207 research outputs found
Integrating distribution kinetics and toxicodynamics to assess repeat dose neurotoxicity in vitro using human BrainSpheres: a case study on amiodarone.
For ethical, economical, and scientific reasons, animal experimentation, used to evaluate the potential neurotoxicity of chemicals before their release in the market, needs to be replaced by new approach methodologies. To illustrate the use of new approach methodologies, the human induced pluripotent stem cell-derived 3D model BrainSpheres was acutely (48 h) or repeatedly (7 days) exposed to amiodarone (0.625-15 µM), a lipophilic antiarrhythmic drug reported to have deleterious effects on the nervous system. Neurotoxicity was assessed using transcriptomics, the immunohistochemistry of cell type-specific markers, and real-time reverse transcription-polymerase chain reaction for various genes involved in the lipid metabolism. By integrating distribution kinetics modeling with neurotoxicity readouts, we show that the observed time- and concentration-dependent increase in the neurotoxic effects of amiodarone is driven by the cellular accumulation of amiodarone after repeated dosing. The development of a compartmental in vitro distribution kinetics model allowed us to predict the change in cell-associated concentrations in BrainSpheres with time and for different exposure scenarios. The results suggest that human cells are intrinsically more sensitive to amiodarone than rodent cells. Amiodarone-induced regulation of lipid metabolism genes was observed in brain cells for the first time. Astrocytes appeared to be the most sensitive human brain cell type in vitro. In conclusion, assessing readouts at different molecular levels after the repeat dosing of human induced pluripotent stem cell-derived BrainSpheres in combination with the compartmental modeling of in vitro kinetics provides a mechanistic means to assess neurotoxicity pathways and refine chemical safety assessment for humans
A survey of UK medical schools' arrangements for early patient contact
Background: Many U.K. medical schools have patient contact in the first two years of the undergraduate course. Aim: To compare the purposes and organization of early patient contact in UK medical schools and to relate these arrangements to the schools' curricular objectives. Methods: A telephone survey of lead educators in UK medicals schools. Categories of contact were plotted against phases of the course to discern patterns of organisation. Results: The quantity of contact varies considerably (four to 65 days). There is a pattern, with learning objectives around the social context of health and illness preceding skills based work and integrated clinical knowledge for practice coming later. Schools fall into three categories: close adherence to the preclinical/clinical split, with limited early contact acting as an introduction to social aspects of health; provision of substantial patient contact to maximize the integration of knowledge and skills; and transitional, with limited clinical goals. General practice provides between one third and one half of early patient contact. Conclusions: Arrangements meet the objectives set by each school and reflect differing educational philosophies. Change is toward more early contact. There appears to be no national guidance which supports a minimum quantity of patient contact or specific educational purpose in the early years of U.K. basic medical training
Estimation of the noise emissions generated by a single vehicle while driving
This article presents a method of calculation that allows us to separate the contribution of a specific vehicle to the overall noise pollution in an urban environment. This method will provide local authorities with new operating models so that the cost of noise can be allocated to a vehicle according to factors such as the number of people it affects, the distance traveled and journey time, the driving style and the type of vehicle and tires. The proposed methodology can be adapted to different noise emission and propagation models, and we select as a basis the CNOSSOS-EU framework for compatibility with the European noise mapping strategy.
This method will make it possible to reduce road traffic noise using two long-term strategies: (a) separate distributions of the costs of noise among the vehicles that generate it, with the aim of achieving (b) an increase in pro-environmental behavior with regard to this pollutant
Analytical and numerical analyses of the micromechanics of soft fibrous connective tissues
State of the art research and treatment of biological tissues require
accurate and efficient methods for describing their mechanical properties.
Indeed, micromechanics motivated approaches provide a systematic method for
elevating relevant data from the microscopic level to the macroscopic one. In
this work the mechanical responses of hyperelastic tissues with one and two
families of collagen fibers are analyzed by application of a new variational
estimate accounting for their histology and the behaviors of their
constituents. The resulting, close form expressions, are used to determine the
overall response of the wall of a healthy human coronary artery. To demonstrate
the accuracy of the proposed method these predictions are compared with
corresponding 3-D finite element simulations of a periodic unit cell of the
tissue with two families of fibers. Throughout, the analytical predictions for
the highly nonlinear and anisotropic tissue are in agreement with the numerical
simulations
The Role of Native Language and the Fundamental Design of the Auditory System in Detecting Rhythm Changes
Accepted December 13, 2018Purpose: We investigated whether rhythm discrimination
is mainly driven by the native language of the listener or
by the fundamental design of the human auditory system
and universal cognitive mechanisms shared by all people
irrespective of rhythmic patterns in their native language.
Method: In multiple experiments, we asked participants to
listen to 2 continuous acoustic sequences and to determine
whether their rhythms were the same or different (AX
discrimination). Participants were native speakers of
4 languages with different rhythmic properties (Spanish,
French, English, and German) to understand whether the
predominant rhythmic patterns of a native language affect
sensitivity, bias, and reaction time in detecting rhythmic
changes in linguistic (Experiment 2) and in nonlinguistic
(Experiments 1 and 2) acoustic sequences. We examined
sensitivity and bias measures, as well as reaction times.
We also computed Bayes factors in order to assess the
effect of native language.
Results: All listeners performed better (i.e., responded
faster and manifested higher sensitivity and accuracy)
when detecting the presence or absence of a rhythm
change when the 1st stimulus in an AX test pair exhibited
regular rhythm (i.e., a syllable-timed rhythmic pattern)
than when the 1st stimulus exhibited irregular rhythm (i.e.,
stress-timed rhythmic pattern). This result pattern was
observed both on linguistic and nonlinguistic stimuli
and was not modulated by the native language of the
participant.
Conclusion: We conclude that rhythm change detection is
a fundamental function of a processing system that relies
on general auditory mechanisms and is not modulated by
linguistic experience.The authors acknowledge support from Spanish Ministry of Economy and Competitiveness Grant PSI2017-82563-P (awarded to A. G. S.), the “Severo Ochoa” Programme for Centres/Units of Excellence in R&D Grant SEV-2015-490 (BCBL), and the Basque Foundation for Science Grant IKERBASQUE (awarded to A. G. S. and M. O.). D. M. G. was supported by Grant PIA/Basal FB0003 from the Chilean Research Council. L. P. was supported by the Spanish Ministry of Economy and Competitiveness via Juan de la Cierva fellowship
Relationship between Structure, Entropy and Diffusivity in Water and Water-like Liquids
Anomalous behaviour of the excess entropy () and the associated scaling
relationship with diffusivity are compared in liquids with very different
underlying interactions but similar water-like anomalies: water (SPC/E and
TIP3P models), tetrahedral ionic melts (SiO and BeF) and a fluid with
core-softened, two-scale ramp (2SRP) interactions. We demonstrate the presence
of an excess entropy anomaly in the two water models. Using length and energy
scales appropriate for onset of anomalous behaviour, the density range of the
excess entropy anomaly is shown to be much narrower in water than in ionic
melts or the 2SRP fluid. While the reduced diffusivities () conform to the
excess entropy scaling relation, for all the systems
(Y. Rosenfeld, Phys. Rev. A {\bf 1977}, {\it 15}, 2545), the exponential
scaling parameter, , shows a small isochore-dependence in the case of
water. Replacing by pair correlation-based approximants accentuates the
isochore-dependence of the diffusivity scaling. Isochores with similar
diffusivity scaling parameters are shown to have the temperature dependence of
the corresponding entropic contribution. The relationship between diffusivity,
excess entropy and pair correlation approximants to the excess entropy are very
similar in all the tetrahedral liquids.Comment: 24 pages, 4 figures, to be published in Journal of Physical Chemistry
Toward Good Read-Across Practice (GRAP) guidance.
Grouping of substances and utilizing read-across of data within those groups represents an important data gap filling technique for chemical safety assessments. Categories/analogue groups are typically developed based on structural similarity and, increasingly often, also on mechanistic (biological) similarity. While read-across can play a key role in complying with legislations such as the European REACH regulation, the lack of consensus regarding the extent and type of evidence necessary to support it often hampers its successful application and acceptance by regulatory authorities. Despite a potentially broad user community, expertise is still concentrated across a handful of organizations and individuals. In order to facilitate the effective use of read-across, this document aims to summarize the state-of-the-art, summarizes insights learned from reviewing ECHA published decisions as far as the relative successes/pitfalls surrounding read-across under REACH and compile the relevant activities and guidance documents. Special emphasis is given to the available existing tools and approaches, an analysis of ECHA's published final decisions associated with all levels of compliance checks and testing proposals, the consideration and expression of uncertainty, the use of biological support data and the impact of the ECHA Read-Across Assessment Framework (RAAF) published in 2015
Correlation of the ratio of metastatic to non-metastatic cancer cases with the degree of socioeconomic deprivation among Texas counties
<p>Abstract</p> <p>Background</p> <p>Previous studies have demonstrated that cancer registrations and hospital discharge rate are closely correlated with census data-based socioeconomic deprivation indices. We hypothesized that communities with higher degrees of socioeconomic deprivation tend to have a higher ratio of metastatic to non-metastatic cancer cases (lung, breast, prostate, female genital system, colorectal cancers or all types of cancers combined). In this study, we investigate the potential link between this ratio and the Wellbeing Index (WI) among Texas counties.</p> <p>Results</p> <p>Cancer data in 2000 were provided by the Texas Cancer Registry, while data on the ten socioeconomic variables among the 254 Texas counties in 2000 for building the WI were obtained from U.S. Census Bureau. The ten socioeconomic status variables were subjected to the principal component analysis, and the first principal component scores were grouped into deciles for the WI (1 to 10) and the 254 Texas counties were classified into 10 corresponding groups. Weighted linear regression analyses and a Cochran-Armitage trend test were performed to determine the relationship between the ratio of age-adjusted metastatic to non-metastatic cancer incidence cases and WI. The ratios of metastatic to non-metastatic cases of female genital system cancer (<it>r</it><sup>2 </sup>= 0.84, <it>p </it>= 0.0002), all-type cancers (<it>r</it><sup>2</sup>= 0.73, <it>p </it>= 0.0017) and lung cancer (<it>r</it><sup>2</sup>= 0.54, <it>p </it>= 0.0156) at diagnosis were positively correlated with WI.</p> <p>Conclusions</p> <p>The ratios of metastatic to non-metastatic cases of all-type, female genital system and lung cancers at diagnosis were statistically correlated with socioeconomic deprivation. Potential mediators for the correlation warrant further investigation in order to reduce health disparities associated with socioeconomic inequality.</p
Lung tumour markers in oncology practice: a study of TPA and CA125
Several substances mark the course of lung cancer and may reliably help the clinician in decision-making. This is the first clinical study specifically designed to compare tissue polypeptide antigen and CA 125 tumour associated antigen. Three hundred and eighty-four new lung cancer patients (309 males) were studied at their first clinical presentation and then strictly followed-up. Anthropometric, clinical and laboratory data – including tissue polypeptide antigen and CA 125 tumour associated antigen serum levels – were prospectively recorded. A total of 1000 tissue polypeptide antigen and CA 125 tumour associated antigen serum assays (384 pre-treatment and 616 posttreatment assays) were performed. Both tissue polypeptide antigen and CA 125 tumour associated antigen correlated significantly with the T, N and M stage descriptors at diagnosis (Rho: 0.200, 0.203, 0.263 and 0.181, 0.240, 0.276, respectively), and then with the objective response to treatment (Rho: 0.388 and 0.207, respectively). A pleural neoplastic involvement was mainly associated to an increase of CA 125 tumour associated antigen (Rho: 0.397). Both tissue polypeptide antigen and CA 125 tumour associated antigen were strongly predictive of the patients' outcome, as assessed by the univariate analysis of survival (log-rank test: 37.24 and 29.01) and several Cox' proportional hazards regression models. The two marker tests are similarly helpful and appear complementary, given the low inter-marker correlation and their independent prognostic capability
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