. M., Ward, P. A. Adverse functions of ILâ17A in experimental sepsis. FASEB J. 22, 2198â2205 (2008)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154352/1/fsb2fj07105221.pd
Phagocyte-derived catecholamines enhance acute inflammatory injury
It is becoming increasingly clear that the autonomic nervous system and the immune system demonstrate cross-talk during inflammation by means of sympathetic and parasympathetic pathways(1,2). We investigated whether phagocytes are capable of de novo production of catecholamines, suggesting an autocrine/paracrine self-regulatory mechanism by catecholamines during inflammation, as has been described for lymphocytes(3). Here we show that exposure of phagocytes to lipopolysaccharide led to a release of catecholamines and an induction of catecholamine-generating and degrading enzymes, indicating the presence of the complete intracellular machinery for the generation, release and inactivation of catecholamines. To assess the importance of these findings in vivo, we chose two models of acute lung injury. Blockade of alpha(2)-adrenoreceptors or catecholamine-generating enzymes greatly suppressed lung inflammation, whereas the opposite was the case either for an alpha(2)-adrenoreceptor agonist or for inhibition of catecholamine-degrading enzymes. We were able to exclude T cells or sympathetic nerve endings as sources of the injury-modulating catecholamines. Our studies identify phagocytes as a new source of catecholamines, which enhance the inflammatory response.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62733/1/nature06185.pd
New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes
Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial
Background
Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy
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