Fat intravasation, fat emboli and fat embolism syndrome in adult major trauma patients with intraosseous catheters: a systematic review.

INTRODUCTION: Intraosseous (IO) administration of medication, fluids and blood products is accepted practice for critically injured patients in whom intravenous access is not immediately available. However, there are concerns that high intramedullary pressures resulting from IO infusion may cause bone marrow intravasation and subsequent fat embolisation. The aim of this systematic review is to synthesise the existing evidence describing fat intravasation, fat embolism and fat embolism syndrome (FES) following IO infusion. METHODS: A systematic search of CINAHL, MEDLINE and Embase was undertaken using the search terms "intraosseous", "fat embolism", "fat intravasation" and "fat embolism syndrome". Two authors independently screened abstracts and full texts, against eligibility criteria and assessed risk of bias. A grey literature search (including references) was undertaken. Inclusion criteria were: all human and animal studies reporting novel data on IO-associated fat emboli. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. RESULTS: 22 papers were identified from the search, with a further 5 found from reference lists. N=7 full papers met inclusion criteria. These papers were all translational animal studies. The overall risk of bias was high. Studies demonstrated that fat intravasation and fat embolisation are near universal after IO infusion, but of uncertain clinical significance. The initial IO flush appears to cause the highest intramedullary pressure and highest chance of fat intravasation and embolisation. No conclusions could be drawn on FES. CONCLUSIONS: IO catheters remain a useful intervention in the armamentarium of trauma clinicians. Although their use is widely accepted, there is a paucity of evidence investigating fat embolisation in IO infusions. Despite this, pulmonary fat emboli after IO infusion are very common. The existing data are of low quality with a high risk of bias. More research is needed to address this important subject. PROSPERO REGISTRATION NUMBER: CRD42023399333.

Nitric Oxide Engages an Anti-inflammatory Feedback Loop Mediated by Peroxiredoxin 5 in Phagocytes.

Phagocyte microbiocidal mechanisms and inflammatory cytokine production are temporally coordinated, although their respective interdependencies remain incompletely understood. Here, we identify a nitric-oxide-mediated antioxidant response as a negative feedback regulator of inflammatory cytokine production in phagocytes. In this context, Keap1 functions as a cellular redox sensor that responds to elevated reactive nitrogen intermediates by eliciting an adaptive transcriptional program controlled by Nrf2 and comprised of antioxidant genes, including Prdx5. We demonstrate that engaging the antioxidant response is sufficient to suppress Toll-like receptor (TLR)-induced cytokine production in dendritic cells and that Prdx5 is required for attenuation of inflammatory cytokine production. Collectively, these findings delineate the reciprocal regulation of inflammation and cellular redox systems in myeloid cells.

Hypothalamic epigenetics driving female puberty.

Puberty involves a series of morphological, physiological and behavioural changes during the last part of the juvenile period that culminates in the attainment of fertility. The activation of the pituitary-gonadal axis by increased hypothalamic secretion of gonadotrophin-releasing hormone (GnRH) is an essential step in the process. The current hypothesis postulates that a loss of transsynaptic inhibition and a rise in excitatory inputs are responsible for the activation of GnRH release. Similarly, a shift in the balance in the expression of puberty activating and puberty inhibitory genes exists during the pubertal transition. In addition, recent evidence suggests that the epigenetic machinery controls this genetic balance, giving rise to the tantalising possibility that epigenetics serves as a relay of environmental signals known for many years to modulate pubertal development. Here, we review the contribution of epigenetics as a regulatory mechanism in the hypothalamic control of female puberty.

TMEM258 Is a Component of the Oligosaccharyltransferase Complex Controlling ER Stress and Intestinal Inflammation.

Significant insights into disease pathogenesis have been gleaned from population-level genetic studies; however, many loci associated with complex genetic disease contain numerous genes, and phenotypic associations cannot be assigned unequivocally. In particular, a gene-dense locus on chromosome 11 (61.5-61.65 Mb) has been associated with inflammatory bowel disease, rheumatoid arthritis, and coronary artery disease. Here, we identify TMEM258 within this locus as a central regulator of intestinal inflammation. Strikingly, Tmem258 haploinsufficient mice exhibit severe intestinal inflammation in a model of colitis. At the mechanistic level, we demonstrate that TMEM258 is a required component of the oligosaccharyltransferase complex and is essential for N-linked protein glycosylation. Consequently, homozygous deficiency of Tmem258 in colonic organoids results in unresolved endoplasmic reticulum (ER) stress culminating in apoptosis. Collectively, our results demonstrate that TMEM258 is a central mediator of ER quality control and intestinal homeostasis.

Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst.

The phagocyte oxidative burst, mediated by Nox2 NADPH oxidase-derived reactive oxygen species, confers host defense against a broad spectrum of bacterial and fungal pathogens. Loss-of-function mutations that impair function of the Nox2 complex result in a life-threatening immunodeficiency, and genetic variants of Nox2 subunits have been implicated in pathogenesis of inflammatory bowel disease (IBD). Thus, alterations in the oxidative burst can profoundly impact host defense, yet little is known about regulatory mechanisms that fine-tune this response. Here we report the discovery of regulatory nodes controlling oxidative burst by functional screening of genes within loci linked to human inflammatory disease. Implementing a multi-omics approach, we define transcriptional, metabolic and ubiquitin-cycling nodes controlled by Rbpj, Pfkl and Rnf145, respectively. Furthermore, we implicate Rnf145 in proteostasis of the Nox2 complex by endoplasmic reticulum-associated degradation. Consequently, ablation of Rnf145 in murine macrophages enhances bacterial clearance, and rescues the oxidative burst defects associated with Ncf4 haploinsufficiency.

Epidemiology and outcome of vascular trauma at a British Major Trauma Centre.

OBJECTIVES: In the United Kingdom, the epidemiology, management strategies and outcomes from vascular trauma are unknown. The aim of this study was to describe the vascular trauma experience of a British Trauma Centre. METHODS: A retrospective observational study of all patients admitted to hospital with traumatic vascular injury between 2005 and 2010. RESULTS: Vascular injuries were present in 256 patients (4.4%) of the 5823 total trauma admissions. Penetrating trauma caused 135 (53%) vascular injuries whilst the remainder resulted from blunt trauma. Compared to penetrating vascular trauma, patients with blunt trauma were more severely injured (median ISS 29 [18-38] vs. ISS 11 [9-17], p < 0.0001), had greater mortality (26% vs. 10%; OR 3.0, 95% CI 1.5-5.9; p < 0.01) and higher limb amputation rates (12% vs. 0%; p < 0.0001). Blunt vascular trauma patients were also twice as likely to require a massive blood transfusion (48% vs. 25%; p = 0.0002) and had a five-fold longer hospital length of stay (median 35 days (15-58) vs. 7 (4-13), p<0.0001) and critical care stay (median 5 days (0-11) vs. 0 (0-2), p < 0.0001) compared to patients with penetrating trauma. Multivariate regression analysis showed that age, ISS, shock and zone of injury were independent predictors of death following vascular trauma. CONCLUSION: Traumatic vascular injury accounts for 4% of admissions to a British Trauma Centre. These patients are severely injured with high mortality and morbidity, and place a significant demand on hospital resources. Integration of vascular services with regional trauma systems will be an essential part of current efforts to improve trauma care in the UK.

Human leucine-rich repeat proteins: a genome-wide bioinformatic categorization and functional analysis in innate immunity.

In innate immune sensing, the detection of pathogen-associated molecular patterns by recognition receptors typically involve leucine-rich repeats (LRRs). We provide a categorization of 375 human LRR-containing proteins, almost half of which lack other identifiable functional domains. We clustered human LRR proteins by first assigning LRRs to LRR classes and then grouping the proteins based on these class assignments, revealing several of the resulting protein groups containing a large number of proteins with certain non-LRR functional domains. In particular, a statistically significant number of LRR proteins in the typical (T) and bacterial + typical (S+T) categories have transmembrane domains, whereas most of the LRR proteins in the cysteine-containing (CC) category contain an F-box domain (which mediates interactions with the E3 ubiquitin ligase complex). Furthermore, by examining the evolutionary profiles of the LRR proteins, we identified a subset of LRR proteins exhibiting strong conservation in fungi and an enrichment for "nucleic acid-binding" function. Expression analysis of LRR genes identifies a subset of pathogen-responsive genes in human primary macrophages infected with pathogenic bacteria. Using functional RNAi, we show that MFHAS1 regulates Toll-like receptor (TLR)-dependent signaling. By using protein interaction network analysis followed by functional RNAi, we identified LRSAM1 as a component of the antibacterial autophagic response.

Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection.

Genetic ablation of autophagy in mice leads to liver and brain degeneration accompanied by the appearance of ubiquitin (Ub) inclusions, which has been considered to support the hypothesis that ubiquitination serves as a cis-acting signal for selective autophagy. We show that tissue-specific disruption of the essential autophagy genes Atg5 and Atg7 leads to the accumulation of all detectable Ub-Ub topologies, arguing against the hypothesis that any particular Ub linkage serves as a specific autophagy signal. The increase in Ub conjugates in Atg7(-/-) liver and brain is completely suppressed by simultaneous knockout of either p62 or Nrf2. We exploit a novel assay for selective autophagy in cell culture, which shows that inactivation of Atg5 leads to the selective accumulation of aggregation-prone proteins, and this does not correlate with an increase in substrate ubiquitination. We propose that protein oligomerization drives autophagic substrate selection and that the accumulation of poly-Ub chains in autophagy-deficient circumstances is an indirect consequence of activation of Nrf2-dependent stress response pathways.

Integrative systems biology and networks in autophagy.

The growing recognition that autophagy has important roles in many biological pathways, physiological systems, and infection and disease states necessitates a multidimensional perspective and systems-wide understanding of how autophagy is triggered or modulated by diverse stimuli. To delineate the nonlinearity and combinatorial complexity of biological networks and signaling pathways impinging on autophagy requires an integrative framework that brings together diverse information from genome-scale data (genomics, transcriptomics, proteomics, interactomics, functional RNAi screens) to dynamic time-series analyses and biochemical assays across a variety of biological and clinical contexts. We outline recent applications of genome-wide approaches to studying autophagy and highlight how some of these could be integrated to derive sub-networks that are more functionally focused. Viewed from a network perspective, the extensive interconnectivity between pathway systems converging on autophagy provides the essential foundation from which to systematically elucidate the regulatory nuances and crosstalks that orchestrate autophagic processes in different pathophysiological contexts.

Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine.

It is unclear why disease occurs in only a small proportion of persons carrying common risk alleles of disease susceptibility genes. Here we demonstrate that an interaction between a specific virus infection and a mutation in the Crohn's disease susceptibility gene Atg16L1 induces intestinal pathologies in mice. This virus-plus-susceptibility gene interaction generated abnormalities in granule packaging and unique patterns of gene expression in Paneth cells. Further, the response to injury induced by the toxic substance dextran sodium sulfate was fundamentally altered to include pathologies resembling aspects of Crohn's disease. These pathologies triggered by virus-plus-susceptibility gene interaction were dependent on TNFalpha and IFNgamma and were prevented by treatment with broad spectrum antibiotics. Thus, we provide a specific example of how a virus-plus-susceptibility gene interaction can, in combination with additional environmental factors and commensal bacteria, determine the phenotype of hosts carrying common risk alleles for inflammatory disease.

A major trauma centre is a specialty hospital not a hospital of specialties.

BACKGROUND: High estimates of preventable death rates have renewed the impetus for national regionalization of trauma care. Institution of a specialist multidisciplinary trauma service and performance improvement programme was hypothesized to have resulted in improved outcomes for severely injured patients. METHODS: This was a comparative analysis of data from the Royal London Hospital (RLH) trauma registry and Trauma Audit and Research Network (England and Wales), 2000-2005. Preventable mortality was evaluated by prospective analysis of the RLH performance improvement programme. RESULTS: Mortality from critical injury at the RLH was 48 per cent lower in 2005 than 2000 (17.9 versus 34.2 per cent; P = 0.001). Overall mortality rates were unchanged for acute hospitals (4.3 versus 4.4 per cent) and other multispecialty hospitals (8.7 versus 7.3 per cent). Secondary transfer mortality in critically injured patients was 53 per cent lower in the regional network than the national average (5.2 versus 11.0 per cent; P = 0.001). Preventable death rates fell from 9 to 2 per cent (P = 0.040) and significant gains were made in critical care and ward bed utilization. CONCLUSION: Institution of a specialist trauma service and performance improvement programme was associated with significant improvements in outcomes that exceeded national variations.

Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions.

Translating a set of disease regions into insight about pathogenic mechanisms requires not only the ability to identify the key disease genes within them, but also the biological relationships among those key genes. Here we describe a statistical method, Gene Relationships Among Implicated Loci (GRAIL), that takes a list of disease regions and automatically assesses the degree of relatedness of implicated genes using 250,000 PubMed abstracts. We first evaluated GRAIL by assessing its ability to identify subsets of highly related genes in common pathways from validated lipid and height SNP associations from recent genome-wide studies. We then tested GRAIL, by assessing its ability to separate true disease regions from many false positive disease regions in two separate practical applications in human genetics. First, we took 74 nominally associated Crohn's disease SNPs and applied GRAIL to identify a subset of 13 SNPs with highly related genes. Of these, ten convincingly validated in follow-up genotyping; genotyping results for the remaining three were inconclusive. Next, we applied GRAIL to 165 rare deletion events seen in schizophrenia cases (less than one-third of which are contributing to disease risk). We demonstrate that GRAIL is able to identify a subset of 16 deletions containing highly related genes; many of these genes are expressed in the central nervous system and play a role in neuronal synapses. GRAIL offers a statistically robust approach to identifying functionally related genes from across multiple disease regions--that likely represent key disease pathways. An online version of this method is available for public use (http://www.broad.mit.edu/mpg/grail/).