Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdr1a P-glycoprotein

To gain more insight into the pharmacological role of endogenous P-glycoprotein in the metabolism of the widely used substrate drug doxorubicin, we have studied the plasma pharmacokinetics, tissue distribution and excretion of this compound in mdr1a(–/– and wild-type mice. Doxorubicin was administered as an i.v. bolus injection at a dose level of 5 mg kg−1. Drug and metabolite concentrations were determined in plasma, tissues, urine and faeces by high-performance liquid chromatography. In comparison with wild-type mice, the terminal half-life and the area under the plasma concentration–time curve of doxorubicin in it>mdr1a(–/–) mice were 1.6- and 1.2-fold higher respectively.The retention of both doxorubicin and its metabolite doxorubicinol in the hearts of mdr1a(–/–) mice was substantially prolonged. In addition, a significantly increased drug accumulation was observed in the brain and the liver of mdr1a(–/–) mice. The relative accumulation in most other tissues was not or only slightly increased. The differences in cumulative faecal and urinary excretion of doxorubicin and metabolites between both types of mice were small. These experiments demonstrate that the absence of mdr1a P-glycoprotein only slightly alters the plasma pharmacokinetics of oxorubicin. Furthermore, the substantially prolonged presence of both doxorubicin and doxorubicinol in cardiac tissue of mdr1a(–/–) mice suggests that a blockade of endogenous P-glycoprotein in patients, for example by a reversal agent, may enhance the risk of cardiotoxicity upon administration of doxorubicin. © 1999 Cancer Research Campaig

Biomechanical constraints remain major risk factors for low back pain. Results from a prospective cohort study in French male employees

BACKGROUND CONTEXT: Low back pain (LBP) is a major public health problem, with a considerable impact on workers. PURPOSE: To model the risk of LBP in the male general working population. STUDY DESIGN/SETTING: Repeated cross-sectional surveys in a wide occupational setting. PATIENT SAMPLE: A random sample of 2,161 men working in various occupations in a French region participated in a first survey in 2002, and 1,313 of these (60.8%) participated in a second survey in 2007. OUTCOME MEASURE: The self-reported prevalence of LBP during the previous week in the second survey. METHODS: Twenty-one biomechanical, organizational, psychosocial, and individual factors were assessed in the first survey. The association between these potential risk factors and the prevalence of later LBP (in the second survey) was studied, using multistep logistic regression models. RESULTS: Three hundred ninety-four men reported LBP in the second survey (prevalence 30.0%). The final multivariate model highlighted four risk factors: frequent bending (odds ratio [OR], 1.45, 95% confidence interval [CI], 1.07-1.97 for bending forward only; and OR, 2.13, 95% CI, 1.52-3.00 for bending both forward and sideways), driving industrial vehicles (OR, 1.35; 95% CI, 1.00-1.81), working more hours than officially planned (OR, 1.38; 95% CI, 1.05-1.81), and reported low support from supervisors (OR, 1.35; 95% CI, 1.02-1.79). CONCLUSIONS: These results emphasize that biomechanical factors remain worth considering, even when psychosocial factors are taken into account, and provide a significant contribution to preventive strategies

Interferometric imaging with the 32 element Murchison Wide-field Array

The Murchison Wide-field Array (MWA) is a low frequency radio telescope, currently under construction, intended to search for the spectral signature of the epoch of re-ionisation (EOR) and to probe the structure of the solar corona. Sited in Western Australia, the full MWA will comprise 8192 dipoles grouped into 512 tiles, and be capable of imaging the sky south of 40 degree declination, from 80 MHz to 300 MHz with an instantaneous field of view that is tens of degrees wide and a resolution of a few arcminutes. A 32-station prototype of the MWA has been recently commissioned and a set of observations taken that exercise the whole acquisition and processing pipeline. We present Stokes I, Q, and U images from two ~4 hour integrations of a field 20 degrees wide centered on Pictoris A. These images demonstrate the capacity and stability of a real-time calibration and imaging technique employing the weighted addition of warped snapshots to counter extreme wide field imaging distortions.Comment: Accepted for publication in PASP. This is the draft before journal typesetting corrections and proofs so does contain formatting and journal style errors, also has with lower quality figures for space requirement

Facteurs associés à la lombalgie chez les hommes salariés des Pays de la Loire

Objectif : Les lombalgies ont des répercussions majeures sur le monde du travail. Un manque de données prospectives et représentatives de la diversité des emplois limite l’analyse des facteurs de risque chez les travailleurs. L’objectif de cette étude était d’estimer, à l’aide d’une modélisation, les facteurs associés à la lombalgie chez les salariés des Pays de la Loire.Méthodes : Un échantillon aléatoire de salariés a fait l’objet de deux enquêtes successives. La prévalence des lombalgies lors de la deuxième enquête a été modélisée, par régression logistique multi-étapes, à partir de facteurs de risque individuels et professionnels recueillis lors de la première enquête. Des analyses de sensibilité ont été réalisées. Les analyses ont été stratifiées par sexe ; seuls les résultats pour les hommes sont présentés. Résultats : Parmi les 3 710 participants à la première enquête, 2 332 ont répondu à la deuxième enquête, dont 1 313 hommes. La prévalence des lombalgies était de 30 % chez les hommes. Des douleurs du cou ou des membres supérieurs, se pencher fréquemment et travailler plus que prévu étaient les facteurs de risque principaux de lombalgie ultérieure. L’association observée entre un faible soutien de la hiérarchie et des lombalgies ultérieures devenait non significative dans une analyse restreinte aux salariés sans lombalgie lors de la première enquête. Conclusions : Le rôle des facteurs biomécaniques et organisationnels semble prédominant sur celui des facteurs psychosociaux. Celui des facteurs individuels est d’interprétation délicate. Quelques limites méthodologiques doivent être discutées, mais l’analyse simultanée de multiples facteurs dans une population diversifiée de travailleurs constitue un apport original et utile pour des actions de prévention

A systematic review of the effectiveness and cost-effectiveness of peer education and peer support in prisons.

BACKGROUND: Prisoners experience significantly worse health than the general population. This review examines the effectiveness and cost-effectiveness of peer interventions in prison settings. METHODS: A mixed methods systematic review of effectiveness and cost-effectiveness studies, including qualitative and quantitative synthesis was conducted. In addition to grey literature identified and searches of websites, nineteen electronic databases were searched from 1985 to 2012. Study selection criteria were: Population: Prisoners resident in adult prisons and children resident in Young Offender Institutions (YOIs). INTERVENTION: Peer-based interventions Comparators: Review questions 3 and 4 compared peer and professionally led approaches. OUTCOMES: Prisoner health or determinants of health; organisational/ process outcomes; views of prison populations. STUDY DESIGNS: Quantitative, qualitative and mixed method evaluations. RESULTS: Fifty-seven studies were included in the effectiveness review and one study in the cost-effectiveness review; most were of poor methodological quality. Evidence suggested that peer education interventions are effective at reducing risky behaviours, and that peer support services are acceptable within the prison environment and have a positive effect on recipients, practically or emotionally. Consistent evidence from many, predominantly qualitative, studies, suggested that being a peer deliverer was associated with positive effects. There was little evidence on cost-effectiveness of peer-based interventions. CONCLUSIONS: There is consistent evidence from a large number of studies that being a peer worker is associated with positive health; peer support services are also an acceptable source of help within the prison environment and can have a positive effect on recipients. Research into cost-effectiveness is sparse. SYSTEMATIC REVIEW REGISTRATION: PROSPERO ref: CRD42012002349

Pharmacokinetics of Quinacrine Efflux from Mouse Brain via the P-glycoprotein Efflux Transporter

The lipophilic cationic compound quinacrine has been used as an antimalarial drug for over 75 years but its pharmacokinetic profile is limited. Here, we report on the pharmacokinetic properties of quinacrine in mice. Following an oral dose of 40 mg/kg/day for 30 days, quinacrine concentration in the brain of wild-type mice was maintained at a concentration of ∼1 µM. As a substrate of the P-glycoprotein (P-gp) efflux transporter, quinacrine is actively exported from the brain, preventing its accumulation to levels that may show efficacy in some disease models. In the brains of P-gp–deficient Mdr10/0 mice, we found quinacrine reached concentrations of ∼80 µM without any signs of acute toxicity. Additionally, we examined the distribution and metabolism of quinacrine in the wild-type and Mdr10/0 brains. In wild-type mice, the co-administration of cyclosporin A, a known P-gp inhibitor, resulted in a 6-fold increase in the accumulation of quinacrine in the brain. Our findings argue that the inhibition of the P-gp efflux transporter should improve the poor pharmacokinetic properties of quinacrine in the CNS