Acute Traumatic Coagulopathy occurs immediately after massive trauma when shock, hypoperfusion, and vascular damage are present. Mechanisms for this acute coagulopathy include activation of protein ...C, endothelial glycocalyx disruption, depletion of fibrinogen, and platelet dysfunction. Hypothermia and acidaemia amplify the endogenous coagulopathy and often accompany trauma. These multifactorial processes lead to decreased clot strength, autoheparinization, and hyperfibrinolysis. Furthermore, the effects of aggressive crystalloid administration, haemodilution from inappropriate blood product transfusion, and prolonged surgical times may worsen clinical outcomes. We review normal coagulation using the cell-based model of haemostasis and the pathophysiology of acute traumatic coagulopathy. Developed trauma systems reduce mortality, highlighting critical goals for the trauma patient in different phases of care. Once patients reach a trauma hospital, certain triggers reliably indicate when they require massive transfusion and specialized trauma care. These triggers include base deficit, international normalized radio (INR), systolic arterial pressure, haemoglobin concentration, and temperature. Early identification for massive transfusion is critically important, as exsanguination in the first few hours of trauma is a leading cause of death. To combat derangements caused by massive haemorrhage, damage control resuscitation is a technique that addresses each antagonist to normal haemostasis. Components of damage control resuscitation include damage control surgery, permissive hypotension, limited crystalloid administration, haemostatic resuscitation, and correction of hyperfibrinolysis.
As the number of people diagnosed with Alzheimer's disease (AD) reaches epidemic proportions, there is an urgent need to develop effective treatment strategies to tackle the social and economic costs ...of this fatal condition. Dozens of candidate therapeutics are currently being tested in clinical trials, and compounds targeting the aberrant accumulation of tau proteins into neurofibrillary tangles (NFTs) are the focus of substantial current interest. Reliable, translatable biomarkers sensitive to both tau pathology and its modulation by treatment along with animal models that faithfully reflect aspects of the human disease are urgently required. Magnetic resonance imaging (MRI) is well established as a valuable tool for monitoring the structural brain changes that accompany AD progression. However the descent into dementia is not defined by macroscopic brain matter loss alone: non-invasive imaging measurements sensitive to protein accumulation, white matter integrity and cerebral haemodynamics probe distinct aspects of AD pathophysiology and may serve as superior biomarkers for assessing drug efficacy. Here we employ a multi-parametric array of five translatable MRI techniques to characterise the in vivo pathophysiological phenotype of the rTg4510 mouse model of tauopathy (structural imaging, diffusion tensor imaging (DTI), arterial spin labelling (ASL), chemical exchange saturation transfer (CEST) and glucose CEST). Tau-induced pathological changes included grey matter atrophy, increased radial diffusivity in the white matter, decreased amide proton transfer and hyperperfusion. We demonstrate that the above markers unambiguously discriminate between the transgenic group and age-matched controls and provide a comprehensive profile of the multifaceted neuropathological processes underlying the rTg4510 model. Furthermore, we show that ASL and DTI techniques offer heightened sensitivity to processes believed to precede detectable structural changes and, as such, provides a platform for the study of disease mechanisms and therapeutic intervention.
•The rTg4510 mouse model exhibits specific tau pathology.•This enables dissection of the unique role of tau in Alzheimer's Disease.•We applied five quantitative, non-invasive MRI techniques to the rTg4510.•We demonstrate the sensitivity of each to discriminate regions of high tau burden.•This study provides a platform for the longitudinal assessment of tau therapies.
Macular degeneration is a leading cause of blindness. Treatments to rescue vision are currently limited. Here, we study how loss of central vision affects lateral feedback to spared areas of the ...human retina. We identify a cone-driven gain control mechanism that reduces visual function beyond the atrophic area in macular degeneration. This finding provides an insight into the negative effects of geographic atrophy on vision. Therefore, we develop a strategy to restore this feedback mechanism, through activation of laterally projecting cells. This results in improved vision in Cnga3
mice, which lack cone function, as well as a mouse model of geographic atrophy. Our work shows that a loss of lateral gain control contributes to the vision deficit in macular degeneration. Furthermore, in mouse models we show that lateral feedback can be harnessed to improve vision following retinal degeneration.
Background and Purpose
Sphingosine1‐phosphate (S1P) receptors mediate multiple events including lymphocyte trafficking, cardiac function, and endothelial barrier integrity. Stimulation of S1P1 ...receptors sequesters lymphocyte subsets in peripheral lymphoid organs, preventing their trafficking to inflamed tissue sites, modulating immunity. Targeting S1P receptors for treating autoimmune disease has been established in clinical studies with the non‐selective S1P modulator, FTY720 (fingolimod, Gilenya™). The purpose of this study was to assess RPC1063 for its therapeutic utility in autoimmune diseases.
Experimental Approach
The specificity and potency of RPC1063 (ozanimod) was evaluated for all five S1P receptors, and its effect on cell surface S1P1 receptor expression, was characterized in vitro. The oral pharmacokinetic (PK) parameters and pharmacodynamic effects were established in rodents, and its activity in three models of autoimmune disease (experimental autoimmune encephalitis, 2,4,6‐trinitrobenzenesulfonic acid colitis and CD4+CD45RBhi T cell adoptive transfer colitis) was assessed.
Key Results
RPC1063 was specific for S1P1 and S1P5 receptors, induced S1P1 receptor internalization and induced a reversible reduction in circulating B and CCR7+ T lymphocytes in vivo. RPC1063 showed high oral bioavailability and volume of distribution, and a circulatory half‐life that supports once daily dosing. Oral RPC1063 reduced inflammation and disease parameters in all three autoimmune disease models.
Conclusions and Implications
S1P receptor selectivity, favourable PK properties and efficacy in three distinct disease models supports the clinical development of RPC1063 for the treatment of relapsing multiple sclerosis and inflammatory bowel disease, differentiates RPC1063 from other S1P receptor agonists, and could result in improved safety outcomes in the clinic.
To assess the relationship between time spent in light physical activity and cardiometabolic health and mortality in adults.
Systematic review and meta-analysis.
Searches in Medline, Embase, ...PsycInfo, CINAHL and three rounds of hand searches.
Experimental (including acute mechanistic studies and physical activity intervention programme) and observational studies (excluding case and case-control studies) conducted in adults (aged ≥18 years) published in English before February 2018 and reporting on the relationship between light physical activity (<3 metabolic equivalents) and cardiometabolic health outcomes or all-cause mortality.
Study quality appraisal with QUALSYST tool and random effects inverse variance meta-analysis.
Seventy-two studies were eligible including 27 experimental studies (and 45 observational studies). Mechanistic experimental studies showed that short but frequent bouts of light-intensity activity throughout the day reduced postprandial glucose (-17.5%; 95% CI -26.2 to -8.7) and insulin (-25.1%; 95% CI -31.8 to -18.3) levels compared with continuous sitting, but there was very limited evidence for it affecting other cardiometabolic markers. Three light physical activity programme intervention studies (n ranging from 12 to 58) reduced adiposity, improved blood pressure and lipidaemia; the programmes consisted of activity of >150 min/week for at least 12 weeks. Six out of eight prospective observational studies that were entered in the meta-analysis reported that more time spent in daily light activity reduced risk of all-cause mortality (pooled HR 0.71; 95% CI 0.62 to 0.83).
Light-intensity physical activity could play a role in improving adult cardiometabolic health and reducing mortality risk. Frequent short bouts of light activity improve glycaemic control. Nevertheless, the modest volume of the prospective epidemiological evidence base and the moderate consistency between observational and laboratory evidence inhibits definitive conclusions.
Fruit ripening is characterized by processes that modify texture and flavor but also by a dramatic increase in susceptibility to necrotrophic pathogens, such as Botrytis cinerea. Disassembly of the ...major structural polysaccharides of the cell wall (CW) is a significant process associated with ripening and contributes to fruit softening. In tomato, polygalacturonase (PG) and expansin (Exp) are among the CW proteins that cooperatively participate in ripening-associated CW disassembly. To determine whether endogenous CW disassembly influences the ripening-regulated increase in necrotropic pathogen susceptibility, B. cinerea susceptibility was assessed in transgenic fruit with suppressed polygalacturonase (LePG) and expansin (LeExp1) expression. Suppression of either LePG or LeExp1 alone did not reduce susceptibility but simultaneous suppression of both dramatically reduced the susceptibility of ripening fruit to B. cinerea, as measured by fungal biomass accumulation and by macerating lesion development. These results demonstrate that altering endogenous plant CW disassembly during ripening influences the course of infection by B. cinerea, perhaps by changing the structure or the accessibility of CW substrates to pathogen CW-degrading enzymes. Recognition of the role of ripening-associated CW metabolism in postharvest pathogen susceptibility may be useful in the design and development of strategies to limit pathogen losses during fruit storage, handling, and distribution.
The Second Victim: a Review Coughlan, B; Powell, D; Higgins, M.F
European journal of obstetrics & gynecology and reproductive biology,
06/2017, Letnik:
213
Journal Article
Recenzirano
Abstract Amongst the lay and media population there is a perception that pregnancy, labour and delivery is always physiological, morbidity and mortality should be “never events” and that error is the ...only cause of adverse events. Those working in maternity care know that it is an imperfect art, where adverse outcomes and errors will occur. When errors do occur, there is a domino effect with three groups being involved − the patient (first victim), the staff (second victims) and the organization (third victims). If the perceived expectation of patients on all clinicians is that of perfection, then clinicians may suffer the consequences of adverse outcomes in isolation and silence. More recently identification and discussion on the phenomenon of the second victim has become a popular research topic. This review aimed to study not only the phenomenon of second victim in general medical care but to also concentrate on maternity care where the expectation of perfection may be argued to be greater. Risk factors, prevalence and effect of second victims were identified from a thorough search of the literature on the topic. The review focuses on the recent research of the effect on maternity staff of adverse outcomes and discusses topical issues of resilience, disclosure, support systems as well as Learning from Excellence. It is now well documented that when staff members are supported in their disclosure of errors this domino effect is less traumatic. It is the responsibility of everyone working in healthcare to support all the victims of an error, as an ethical duty and to have a supportive culture of disclosure. In addition, balance can be provided by developing a culture of learning from excellence as well as from errors.
Introduction
The aim of this study was to identify factors associated with the level of periprosthetic fracture involving a cemented polished tapered stem: Vancouver B or Vancouver C.
Methods
A ...retrospective cohort study of 181 unilateral periprosthetic fractures involving Exeter stems was assessed by three observers (mean age 78.5, range 39–103; mean BMI 27.1, 17–39; 97 (54%) male). Patient demographics, deprivation scores, BMI and time since primary prosthesis were recorded. Femoral diameter, femoral cortical thickness, Dorr classification and distal cement mantle length were measured from calibrated radiographs. Interobserver reliability was calculated using intraclass correlation coefficients (ICCs). Univariate and multivariate analysis was performed to identify associations with Vancouver B or C fractures.
Results
160/181 (88%) Vancouver B and 21/181 (12%) Vancouver C-level fractures occurred at a mean of 5.9 ± 5.4 years (0.2–26.5) following primary surgery. Radiographic measurements demonstrated excellent agreement (ICC > 0.8,
p
< 0.001). Mortality was significantly higher following Vancouver C compared to B fractures: 90 day 14/160 Vs 5/21 (
p
= 0.05); 1 year 29/160 Vs 8/21 (
p
= 0.03). Univariate analysis demonstrated that Vancouver C fractures were associated with female sex, bisphosphonate use, cortical bone thickness, and distal cement mantle length (
p
< 0.05). On multivariate analysis, only female sex was an independent predictor of Vancouver C-level fractures (
R
2
=0.354,
p
= 0.005).
Conclusion
Most PFFs involving the Exeter stem design are Vancouver B-type fractures and appear to be independent of osteoporosis. In contrast, Vancouver C periprosthetic fractures display typical fragility fracture characteristics and are associated with female sex, thinner femoral cortices, longer distal cement mantles and high mortality.
Summary
Background The flow cytometric basophil activation test by detection of CD63 expression has been developed as an alternative method for in vitro diagnosis of IgE‐mediated reactions to various ...allergens. Despite promising initial studies, the test remains disappointing in terms of sensitivity. CD203c has recently been demonstrated as a specific activation marker of basophils that is rapidly up‐regulated after allergen challenge in sensitized patients.
Objective The goal of the present study was to compare basophil activation tests by using either CD203c or CD63 in the diagnosis of immediate‐type allergy to latex.
Methods Twenty‐seven patients (health care workers of our institution) who developed clinical features evocative of allergy after contact with latex were included and classified into two groups. Group 1 (n = 16) comprised true allergic patients who presented with typical signs of immediate allergic reaction associated with a positive skin test (prick test). Group 2 (n = 11) consisted of patients whose clinical history was not typical and had negative skin test. Twelve healthy subjects were also studied as controls. We compared the sensitivity of two triple‐staining flow cytometric protocols measuring basophil activation after latex stimulation: CD45‐IgE‐CD63 and CD45‐IgE‐CD203c.
Results The CD203c protocol showed a higher sensitivity than the CD63 protocol (75% vs. 50%). In comparison, latex‐specific IgE sensitivity was found to be 69%. Furthermore, the magnitude of the basophil response was significantly higher with CD203c in comparison with CD63. Specificity was 100% for both protocols.
Conclusion Due to superior gating of basophils and a higher range of activation in response to allergen, the basophil activation test is markedly improved by use of CD203c instead of CD63.
Interleukin-1 (IL-1)-mediated signaling in T cells is essential for T helper 17 (Th17) cell differentiation. We showed here that SIGIRR, a negative regulator of IL-1 receptor and Toll-like receptor ...signaling, was induced during Th17 cell lineage commitment and governed Th17 cell differentiation and expansion through its inhibitory effects on IL-1 signaling. The absence of SIGIRR in T cells resulted in increased Th17 cell polarization in vivo upon myelin oligodendrocyte glycoprotein (MOG
35-55) peptide immunization. Recombinant IL-1 promoted a marked increase in the proliferation of SIGIRR-deficient T cells under an in vitro Th17 cell-polarization condition. Importantly, we detected increased IL-1-induced phosphorylation of JNK and mTOR kinase in SIGIRR-deficient Th17 cells compared to wild-type Th17 cells. IL-1-induced proliferation was abolished in mTOR-deficient Th17 cells, indicating the essential role of mTOR activation. Our results demonstrate an important mechanism by which SIGIRR controls Th17 cell expansion and effector function through the IL-1-induced mTOR signaling pathway.
► SIGIRR is induced during Th17 cell lineage commitment ► SIGIRR suppresses Th17 cell effector function via inhibition of IL-1 signaling ► IL-1-induced proliferation is abolished in mTOR-deficient Th17 cells ► SIGIRR suppresses Th17 cell proliferation via inhibition of mTOR activation
PDF
