Chronic granulomatous disease (CGD) is characterized by overexuberant inflammation and autoimmunity that are attributed to deficient anti-inflammatory signaling. Although regulation of these ...processes is complex, phosphatidylserine (PS)–dependent recognition and removal of apoptotic cells (efferocytosis) by phagocytes are potently anti-inflammatory. Since macrophage phenotype also plays a beneficial role in resolution of inflammation, we hypothesized that impaired efferocytosis in CGD due to macrophage skewing contributes to enhanced inflammation. Here we demonstrate that efferocytosis by macrophages from CGD (gp91phox−/−) mice was suppressed ex vivo and in vivo. Alternative activation with interleukin 4 (IL-4) normalized CGD macrophage efferocytosis, whereas classical activation by lipopolysaccharide (LPS) plus interferon γ (IFNγ) had no effect. Importantly, neutralization of IL-4 in wild-type macrophages reduced macrophage efferocytosis, demonstrating a central role for IL-4. This effect was shown to involve 12/15 lipoxygenase and activation of peroxisome-proliferator activated receptor γ (PPARγ). Finally, injection of PS (whose exposure is lacking on CGD apoptotic neutrophils) in vivo restored IL-4–dependent macrophage reprogramming and efferocytosis via a similar mechanism. Taken together, these findings support the hypothesis that impaired PS exposure on dying cells results in defective macrophage programming, with consequent efferocytic impairment and has important implications in understanding the underlying cause of enhanced inflammation in CGD.
Physical activity (PA) interventions are an important but underutilised component in the management of gestational diabetes mellitus (GDM). The challenge remains how to deliver cost effective PA ...interventions that have impact on individual behaviour. Digital technologies can support and promote PA remotely at scale. We describe the development of a behaviourally informed smartphone application (Stay-Active) for women attending an NHS GDM clinic. Stay-Active will support an existing motivational interviewing intervention to increase and maintain PA in this population.
The behaviour change wheel (BCW) eight step theoretical approach was used to design the application. It provided a systematic approach to understanding the target behaviour, identifying relevant intervention functions, and specifying intervention content. The target behaviour was to increase and maintain PA. To obtain a behavioural diagnosis, qualitative evidence was combined with focus groups on the barriers and facilitators to PA in women with GDM. The findings were mapped onto the Capability Opportunity Motivation-Behaviour (COM-B) model and Theoretical Domains Framework to identify what needs to change for the target behaviour and linked to appropriate intervention functions. Finally, behaviour changes techniques (BCT) and modes of delivery that are most likely to serve the intervention functions were selected. Current evidence, patient focus groups and input from key stakeholders informed Stay-Active's development.
We found that psychological capability, reflective and automatic motivation, social and physical opportunity needed to change to increase PA in women with GDM. The four key intervention functions identified were Enablement, Education, Persuasion and Training. Stay-Active incorporates these four intervention functions delivering ten BCTs including: goal setting, credible source, self-monitoring, action planning, prompts and cues. The final design of Stay-Active delivers these BCTs via an educational resource centre, with goal setting and action planning features, personalised performance feedback and individualised promotional messages.
The BCW has enabled the systematic and comprehensive development of Stay-Active to promote PA in women with GDM within an NHS Maternity service. The next phase is to conduct a trial to assess the feasibility and acceptability of a multi-component intervention that combines Stay-Active with PA Motivational Interviewing.
To examine how the mantle lithosphere stabilises continents, we present a synthesis of the mantle beneath Zealandia in the SW Pacific Ocean. Zealandia, Earth's “8th continent”, occurs over 4.9 M km2 ...and comprises a fore-arc, arc and back-arc fragment rifted from the Australia–Antarctica Gondwana margin 85 Myr ago. The oldest extant crust is ∼500 Ma and the majority is Permian–Jurassic. Peridotitic rocks from most known locations reveal the underpinning mantle to comprise regional domains varying from refractory (Al2O3 < 1 wt%, olivine Mg# > 92, spinel Cr# up to 80, Pt/Ir < 1) to moderately depleted (Al2O3 = 2–4 wt%, olivine Mg# ∼90.5, spinel Cr# < ∼60). There is no systematic distribution of these domains relative to the former arc configuration and some refractory domains underlie crust that is largely devoid of magmatic rocks. Re-depletion Os model ages have no correlation with depletion indices but do have a distribution that is very similar to global convecting mantle. Whole rock, mineral and isotopic data are interpreted to show that the Zealandia mantle lithosphere was constructed from isotopically heterogeneous convecting mantle fragments swept into the sub-arc environment, amalgamated, and variably re-melted under low-P hydrous conditions. The paucity of mafic melt volumes in most of the overlying crust that could relate to the depleted domains requires melting to have been followed by lateral accretion either during subduction or slab rollback. Recent Australia–Pacific convergence has thickened portions of the Zealandia mantle to >160 km. Zealandia shows that the generation of refractory and/or thick continental lithosphere is not restricted to the Archean. Since Archean cratons also commonly display crust–mantle age decoupling, contain spinel peridotites with extreme Cr# numbers that require low-P hydrous melting, and often have a paucity of mafic melts relative to the extreme depletion indicated by their peridotitic roots, they too may – in part – be compilations of peridotite shallowly melted and then laterally accreted at subduction margins.
•Peridotites from a Cretaceous fore-arc, arc and back-arc fragment rifted of Gondwana.•Zealandia mantle constructed from convecting mantle fragments in a sub-arc environment.•Zealandia mantle variably re-melted under low-P hydrous conditions and laterally accreted.•Similarities to the formation of the Zealandia mantle with the mantle beneath Archean cratons.
On October 26, 2002, Russian Special Forces deployed a chemical aerosol against Chechen terrorists to rescue hostages in the Dubrovka theatre. Its use confirmed Russian military interest in chemicals ...with effects on personnel and caused 125 deaths through a combination of the aerosol and inadequate medical care. This study provides evidence from liquid chromatography-tandem mass spectrometry analysis of extracts of clothing from two British survivors, and urine from a third survivor, that the aerosol comprised a mixture of two anaesthetics-carfentanil and remifentanil-whose relative proportions this study was unable to identify. Carfentanil and remifentanil were found on a shirt sample and a metabolite called norcarfentanil was found in a urine sample. This metabolite probably originated from carfentanil.
Absence of a functional nicotinamide adenine dinucleotide phosphate (NADPH) oxidase predisposes chronic granulomatous disease (CGD) patients to infection, and also to unexplained, exaggerated ...inflammation. The impaired recognition and removal (efferocytosis) of apoptotic neutrophils by CGD macrophages may contribute to this effect. We hypothesized that peroxisome proliferator-activated receptor γ (PPARγ) activation during CGD inflammation is deficient, leading to altered macrophage programming and decreased efferocytosis, and that PPARγ agonism would enhance resolution. using the gp91phox−/− murine model of X-linked CGD in a well-characterized model of sterile, zymosan-induced peritonitis, it was demonstrated that PPARγ expression and activation in CGD macrophages were significantly deficient at baseline, and acquisition was delayed over the course of inflammation relative to that of wild-type. Efferocytosis by macrophages reflected PPARγ activation during peritonitis and was impaired in CGD mice (versus wild-type), leading to accumulation of apoptotic neutrophils. Importantly, provision of the PPARγ agonist, pioglitazone, either prophylactically or during inflammation, significantly enhanced macrophage PPARγ-mediated programming and efferocytosis, reduced accumulation of apoptotic neutrophils, and normalized the course of peritonitis in CGD mice. As such, PPARγ may be a therapeutic target for CGD, and possibly other inflammatory conditions where aberrant macrophage programming and impaired efferocytosis delay resolution of inflammation.
Coupled 187Os/188Os compositions and highly-siderophile-element (HSE: Os, Ir, Ru, Pt, Pd, and Re) abundance data are reported for eight angrite achondrite meteorites that include quenched- and ...slowly-cooled textural types. These data are combined with new major- and trace-element concentrations determined for bulk-rock powder fractions and constituent mineral phases, to assess angrite petrogenesis. Angrite meteorites span a wide-range of HSE abundances from <0.005ppb Os (e.g., Northwest Africa NWA 1296; Angra dos Reis) to >100ppb Os (NWA 4931). Chondritic to supra-chondritic 187Os/188Os (0.1201–0.2127) measured for Angra dos Reis and quenched-angrites correspond to inter- and intra-sample heterogeneities in Re/Os and HSE abundances. Quenched-angrites have chondritic-relative rare-earth-element (REE) abundances at 10–15×CI-chondrite, and their Os-isotope and HSE abundance variations represent mixtures of pristine uncontaminated crustal materials that experienced addition (<0.8%) of exogenous chondritic materials during or after crystallization. Slowly-cooled angrites (NWA 4590 and NWA 4801) have fractionated REE-patterns, chondritic to sub-chondritic 187Os/188Os (0.1056–0.1195), as well as low-Re/Os (0.03–0.13), Pd/Os (0.071–0.946), and relatively low-Pt/Os (0.792–2.640). Sub-chondritic 187Os/188Os compositions in NWA 4590 and NWA 4801 are unusual amongst planetary basalts, and their HSE and REE characteristics may be linked to melting of mantle sources that witnessed prior basaltic melt depletion. Angrite HSE-Yb systematics suggest that the HSE behaved moderately-incompatibly during angrite magma crystallization, implying the presence of metal in the crystallizing assemblage.
The new HSE abundance and 187Os/188Os compositions indicate that the silicate mantle of the angrite parent body(ies) (APB) had HSE abundances in chondritic-relative proportions but at variable abundances at the time of angrite crystallization. The HSE systematics of angrites are consistent with protracted post-core formation accretion of materials with chondritic-relative abundances of HSE to the APB, and these accreted materials were rapidly, yet inefficiently, mixed into angrite magma source regions early in Solar System history.
► We provide 187Os/188Os compositions and HSE abundance data for eight angrite meteorites. ► Some angrites have extremely unusual sub-chondritic 187Os/188Os. ► Angrites witnessed variable amounts of pre-crystallization chondritic additions during late accretion.
Although the importance of clathrin- and caveolin-independent endocytic pathways has recently emerged, key aspects of these routes remain unknown. Using quantitative ultrastructural approaches, we ...show that clathrin-independent carriers (CLICs) account for approximately three times the volume internalized by the clathrin-mediated endocytic pathway, forming the major pathway involved in uptake of fluid and bulk membrane in fibroblasts. Electron tomographic analysis of the 3D morphology of the earliest carriers shows that they are multidomain organelles that form a complex sorting station as they mature. Proteomic analysis provides direct links between CLICs, cellular adhesion turnover, and migration. Consistent with this, CLIC-mediated endocytosis of key cargo proteins, CD44 and Thy-1, is polarized at the leading edge of migrating fibroblasts, while transient ablation of CLICs impairs their ability to migrate. These studies provide the first quantitative ultrastructural analysis and molecular characterization of the major endocytic pathway in fibroblasts, a pathway that provides rapid membrane turnover at the leading edge of migrating cells.
Patients undergoing hematopoietic stem cell transplant (HSCT) are at risk for bloodstream infection (BSI) secondary to translocation of bacteria through the injured mucosa, termed mucosal barrier ...injury-laboratory confirmed bloodstream infection (MBI-LCBI), in addition to BSI secondary to indwelling catheters and infection at other sites (BSI-other).
To determine the incidence, timing, risk factors, and outcomes of patients who develop MBI-LCBI in the first 100 days after HSCT.
A case-cohort retrospective analysis was performed using data from the Center for International Blood and Marrow Transplant Research database on 16 875 consecutive pediatric and adult patients receiving a first allogeneic HSCT from January 1, 2009, to December 31, 2016. Patients were classified into 4 categories: MBI-LCBI (1481 8.8%), MBI-LCBI and BSI-other (698 4.1%), BSI-other only (2928 17.4%), and controls with no BSI (11 768 69.7%). Statistical analysis was performed from April 5 to July 17, 2018.
Demographic characteristics and outcomes, including overall survival, chronic graft-vs-host disease, and transplant-related mortality (only for patients with malignant disease), were compared among groups.
Of the 16 875 patients in the study (9737 57.7% male; median range age, 47 0.04-82 years) 13 686 (81.1%) underwent HSCT for a malignant neoplasm, and 3189 (18.9%) underwent HSCT for a nonmalignant condition. The cumulative incidence of MBI-LCBI was 13% (99% CI, 12%-13%) by day 100, and the cumulative incidence of BSI-other was 21% (99% CI, 21%-22%) by day 100. Median (range) time from transplant to first MBI-LCBI was 8 (<1 to 98) days vs 29 (<1 to 100) days for BSI-other. Multivariable analysis revealed an increased risk of MBI-LCBI with poor Karnofsky/Lansky performance status (hazard ratio HR, 1.21 99% CI, 1.04-1.41), cord blood grafts (HR, 2.89 99% CI, 1.97-4.24), myeloablative conditioning (HR, 1.46 99% CI, 1.19-1.78), and posttransplant cyclophosphamide graft-vs-host disease prophylaxis (HR, 1.85 99% CI, 1.38-2.48). One-year mortality was significantly higher for patients with MBI-LCBI (HR, 1.81 99% CI, 1.56-2.12), BSI-other (HR, 1.81 99% CI, 1.60-2.06), and MBI-LCBI plus BSI-other (HR, 2.65 99% CI, 2.17-3.24) compared with controls. Infection was more commonly reported as a cause of death for patients with MBI-LCBI (139 of 740 18.8%), BSI (251 of 1537 16.3%), and MBI-LCBI plus BSI (94 of 435 21.6%) than for controls (566 of 4740 11.9%).
In this cohort study, MBI-LCBI, in addition to any BSIs, were associated with significant morbidity and mortality after HSCT. Further investigation into risk reduction should be a clinical and scientific priority in this patient population.
The acute gout flare results from a localised self-limiting innate immune response to monosodium urate (MSU) crystals deposited in joints in hyperuricaemic individuals. Activation of the caspase ...recruitment domain-containing protein 8 (CARD8) NOD-like receptor pyrin-containing 3 (NLRP3) inflammasome by MSU crystals and production of mature interleukin-1β (IL-1β) is central to acute gouty arthritis. However very little is known about genetic control of the innate immune response involved in acute gouty arthritis. Therefore our aim was to test functional single nucleotide polymorphism (SNP) variants in the toll-like receptor (TLR)-inflammasome-IL-1β axis for association with gout.
1,494 gout cases of European and 863 gout cases of New Zealand (NZ) Polynesian (Māori and Pacific Island) ancestry were included. Gout was diagnosed by the 1977 ARA gout classification criteria. There were 1,030 Polynesian controls and 10,942 European controls including from the publicly-available Atherosclerosis Risk in Communities (ARIC) and Framingham Heart (FHS) studies. The ten SNPs were either genotyped by Sequenom MassArray or by Affymetrix SNP array or imputed in the ARIC and FHS datasets. Allelic association was done by logistic regression adjusting by age and sex with European and Polynesian data combined by meta-analysis. Sample sets were pooled for multiplicative interaction analysis, which was also adjusted by sample set.
Eleven SNPs were tested in the TLR2, CD14, IL1B, CARD8, NLRP3, MYD88, P2RX7, DAPK1 and TNXIP genes. Nominally significant (P < 0.05) associations with gout were detected at CARD8 rs2043211 (OR = 1.12, P = 0.007), IL1B rs1143623 (OR = 1.10, P = 0.020) and CD14 rs2569190 (OR = 1.08; P = 0.036). There was significant multiplicative interaction between CARD8 and IL1B (P = 0.005), with the IL1B risk genotype amplifying the risk effect of CARD8.
There is evidence for association of gout with functional variants in CARD8, IL1B and CD14. The gout-associated allele of IL1B increases expression of IL-1β - the multiplicative interaction with CARD8 would be consistent with a synergy of greater inflammasome activity (resulting from reduced CARD8) combined with higher levels of pre-IL-1β expression leading to increased production of mature IL-1β in gout.
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