Neural cell responses to wear debris from metal-on-metal total disc replacements

PURPOSE: Total disc replacements, comprising all-metal articulations, are compromised by wear and particle production. Metallic wear debris and ions trigger a range of biological responses including inflammation, genotoxicity, cytotoxicity, hypersensitivity and pseudotumour formation, therefore we hypothesise that, due to proximity to the spinal cord, glial cells may be adversely affected. METHODS: Clinically relevant cobalt chrome (CoCr) and stainless steel (SS) wear particles were generated using a six-station pin-on-plate wear simulator. The effects of metallic particles (0.5-50 μm3 debris per cell) and metal ions on glial cell viability, cellular activity (glial fibrillary acidic protein (GFAP) expression) and DNA integrity were investigated in 2D and 3D culture using live/dead, immunocytochemistry and a comet assay, respectively. RESULTS: CoCr wear particles and ions caused significant reductions in glial cell viability in both 2D and 3D culture systems. Stainless steel particles did not affect glial cell viability or astrocyte activation. In contrast, ions released from SS caused significant reductions in glial cell viability, an effect that was especially noticeable when astrocytes were cultured in isolation without microglia. DNA damage was observed in both cell types and with both biomaterials tested. CoCr wear particles had a dose-dependent effect on astrocyte activation, measured through expression of GFAP. CONCLUSIONS: The results from this study suggest that microglia influence the effects that metal particles have on astrocytes, that SS ions and particles play a role in the adverse effects observed and that SS is a less toxic biomaterial than CoCr alloy for use in spinal devices. These slides can be retrieved under Electronic Supplementary Material

Potential for HPV vaccination and primary HPV screening to reduce cervical cancer disparities: Example from New Zealand

Background Cervical cancer rates are over twice as high, and screening coverage is lower, in Māori women compared to other women in New Zealand, whereas uptake of HPV vaccine is higher in Maori females. We aimed to assess the impact of HPV vaccination and the proposed transition to 5-yearly primary HPV screening in Māori and other women in New Zealand, at current participation levels; and additionally to investigate which improvements to participation in Māori females (in vaccination, screening, or surveillance for screening-defined higher-risk women) would have the greatest impact on cervical cancer incidence/mortality. Methods An established model of HPV vaccination and cervical screening in New Zealand was adapted to fit observed ethnicity-specific data. Ethnicity-specific models were used to estimate the long-term impact of vaccination and screening (vaccination coverage 63% vs 47%; five-year screening coverage 68% vs 81% in Maori vs European/Other women, respectively). Results Shifting from cytology to HPV-based screening is predicted to reduce cervical cancer incidence by 17% (14%) in Maori (European/Other) women, respectively. The corresponding reductions due to vaccination and HPV-based screening combined were 58% (44%), but at current participation levels long-term incidence would remain almost twice as high in Māori women (6.1/100,000 compared to 3.1/100,00 in European/Other women). Among strategies we examined, the greatest impact came from high vaccine coverage and achieving higher attendance by Māori women under surveillance for screen-detected abnormalities. Conclusion Relative reductions in cervical cancer due to vaccination and HPV-based screening are predicted to be greater in Maori than in European/Other women. While these interventions have the potential to substantially reduce between-group differences, cervical cancer incidence would remain higher in Maori women. These findings highlight the importance of multiple approaches and the potential influence of factors beyond HPV prevention

Magnetoresistive biosensors with on-chip pulsed excitation and magnetic correlated double sampling.

Giant magnetoresistive (GMR) sensors have been shown to be among the most sensitive biosensors reported. While high-density and scalable sensor arrays are desirable for achieving multiplex detection, scalability remains challenging because of long data acquisition time using conventional readout methods. In this paper, we present a scalable magnetoresistive biosensor array with an on-chip magnetic field generator and a high-speed data acquisition method. The on-chip field generators enable magnetic correlated double sampling (MCDS) and global chopper stabilization to suppress 1/f noise and offset. A measurement with the proposed system takes only 20 ms, approximately 50× faster than conventional frequency domain analysis. A corresponding time domain temperature correction technique is also presented and shown to be able to remove temperature dependence from the measured signal without extra measurements or reference sensors. Measurements demonstrate detection of magnetic nanoparticles (MNPs) at a signal level as low as 6.92 ppm. The small form factor enables the proposed platform to be portable as well as having high sensitivity and rapid readout, desirable features for next generation diagnostic systems, especially in point-of-care (POC) settings

Coevolution with bacteriophages drives genome-wide host evolution and constrains the acquisition of abiotic-beneficial mutations

This is the author accepted manuscript. The final version is available from OUP via the DOI in this record.Studies of antagonistic coevolution between hosts and parasites typically focus on resistance and infectivity traits. However, coevolution could also have genome-wide effects on the hosts due to pleiotropy, epistasis, or selection for evolvability. Here, we investigate these effects in the bacterium Pseudomonas fluorescens SBW25 during approximately 400 generations of evolution in the presence or absence of bacteriophage (coevolution or evolution treatments, respectively). Coevolution resulted in variable phage resistance, lower competitive fitness in the absence of phages, and greater genome-wide divergence both from the ancestor and between replicates, in part due to the evolution of increased mutation rates. Hosts from coevolution and evolution treatments had different suites of mutations. A high proportion of mutations observed in coevolved hosts were associated with a known phage target binding site, the lipopolysaccharide (LPS), and correlated with altered LPS length and phage resistance. Mutations in evolved bacteria were correlated with higher fitness in the absence of phages. However, the benefits of these growth-promoting mutations were completely lost when these bacteria were subsequently coevolved with phages, indicating that they were not beneficial in the presence of resistance mutations (consistent with negative epistasis). Our results show that in addition to affecting genome-wide evolution in loci not obviously linked to parasite resistance, coevolution can also constrain the acquisition of mutations beneficial for growth in the abiotic environment.This work was funded by European Research Council and NERC (UK)

Neural cell responses to wear debris from metal-on-metal total disc replacements

Abstract: Total disc replacements, comprising all-metal articulations, are compromised by wear and particle production. Metallic wear debris and ions trigger a range of biological responses including inflammation, genotoxicity, cytotoxicity, hypersensitivity and pseudotumour formation, therefore we hypothesise that, due to proximity to the spinal cord, glial cells may be adversely affected. Methods: Clinically relevant cobalt chrome (CoCr) and stainless steel (SS) wear particles were generated using a six-station pin-on-plate wear simulator. The effects of metallic particles (0.5–50 μm3 debris per cell) and metal ions on glial cell viability, cellular activity (glial fibrillary acidic protein (GFAP) expression) and DNA integrity were investigated in 2D and 3D culture using live/dead, immunocytochemistry and a comet assay, respectively. Results: CoCr wear particles and ions caused significant reductions in glial cell viability in both 2D and 3D culture systems. Stainless steel particles did not affect glial cell viability or astrocyte activation. In contrast, ions released from SS caused significant reductions in glial cell viability, an effect that was especially noticeable when astrocytes were cultured in isolation without microglia. DNA damage was observed in both cell types and with both biomaterials tested. CoCr wear particles had a dose-dependent effect on astrocyte activation, measured through expression of GFAP. Conclusions: The results from this study suggest that microglia influence the effects that metal particles have on astrocytes, that SS ions and particles play a role in the adverse effects observed and that SS is a less toxic biomaterial than CoCr alloy for use in spinal devices

First Evidence of Dinosaurian Secondary Cartilage in the Post-Hatching Skull of Hypacrosaurus stebingeri (Dinosauria, Ornithischia)

Bone and calcified cartilage can be fossilized and preserved for hundreds of millions of years. While primary cartilage is fairly well studied in extant and fossilized organisms, nothing is known about secondary cartilage in fossils. In extant birds, secondary cartilage arises after bone formation during embryonic life at articulations, sutures and muscular attachments in order to accommodate mechanical stress. Considering the phylogenetic inclusion of birds within the Dinosauria, we hypothesized a dinosaurian origin for this “avian” tissue. Therefore, histological thin sectioning was used to investigate secondary chondrogenesis in disarticulated craniofacial elements of several post-hatching specimens of the non-avian dinosaur Hypacrosaurus stebingeri (Ornithischia, Lambeosaurinae). Secondary cartilage was found on three membrane bones directly involved with masticatory function: (1) as nodules on the dorso-caudal face of a surangular; and (2) on the bucco-caudal face of a maxilla; and (3) between teeth as islets in the alveolar processes of a dentary. Secondary chondrogenesis at these sites is consistent with the locations of secondary cartilage in extant birds and with the induction of the cartilage by different mechanical factors - stress generated by the articulation of the quadrate, stress of a ligamentous or muscular insertion, and stress of tooth formation. Thus, our study reveals the first evidence of “avian” secondary cartilage in a non-avian dinosaur. It pushes the origin of this “avian” tissue deep into dinosaurian ancestry, suggesting the creation of the more appropriate term “dinosaurian” secondary cartilage

A model for reactive porous transport during re-wetting of hardened concrete

A mathematical model is developed that captures the transport of liquid water in hardened concrete, as well as the chemical reactions that occur between the imbibed water and the residual calcium silicate compounds residing in the porous concrete matrix. The main hypothesis in this model is that the reaction product -- calcium silicate hydrate gel -- clogs the pores within the concrete thereby hindering water transport. Numerical simulations are employed to determine the sensitivity of the model solution to changes in various physical parameters, and compare to experimental results available in the literature.Comment: 30 page

Understanding pregnancy planning in a low-income country setting: validation of the London measure of unplanned pregnancy in Malawi

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: The London Measure of Unplanned Pregnancy (LMUP) is a new and psychometrically valid measure of pregnancy intention that was developed in the United Kingdom. An improved understanding of pregnancy intention in low-income countries, where unintended pregnancies are common and maternal and neonatal deaths are high, is necessary to inform policies to address the unmet need for family planning. To this end this research aimed to validate the LMUP for use in the Chichewa language in Malawi.Methods: Three Chichewa speakers translated the LMUP and one translation was agreed which was back-translated and pre-tested on five pregnant women using cognitive interviews. The measure was field tested with pregnant women who were recruited at antenatal clinics and data were analysed using classical test theory and hypothesis testing.Results: 125 women aged 15-43 (median 23), with parities of 1-8 (median 2) completed the Chichewa LMUP. There were no missing data. The full range of LMUP scores was captured. In terms of reliability, the scale was internally consistent (Cronbach's alpha = 0.78) and test-retest data from 70 women showed good stability (weighted Kappa 0.80). In terms of validity, hypothesis testing confirmed that unmarried women (p = 0.003), women who had four or more children alive (p = 0.0051) and women who were below 20 or over 29 (p = 0.0115) were all more likely to have unintended pregnancies. Principal component analysis showed that five of the six items loaded onto one factor, with a further item borderline. A sensitivity analysis to assess the effect of the removal of the weakest item of the scale showed slightly improved performance but as the LMUP was not significantly adversely affected by its inclusion we recommend retaining the six-item score.Conclusion: The Chichewa LMUP is a valid and reliable measure of pregnancy intention in Malawi and can now be used in research and/or surveillance. This is the first validation of this tool in a low-income country, helping to demonstrate that the concept of pregnancy planning is applicable in such a setting. Use of the Chichewa LMUP can enhance our understanding of pregnancy intention in Malawi, giving insight into the family planning services that are required to better meet women's needs and save lives. © 2013 Hall et al.; licensee BioMed Central Ltd.Dr Hall’s Wellcome Trust Research Training Fellowship, grant number 097268/Z/11/Z

In vivo tau PET imaging in dementia: Pathophysiology, radiotracer quantification, and a systematic review of clinical findings.

In addition to the deposition of β-amyloid plaques, neurofibrillary tangles composed of aggregated hyperphosphorylated tau are one of the pathological hallmarks of Alzheimer's disease and other neurodegenerative disorders. Until now, our understanding about the natural history and topography of tau deposition has only been based on post-mortem and cerebrospinal fluid studies, and evidence continues to implicate tau as a central driver of downstream neurodegenerative processes and cognitive decline. Recently, it has become possible to assess the regional distribution and severity of tau burden in vivo with the development of novel radiotracers for positron emission tomography (PET) imaging. In this article, we provide a comprehensive discussion of tau pathophysiology, its quantification with novel PET radiotracers, as well as a systematic review of tau PET imaging in normal aging and various dementia conditions: mild cognitive impairment, Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy, and Lewy body dementia. We discuss the main findings in relation to group differences, clinical-cognitive correlations of tau PET, and multi-modal relationships among tau PET and other pathological markers. Collectively, the small but growing literature of tau PET has yielded consistent anatomical patterns of tau accumulation that recapitulate post-mortem distribution of neurofibrillary tangles which correlate with cognitive functions and other markers of pathology. In general, AD is characterised by increased tracer retention in the inferior temporal lobe, extending into the frontal and parietal regions in more severe cases. It is also noted that the spatial topography of tau accumulation is markedly distinct to that of amyloid burden in aging and AD. Tau PET imaging has also revealed characteristic spatial patterns among various non-AD tauopathies, supporting its potential role for differential diagnosis. Finally, we propose novel directions for future tau research, including (a) longitudinal imaging in preclinical dementia, (b) multi-modal mapping of tau pathology onto other pathological processes such as neuroinflammation, and (c) the need for more validation studies against post-mortem samples of the same subjects.The study is supported by the UK National Institute of Health Research Cambridge Biomedical Research Centre and Biomedical Research Unit in Dementia. JBR is supported by the Wellcome Trust (103838). EM is in receipt of a Gates Cambridge scholarship and an Alzheimer’s Research UK Research Grant