The Presence of Inducible Cytochrome P450 Types 1A1 and 1A2 in the BeWo Cell Line

Please note that this is an author-produced PDF of an article accepted for publication following peer review. The publisher version is available on its site.The activity and inducibility of cytochrome P450 systems (CYP1A1:1A2) of the human placenta were assessed in a representative human trophoblast-like cell line, BeWo. The activity of CYP1A1 and CYP1A2 in microsome preparations from human liver, placenta, primary cultures of human cytotrophoblast, and BeWo cells was measured by O-dealkylation of 7-ethoxyresorufin (EROD) and 7-methoxyresorufin O-demethylation (MROD), respectively. Results indicated high EROD and MROD activity associated with human liver microsomes, sometimes comparable activities in human placenta microsomes prepared from smokers, and relatively low activities in human placenta microsomes from nonsmokers and in the primary cultures of cytotrophoblasts isolated from nonsmokers. Microsomes from BeWo cell monolayers exhibited the lowest EROD and MROD activities relative to all other microsome preparations. However, compared to primary cultures of normal trophoblasts, the EROD activity of the BeWo cells was far more sensitive to typical inducers, 3-methylcholanthrene, 1,2-benzanthracene, and β-naphthoflavone. EROD activity in BeWo cells was induced approximately 200-fold by 3-methylcholanthrene. Both EROD and MROD activity in BeWo cells was readily induced by 1,2-benzanthracene, 100-fold and 60-fold, respectively. After induction with 1,2-benzanthracene, the CYP1A1 selective inhibitor, α-naphthoflavone, and the CYP1A2 selective inhibitor, furafylline, effectively inhibited enzyme activities with IC50’s of 2.4μM and 12.8μM, respectively, in microsomes from both trophoblasts culture systems. These results show that major cytochrome P450 forms present in human placenta are present and inducible in BeWo cells, a potential model for investigation of drug metabolism mechanisms in the human trophoblast

Centrifuge modeling of rocking-isolated inelastic RC bridge piers

Experimental proof is provided of an unconventional seismic design concept, which is based on deliberately underdesigning shallow foundations to promote intense rocking oscillations and thereby to dramatically improve the seismic resilience of structures. Termed rocking isolation, this new seismic design philosophy is investigated through a series of dynamic centrifuge experiments on properly scaled models of a modern reinforced concrete (RC) bridge pier. The experimental method reproduces the nonlinear and inelastic response of both the soil-footing interface and the structure. To this end, a novel scale model RC (1:50 scale) that simulates reasonably well the elastic response and the failure of prototype RC elements is utilized, along with realistic representation of the soil behavior in a geotechnical centrifuge. A variety of seismic ground motions are considered as excitations. They result in consistent demonstrably beneficial performance of the rocking-isolated pier in comparison with the one designed conventionally. Seismic demand is reduced in terms of both inertial load and deck drift. Furthermore, foundation uplifting has a self-centering potential, whereas soil yielding is shown to provide a particularly effective energy dissipation mechanism, exhibiting significant resistance to cumulative damage. Thanks to such mechanisms, the rocking pier survived, with no signs of structural distress, a deleterious sequence of seismic motions that caused collapse of the conventionally designed pier. © 2014 The Authors Earthquake Engineering & Structural Dynamics Published by John Wiley & Sons Ltd

Hyperuricaemia: a marker of increased cardiovascular risk in rheumatic patients: analysis of the ACT-CVD cohort

Background Gout and hyperuricaemia may be associated with increased cardiovascular risk, but analyses in different populations show conflicting results. This study investigates the impact of serum uric acid, inflammation and traditional CV risk parameters on CV event risk in patients with gouty arthritis and patients with non-gouty rheumatic disease. Methods cross-sectional and prospective multivariate analysis of the relation between tertiles of serum uric acid and individual traditional CV risk factors in a cohort of gouty arthritis (GA, n=172), rheumatoid arthritis (RA, n=480) and osteoarthritis (OA, n=206) patients. Main outcome measures: systolic blood pressure, TC/HDL ratio, GlyHb, BMI and first CV events. Results Individual CV risk factors were significantly less favourable in GA (systolic blood pressure, TC/HDL ratio, BMI, p<0.05). In RA and OA, but not in GA, individual cardiometabolic parameters correlated with serum uric acid values (OA: RA: systolic blood pressure, TC/HDL ratio, BMI; systolic blood pressure, TC/HDL ratio, GlyHb, BMI; p<0.05). In non-GA individuals the highest tertile of serum uric acid (>0.34 mmol/L) and NT proBNP level were independent predictors of first CV events, against age and GlyHb level in GA (p<0.05). The hazard of first CV events was equally significantly increased in GA patients (HR 3.169, 95% CI 1.287-7.806) and non-GA individuals with a serum uric acid ≥ 0.34 mmol/L (HR 3.721, 95% CI 1.603-8.634) compared to non-GA individuals with a serum uric acid < 0.27. Conclusions GA is associated with a 3.1-fold hazard of first CV events. In non-GA rheumatic patients increasing serum uric acid is associated with increased CV risk, whereas CV risk in GA is independent of serum uric acid values. The presence of GA or a baseline serum uric acid in the upper range are possibly stronger predictors of first CV events than some traditional CV risk factors or parameters of inflammatio

Cardiovascular case fatality in rheumatoid arthritis is decreasing; first prospective analysis of a current low disease activity rheumatoid arthritis cohort and review of the literature

Background Previous studies found increased case fatality after myocardial infarction and more frequent sudden death in RA patients compared to non-RA subjects. The RA associated CV risk might be explained by the combined effects of chronic systemic inflammation and increased lifestyle associated cardiovascular risk factors, and modified by the use of medication such as non steroidal anti-inflammatory drugs, corticosteroids and disease modifying anti-rheumatic drugs. Trends in case fatality rate in RA after the introduction of potent anti-inflammatory biologic therapies and treat-to-target treatment strategies aiming at remission are not known. This study was performed to examine the cardiovascular fatality rate in current low disease activity RA, and to evaluate trends in RA associated CV case fatality over time. Methods Prospective study to determine the incidence of fatal and nonfatal CV events in 480 RA patients included in the ACT-CVD cohort between February 2009 and December 2011. Patients with prior CV disease were excluded. Cox regression analysis was performed to determine CV event risk and contributing risk factors over time. The results of the cohort analysis were put into the context of a review of the literature to evaluate trends in RA associated CV fatality rate over time. Results The study included 480 RA patients, 72.3% female with median disease duration of 4.2 years, 72.1% being in clinical remission (Disease Activity Score in 28 joints). During a mean follow up of 2.9 years 29 patients (6%) experienced a first CV event, 2 fatal and 27 non-fatal, corresponding to a 6.9% case fatality rate. Comparison with previous studies in cohorts with successive enrolment periods shows a trend towards a decrease in CV case fatality in RA from 52.9% in 1998 to 6.9% in our study. Conclusion CV case fatality in current low disease activity RA is importantly lower than in previous studies, and a trend towards decreasing CV fatality in RA is suggeste

Bulk Density of a Sandy Loam: Traffic, Tillage, and Irrigation-Method Effects

Modern crop production creates a cycle between soil compaction caused by traffic and alleviation of this condition by tillage or natural processes such as freezing and thawing. The objective of this study was to evaluate important management practices as they relate to changes in bulk density of a tilled sandy loam soil. Practices evaluated were irrigation method, time between tillage and traffic, tire pressure and wheel load of applied traffic, and controlled traffic. Relationships among bulk density, penetration resistance, and infiltration rate were determined. Experiments were conducted in the San Joaquin Valley of California, on a sandy loam soil (Entisol) with an organic-matter content of <1%. After tillage, settling and trafficking of a soil resulted in rapid changes in its bulk density until a new equilibrium was reached. Tire pressure of 408 kPa and wheel weight of 2724 kg applied at moisture contents near field capacity resulted in a bulk density of 1.92 Mg m-3 , compared with a value of 1.67 for no traffic. The time interval between tillage and traffic did not affect final bulk density. Drip irrigation, which did not saturate the soil, resulted in a bulk density of ≈0.1 Mg m-3 lower than flood irrigation, which saturated the soil surface. Wheel traffic in the furrow resulted in only small changes in the bulk density within the row. When tillage did not occur between cropping seasons, traffic caused high bulk densities in the furrow but only small changes in the row. An increase in bulk density from 1.7 to 1.89 Mg m-3 decreased the infiltration rate by four times and increased resistance to penetration at the end of the season by three times. Knowledge of how management practices affect bulk density can aid growers in reducing recompaction following tillage

Physiotherapy intervention in Parkinson's disease: systematic review and meta-analysis

Objective To assess the effectiveness of physiotherapy compared with no intervention in patients with Parkinson’s disease. Design Systematic review and meta-analysis of randomised controlled trials. Data sources Literature databases, trial registries, journals, abstract books, and conference proceedings, and reference lists, searched up to the end of January 2012. Review methods Randomised controlled trials comparing physiotherapy with no intervention in patients with Parkinson’s disease were eligible. Two authors independently abstracted data from each trial. Standard meta-analysis methods were used to assess the effectiveness of physiotherapy compared with no intervention. Tests for heterogeneity were used to assess for differences in treatment effect across different physiotherapy interventions used. Outcome measures were gait, functional mobility and balance, falls, clinician rated impairment and disability measures, patient rated quality of life, adverse events, compliance, and economic analysis outcomes. Results 39 trials of 1827 participants met the inclusion criteria, of which 29 trials provided data for the meta-analyses. Significant benefit from physiotherapy was reported for nine of 18 outcomes assessed. Outcomes which may be clinically significant were speed (0.04 m/s, 95% confidence interval 0.02 to 0.06, P<0.001), Berg balance scale (3.71 points, 2.30 to 5.11, P<0.001), and scores on the unified Parkinson’s disease rating scale (total score −6.15 points, −8.57 to −3.73, P<0.001; activities of daily living subscore −1.36, −2.41 to −0.30, P=0.01; motor subscore −5.01, −6.30 to −3.72, P<0.001). Indirect comparisons of the different physiotherapy interventions found no evidence that the treatment effect differed across the interventions for any outcomes assessed, apart from motor subscores on the unified Parkinson’s disease rating scale (in which one trial was found to be the cause of the heterogeneity). Conclusions Physiotherapy has short term benefits in Parkinson’s disease. A wide range of physiotherapy techniques are currently used to treat Parkinson’s disease, with little difference in treatment effects. Large, well designed, randomised controlled trials with improved methodology and reporting are needed to assess the efficacy and cost effectiveness of physiotherapy for treating Parkinson’s disease in the longer term

Evaluating Bioinformatic Pipeline Performance for Forensic Microbiome Analysis*,†,‡

Microbial communities have potential evidential utility for forensic applications. However, bioinformatic analysis of high‐throughput sequencing data varies widely among laboratories. These differences can potentially affect microbial community composition and downstream analyses. To illustrate the importance of standardizing methodology, we compared analyses of postmortem microbiome samples using several bioinformatic pipelines, varying minimum library size or minimum number of sequences per sample, and sample size. Using the same input sequence data, we found that three open‐source bioinformatic pipelines, MG‐RAST, mothur, and QIIME2, had significant differences in relative abundance, alpha‐diversity, and beta‐diversity, despite the same input data. Increasing minimum library size and sample size increased the number of low‐abundant and infrequent taxa detected. Our results show that bioinformatic pipeline and parameter choice affect results in important ways. Given the growing potential application of forensic microbiology to the criminal justice system, continued research on standardizing computational methodology will be important for downstream applications.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154468/1/jfo14213_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154468/2/jfo14213.pd

"Post-GDM support would be really good for mothers": A qualitative interview study exploring how to support a healthy diet and physical activity after gestational diabetes.

BACKGROUND: Women with a history of gestational diabetes mellitus (GDM) are at high risk of developing type 2 diabetes mellitus (T2DM). They are therefore recommended to follow a healthy diet and be physically active in order to reduce that risk. However, achieving and maintaining these behaviours in the postpartum period is challenging. This study sought to explore women's views on suggested practical approaches to achieve and maintain a healthy diet and physical activity to reduce T2DM risk. METHODS: Semi-structured interviews with 20 participants in Cambridgeshire, UK were conducted at three to 48 months after GDM. The participants' current diet and physical activity, intentions for any changes, and views on potential interventions to help manage T2DM risk through these behaviours were discussed. Framework analysis was used to analyse the transcripts. The interview schedule, suggested interventions, and thematic framework were based on a recent systematic review. RESULTS: Most of the participants wanted to eat more healthily and be more active. A third of the participants considered that postpartum support for these behaviours would be transformative, a third thought it would be beneficial, and a third did not want additional support. The majority agreed that more information about the impact of diet and physical activity on diabetes risk, support to exercise with others, and advice about eating healthily, exercising with a busy schedule, monitoring progress and sustaining changes would facilitate a healthy diet and physical activity. Four other suggested interventions received mixed responses. It would be acceptable for this support to be delivered throughout pregnancy and postpartum through a range of formats. Clinicians were seen to have important roles in giving or signposting to support. CONCLUSIONS: Many women would appreciate more support to reduce their T2DM risk after GDM and believe that a variety of interventions to integrate changes into their daily lives would help them to sustain healthier lifestyles.RAD was funded by a PhD studentship from the National Institute for Health Research (NIHR) School for Primary Care Research (SPCR; SPCR-S-S102). This paper presents independent research funded by the NIHR SPCR. The views expressed are those of the author(s) and not necessarily those of the NIHR, the NHS or the Department of Health. JAUS was funded by a Cancer Research UK Cancer Prevention Fellowship (C55650/A21464). SJG is supported by the Medical Research Council (MC_UU_12015/4). The University of Cambridge has received salary support in respect of SJG from the NHS in the East of England through the Clinical Academic Reserve. CEA is supported by an Action Medical Research Grant (GN2778) and a Medical Research Council New Investigator Research Grant (MR/T016701/1). CLM is supported by the Diabetes UK Harry Keen Intermediate Clinical Fellowship (DUK-HKF 17/0005712) and the European Foundation for the Study of Diabetes – Novo Nordisk Foundation Future Leaders’ Award (NNF19SA058974). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Imaging shear stress distribution and evaluating the stress concentration factor of the human eye.

Healthy eyes are vital for a better quality of human life. Historically, for man-made materials, scientists and engineers use stress concentration factors to characterise the effects of structural non-homogeneities on their mechanical strength. However, such information is scarce for the human eye. Here we present the shear stress distribution profiles of a healthy human cornea surface in vivo using photo-stress analysis tomography, which is a non-intrusive and non-X-ray based method. The corneal birefringent retardation measured here is comparable to that of previous studies. Using this, we derive eye stress concentration factors and the directional alignment of major principal stress on the surface of the cornea. Similar to thermometers being used for monitoring the general health in humans, this report provides a foundation to characterise the shear stress carrying capacity of the cornea, and a potential bench mark for validating theoretical modelling of stresses in the human eye in future