Analysis of bearing wear, whole blood and synovial fluid metal ion concentrations and histopathological findings in patients with failed ASR hip resurfacings

Background Adverse Reaction to Metal Debris (ARMD) is still a major reason for revision surgeries in patients with metal-on-metal (MoM) hip replacements. ARMD consists of a wide range of alterations in periprosthetic tissues, most important of which are metallosis, inflammation, pseudotumors and necrosis. Studies investigating histopathological findings and their association to implant wear or indirect measures of wear have yielded inconsistent results. Therefore, we aimed to investigate bearing surface wear volume, whole blood and synovial fluid metal ion concentrations, histopathological findings in periprosthetic tissues and their associations. Methods Seventy-eight patients with 85 hips revised for ARMD were included in the study. Prior to revision surgery, all patients had whole blood chromium and cobalt ion levels assessed. In revision surgery, a synovial fluid sample was taken and analyzed for chromium and cobalt. Periprosthetic tissue samples were taken and analyzed for histopathological findings. Explanted implants were analyzed for bearing wear volume of both acetabular cup and femoral head components. Results Volumetric wear of the failed components was highly variable. The total wear volume of the head and cup had a strong correlation with whole blood chromium and cobalt ion concentrations (Cr: ρ = 0.80, p < 0.001 and Co: ρ = 0.84, p < 0.001) and a bit weaker correlation with fluid chromium and cobalt ion concentrations (Cr: ρ = 0.50, p < 0.01 and Co: ρ = 0.41, p = 0.027). Most tissues displayed only low-to-moderate amounts of macrophages and lymphocytes. Total wear volume correlated with macrophage sheet thickness (ρ = 0.25, p = 0.020) and necrosis (ρ = 0.35, p < 0.01). Whole blood chromium and cobalt ion concentrations had similar correlations. Lymphocyte cuff thickness did not correlate with either total wear volume or whole blood metal ion concentrations, but correlated with the grade of necrosis. Conclusions Bearing wear volume correlated with blood metal ion levels and the degree of necrosis and macrophage infiltration in periprosthetic tissues suggesting a dose-response relationship. Whole blood metal ion levels are a useful tool for clinician to estimate bearing wear and subsequent tissue response

Inhibition of ammonia monooxygenase from ammonia oxidising archaea by linear and aromatic alkynes

Ammonia monooxygenase (AMO) is a key nitrogen-transforming enzyme belonging to the same copper-dependent membrane monooxygenase family (CuMMO) as the particulate methane monooxygenase (pMMO). The AMO from ammonia-oxidizing archaea (AOA) is very divergent from both the AMO of ammonia-oxidizing bacteria (AOB) and the pMMO from methanotrophs, and little is known about the structure or substrate range of the archaeal AMO. This study compares inhibition by C 2 to C 8 linear 1-alkynes of AMO from two phylogenetically distinct strains of AOA, " Candidatus Nitrosocosmicus franklandus" C13 and " Candidatus Nitrosotalea sinensis" Nd2, with AMO from Nitrosomonas europaea and pMMO from Methylococcus capsulatus (Bath). An increased sensitivity of the archaeal AMO to short-chain-length alkynes (≤C 5) appeared to be conserved across AOA lineages. Similarities in C 2 to C 8 alkyne inhibition profiles between AMO from AOA and pMMO from M. capsulatus suggested that the archaeal AMO has a narrower substrate range than N. europaea AMO. Inhibition of AMO from " Ca Nitrosocosmicus franklandus" and N. europaea by the aromatic alkyne phenylacetylene was also investigated. Kinetic data revealed that the mechanisms by which phenylacetylene inhibits " Ca Nitrosocosmicus franklandus" and N. europaea are different, indicating differences in the AMO active site between AOA and AOB. Phenylacetylene was found to be a specific and irreversible inhibitor of AMO from " Ca Nitrosocosmicus franklandus," and it does not compete with NH 3 for binding at the active site. IMPORTANCE Archaeal and bacterial ammonia oxidizers (AOA and AOB, respectively) initiate nitrification by oxidizing ammonia to hydroxylamine, a reaction catalyzed by ammonia monooxygenase (AMO). AMO enzyme is difficult to purify in its active form, and its structure and biochemistry remain largely unexplored. The bacterial AMO and the closely related particulate methane monooxygenase (pMMO) have a broad range of hydrocarbon cooxidation substrates. This study provides insights into the AMO of previously unstudied archaeal genera, by comparing the response of the archaeal AMO, a bacterial AMO, and pMMO to inhibition by linear 1-alkynes and the aromatic alkyne, phenylacetylene. Reduced sensitivity to inhibition by larger alkynes suggests that the archaeal AMO has a narrower hydrocarbon substrate range than the bacterial AMO, as previously reported for other genera of AOA. Phenylacetylene inhibited the archaeal and bacterial AMOs at different thresholds and by different mechanisms of inhibition, highlighting structural differences between the two forms of monooxygenase

Lack of evidence-the anti-stepwise introduction of metal-on-metal hip replacements: A systematic review and a comparative assessment of the literature and registry data

Background and purpose - Orthopedics and especially joint replacement surgery have had more than their fair share of unsuccessful innovations that have violated widely endorsed principles for the introduction of new surgical innovations. We aimed to investigate (1) the trends in the use of the Birmingham Hip Resurfacing (BHR), the ASR hip resurfacing (ASR HRA) and the ASR XL total hip replacement (ASR XL THR) system with very different market approval processes and (2) whether their use was corroborated by clinical trials published in the peer-reviewed literature.Methods - The literature was searched for any clinical studies that reported outcomes of the BHR, ASR HRA and ASR XL THRs. Data from 7 national hip arthroplasty registers were collected and the number of annually implanted devices was matched to those reported in the literature.Results - The cumulative number of implanted and published BHRs grew proportionally with a small lag. The growth of implanted BHRs started to decline at the same time as the ASR HR was introduced. With regard to ASR HRAs, the cumulative proportion of implanted hips and those included in the published studies grew disproportionately after the introduction of the ASR in 2003. For ASR XL THRs, the disproportionality is even higher.Interpretation - The adoption of ASR hip replacements did not follow the proposed stepwise introduction of orthopedic implants. The adoption and use of any new implant should follow a strict guideline and algorithm even if the theoretical basis or the results of preclinical studies are excellent

Bivariate genetic modelling of the response to an oral glucose tolerance challenge: A gene x environment interaction approach

AIMS/HYPOTHESIS: Twin and family studies have shown the importance of genetic factors influencing fasting and 2 h glucose and insulin levels. However, the genetics of the physiological response to a glucose load has not been thoroughly investigated. METHODS: We studied 580 monozygotic and 1,937 dizygotic British female twins from the Twins UK Registry. The effects of genetic and environmental factors on fasting and 2 h glucose and insulin levels were estimated using univariate genetic modelling. Bivariate model fitting was used to investigate the glucose and insulin responses to a glucose load, i.e. an OGTT. RESULTS: The genetic effect on fasting and 2 h glucose and insulin levels ranged between 40% and 56% after adjustment for age and BMI. Exposure to a glucose load resulted in the emergence of novel genetic effects on 2 h glucose independent of the fasting level, accounting for about 55% of its heritability. For 2 h insulin, the effect of the same genes that already influenced fasting insulin was amplified by about 30%. CONCLUSIONS/INTERPRETATION: Exposure to a glucose challenge uncovers new genetic variance for glucose and amplifies the effects of genes that already influence the fasting insulin level. Finding the genes acting on 2 h glucose independently of fasting glucose may offer new aetiological insight into the risk of cardiovascular events and death from all causes

Identification of monogenic variants in more than ten per cent of children without type 1 diabetes-related autoantibodies at diagnosis in the Finnish Pediatric Diabetes Register

Peer reviewe

Dynamic calcium-mediated stress response and recovery signatures in the fungal pathogen, Candida albicans

Acknowledgements AB conceived the project and wrote the manuscript. CVG conceived the experimental design. SW designed the GCaMP reporter. AM, KL, LV-M, SC and TB constructed strains and optimised imaging. MF developed the image analysis software. CVG and CP carried out the microfluidics experiments and imaging analysis. NG assisted with preparation of the manuscript. PS, SN and DMR developed and undertook the theoretical data analysis and contributed to the interpretation of the results. Funding AB, CG and TB were funded by the Wellcome Trust [Grant number 206412/A/17/Z]. AB and DR were supported by a Wellcome Trust Institutional Strategic Support Award (WT204909/Z/16/Z). CP was funded by a University of Exeter studentship (113516). This work was also supported by a Royal Society URF (UF080611), an MRC NIRG (G0900211/90671) and the MRC-Centre for Medical Mycology at the University of Exeter (MR/N006364/2). DR was funded by the Medical Research Council (MR/P022405/1). SN was supported by the Medical Research Council via the GW4 BioMed2 DTP (MR/W006308/1). MCA was supported by a European Commission ITN ‘FungiBrain’ studentship (607963). LL and SC were funded by a Wellcome Trust Institutional Strategic Support Award to the University of Aberdeen. NG acknowledges support of Wellcome Trust Investigator, Collaborative, Equipment, Strategic and Biomedical Resource awards (101873, 200208, 215599, 224323). NG and AB thank the MRC (MR/M026663/2) for support. This study/research is funded by the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.Peer reviewedPublisher PD

Host-specific factors affect the pathogenesis of adverse reaction to metal debris

BACKGROUND: Adverse Reaction to Metal Debris (ARMD) is a major reason for revision surgeries in patients with metal-on-metal (MoM) hip replacements. Most failures are related to excessively wearing implant producing harmful metal debris (extrinsic factor). As ARMD may also occur in patients with low-wearing implants, it has been suggested that there are differences in host-specific intrinsic factors contributing to the development of ARMD. However, there are no studies that have directly assessed whether the development of ARMD is actually affected by these intrinsic factors. METHODS: We included all 29 patients (out of 33 patients) with sufficient data who had undergone bilateral revision of ASR MoM hips (58 hips) at our institution. Samples of the inflamed synovia and/or pseudotumour were obtained perioperatively and sent to histopathological analysis. Total wear volumes of the implants were assessed. Patients underwent MARS-MRI imaging of the hips preoperatively. Histological findings, imaging findings and total wear volumes between the hips of each patient were compared. RESULTS: The difference in wear volume between the hips was clinically and statistically significant (median difference 15.35 mm^{3}, range 1 to 39 mm^{3}, IQR 6 to 23 mm^{3}) (p  0.05 for all comparisons). These features included macrophage sheet thickness, perivascular lymphocyte cuff thickness, presence of plasma cells, presence of diffuse lymphocytic infiltration and presence of germinal centers. CONCLUSIONS: Despite the significantly differing amounts of wear (extrinsic factor) seen between the sides, majority of the histological findings were similar in both hips and the presence of pseudotumour was symmetrical in most hips. As a direct consequence, it follows that there must be intrinsic factors which contribute to the symmetry of the findings, ie. the pathogenesis of ARMD, on individual level. This has been hypothesized in the literature but no studies have been conducted to confirm the hypothesis. Further, as the threshold of metal debris needed to develop ARMD appears to be largely variable based on the previous literature, it is likely that there are between-patient differences in these intrinsic factors, ie. the host response to metal debris is individual

Dynamic calcium-mediated stress response and recovery signatures in the fungal pathogen, Candida albicans

This is the final version. Available on open access from the American Society for Microbiology via the DOI in this recordIntracellular calcium signaling plays an important role in the resistance and adaptation to stresses encountered by fungal pathogens within the host. This study reports the optimization of the GCaMP fluorescent calcium reporter for live-cell imaging of dynamic calcium responses in single cells of the pathogen, Candida albicans, for the first time. Exposure to membrane, osmotic or oxidative stress generated both specific changes in single cell intracellular calcium spiking and longer calcium transients across the population. Repeated treatments showed that calcium dynamics become unaffected by some stresses but not others, consistent with known cell adaptation mechanisms. By expressing GCaMP in mutant strains and tracking the viability of individual cells over time, the relative contributions of key signaling pathways to calcium flux, stress adaptation, and cell death were demonstrated. This reporter, therefore, permits the study of calcium dynamics, homeostasis, and signaling in C. albicans at a previously unattainable level of detail.Wellcome TrustUniversity of ExeterRoyal SocietyMedical Research Council (MRC)European CommissionNational Institute for Health and Care Research (NIHR

Genetic influences on the insulin response of the beta cell to different secretagogues

Aims/hypothesis: The aim of the present study was to estimate the heritability of the beta cell insulin response to glucose and to glucose combined with glucagon-like peptide-1 (GLP-1) or with GLP-1 plus arginine. Methods: This was a twin-family study that included 54 families from the Netherlands Twin Register. The participants were healthy twin pairs and their siblings of the same sex, aged 20 to 50 years. Insulin response of the beta cell was assessed by a modified hyperglycaemic clamp with additional GLP-1 and arginine. Insulin sensitivity index (ISI) was assessed by the euglycaemic-hyperinsulinaemic clamp. Multivariate structural equation modelling was used to obtain heritabilities and the genetic factors underlying individual differences in BMI, ISI and secretory responses of the beta cell. Results: The heritability of insulin levels in response to glucose was 52% and 77% for the first and second phase, respectively, 53% in response to glucose+GLP-1 and 80% in response to an additional arginine bolus. Insulin responses to the administration of glucose, glucose+GLP-1 and glucose+GLP-1+arginine were highly correlated (0.62<r<0.79). Heritability of BMI and ISI was 74% and 60% respectively. The genetic factors that influenced BMI and ISI explained about half of the heritability of insulin levels in response to the three secretagogues. The other half was due to genetic factors specific to the beta cell. Conclusions/interpretation: In healthy adults, genetic factors explain most of the individual differences in the secretory capacity of the beta cell. These genetic influences are partly independent from the genes that influence BMI and ISI. © 2009 Springer-Verlag