Objective To investigate the efficacy and safety of paracetamol (acetaminophen) in the management of spinal pain and osteoarthritis of the hip or knee.Design Systematic review and meta-analysis.Data ...sources Medline, Embase, AMED, CINAHL, Web of Science, LILACS, International Pharmaceutical Abstracts, and Cochrane Central Register of Controlled Trials from inception to December 2014.Eligibility criteria for selecting studies Randomised controlled trials comparing the efficacy and safety of paracetamol with placebo for spinal pain (neck or low back pain) and osteoarthritis of the hip or knee.Data extraction Two independent reviewers extracted data on pain, disability, and quality of life. Secondary outcomes were adverse effects, patient adherence, and use of rescue medication. Pain and disability scores were converted to a scale of 0 (no pain or disability) to 100 (worst possible pain or disability). We calculated weighted mean differences or risk ratios and 95% confidence intervals using a random effects model. The Cochrane Collaboration’s tool was used for assessing risk of bias, and the GRADE approach was used to evaluate the quality of evidence and summarise conclusions.Results 12 reports (13 randomised trials) were included. There was “high quality” evidence that paracetamol is ineffective for reducing pain intensity (weighted mean difference −0.5, 95% confidence interval −2.9 to 1.9) and disability (0.4, −1.7 to 2.5) or improving quality of life (0.4, −0.9 to 1.7) in the short term in people with low back pain. For hip or knee osteoarthritis there was “high quality” evidence that paracetamol provides a significant, although not clinically important, effect on pain (−3.7, −5.5 to −1.9) and disability (−2.9, −4.9 to −0.9) in the short term. The number of patients reporting any adverse event (risk ratio 1.0, 95% confidence interval 0.9 to 1.1), any serious adverse event (1.2, 0.7 to 2.1), or withdrawn from the study because of adverse events (1.2, 0.9 to 1.5) was similar in the paracetamol and placebo groups. Patient adherence to treatment (1.0, 0.9 to 1.1) and use of rescue medication (0.7, 0.4 to 1.3) was also similar between groups. “High quality” evidence showed that patients taking paracetamol are nearly four times more likely to have abnormal results on liver function tests (3.8, 1.9 to 7.4), but the clinical importance of this effect is uncertain.Conclusions Paracetamol is ineffective in the treatment of low back pain and provides minimal short term benefit for people with osteoarthritis. These results support the reconsideration of recommendations to use paracetamol for patients with low back pain and osteoarthritis of the hip or knee in clinical practice guidelines.Systematic review registration PROSPERO registration number CRD42013006367.
P-Glycoprotein (Pgp) is one of the best characterized ABC transporters, often involved in the multidrug-resistance phenotype overexpressed by several cancer cell lines. Experimental studies ...contributed to important knowledge concerning substrate polyspecificity, efflux mechanism, and drug-binding sites. This information is, however, scattered through different perspectives, not existing a unifying model for the knowledge available for this transporter. Using a previously refined structure of murine Pgp, three putative drug-binding sites were hereby characterized by means of molecular docking. The modulator site (M-site) is characterized by cross interactions between both Pgp halves herein defined for the first time, having an important role in impairing conformational changes leading to substrate efflux. Two other binding sites, located next to the inner leaflet of the lipid bilayer, were identified as the substrate-binding H and R sites by matching docking and experimental results. A new classification model with the ability to discriminate substrates from modulators is also proposed, integrating a vast number of theoretical and experimental data.
Wildfires represent an important agent of land degradation in temperate sub-humid ecosystems, including southern European Mediterranean countries. Identification of integrated conservation approaches ...that can reduce or prevent degradational impacts is the aim of the EU-funded DESIRE research program, part of which is concerned with quantifying the likely benefit of acceptable alternative conservation strategies to wildfire. The overall aim of this paper is to apply a modification of the Pan-European Soil Erosion Risk Assessment (PESERA) model in order to compare predicted soil erosion rates of one possible conservation strategy, the regular application of prescribed fire, with that of wildfire. The model is applied to two fire-prone study areas in central Portugal (Góis and Mação) and predicts runoff and erosion at much larger spatial (regional) and temporal (decadal) scales than is usually possible with field monitoring. Simulation using the model was carried out for 50years based on a historical climate time-series. Even assuming very frequent management burns (every 2years) and infrequent wildfires (100years), the model suggests that this conservation measure can generally reduce soil erosion relative to infrequent wildfires, although the predicted soil losses for both types of fire are large compared even with those obtained from small-scale field monitoring. The benefits, limitations, scope for improvement and application to future climatic scenarios of the model in a fire context are discussed.
► Post-fire main modelled effects: loss of vegetation, increasing soil erodibility. ► Modelling of forest fire dynamics and post-fire recovery is still exploratory. ► Further analysis of field data for the study sites is still needed. ► PESERA appears to over-estimate post-fire soil erosion of thin stony soils. ► Promising alternative route for assessing medium- to long-term impacts of wildfires.
Studies on environmental consequences of stress on animal production have grown substantially in the last few years for economic and animal welfare reasons. Physiological, hormonal, and immunological ...deficits as well as increases in animals' susceptibility to diseases have been reported after different stressors in broiler chickens. The aim of the current experiment is to describe the effects of 2 different heat stressors (31 ± 1 and 36 ± 1°C/10 h per d) applied to broiler chickens from d 35 to 42 of life on the corticosterone serum levels, performance parameters, intestinal histology, and peritoneal macrophage activity, correlating and discussing the obtained data under a neuroimmune perspective. In our study, we demonstrated that heat stress (31 ± 1 and 36 ± 1°C) increased the corticosterone serum levels and decreased BW gain and food intake. Only chickens submitted to 36 ± 1°C, however, presented a decrease in feed conversion and increased mortality. We also showed a decrease of bursa of Fabricius (31 ± 1 and 36 ± 1°C), thymus (36 ± 1°C), and spleen (36 ± 1°C) relative weights and of macrophage basal (31 ± 1 and 36 ± 1°C) and Staphylococcus aureus-induced oxidative burst (31 ± 1°C). Finally, mild multifocal acute enteritis characterized by an increased presence of lymphocytes and plasmocytes within the jejunum's lamina propria was also observed. The stress-induced hypothalamic-pituitary-adrenal axis activation was taken as responsible for the negative effects observed on the chickens' performance and immune function and also the changes of the intestinal mucosa. The present obtained data corroborate with others in the field of neuroimmunomodulation and open new avenues for the improvement of broiler chicken welfare and production performance.
ABSTRACT
We present a reduction and analysis of the James Webb Space Telescope (JWST) SMACS 0723 field using new post-launch calibrations to conduct a search for ultra-high-redshift galaxies (z > 9) ...present within the Epoch of Reionization. We conduct this search by modelling photometric redshifts in several ways for all sources and by applying conservative magnitude cuts (mF200W < 28) to identify strong Lyman breaks greater than 1 mag. We find four z > 9 candidate galaxies which have not previously been identified, with one object at z = 11.5, and another which is possibly a close pair of galaxies. We measure redshifts for candidate galaxies from other studies and find the recovery rate to be only 23 per cent, with many being assigned lower redshift, dusty solutions in our work. Most of our z > 9 sample show evidence for Balmer-breaks, or extreme emission lines from H β and O iii, demonstrating that the stellar populations could be advanced in age or very young depending on the cause of the F444W excess. We discuss the resolved structures of these early galaxies and find that the Sérsic indices reveal a mixture of light concentration levels, but that the sizes of all our systems are exceptionally small (<0.5 kpc). These systems have stellar masses M* ∼ 109.0 M⊙, with our z ∼ 11.5 candidate a dwarf galaxy with a stellar mass M* ∼ 107.8–108.2 M⊙. These candidate ultra high-redshift galaxies are excellent targets for future NIRSpec observations aimed to better understand their physical nature.
P-Glycoprotein (P-gp) is often involved in multidrug resistance (MDR) to the pharmacological action of a wide number of anticancer agents. In this article, a series of molecular dynamics simulations ...of murine’s P-gp were developed, elucidating the importance of the lipid membrane and linker sequence in the protein structure stability. The behavior of several molecules inside the drug-binding pocket revealed a striking difference between substrates or modulators, and motion patterns were identified that could be correlated with conformational alterations due to substrate binding, corresponding to the initial step in the efflux mechanism. Only one “entrance gate” to the drug-binding pocket was found and, in the presence of a substrate, leads to changes in the motion patterns of the transporter into an efflux-like movement.
The brushless doubly fed induction machine (DFIM) shows great potential as a generator in large-scale wind turbines. The motion of the magnetic field in this machine is not a simple rotation, which ...makes it not so straight forward to understand its operating principles. This paper develops an analytical magnetic field model for the brushless DFIM that includes the effects of rotor time harmonics and space harmonics due to the winding distribution and slotting. Using a case study machine, the developed analytical model is then validated by comparison with finite-element (FE) calculations. In addition, a 2-D spectral analysis is applied to the FE derived radial air-gap magnetic field as a function of time. This analysis verifies the space-time relations of the rotating magnetic field components in the airgap of the brushless DFIM. Finally, the developed analytical magnetic field model is used to analyze the brushless DFIM operating principles. The interaction of the stator magnetic field with the rotor nested loops is explained, as well as the development of electromagnetic torque.
Society depends on goods and services provided by ecosystems, not only for survival but also for general wellbeing. Over the last decades, peri-urban areas have been subject to the pressure of ...urbanization and, thus, land-use changes. These changes modify the natural ecosystems and their ability to support human security and safety, but the extent of these impacts is not well-known. This study investigates the impact of five decades of land-use changes in potential ecosystem services (ESs) supply, in the peri-urban Ribeira dos Covões catchment, located in the periphery of Coimbra one of the largest cities in central Portugal. Based on eight land-use maps from 1958 to 2012, the ESs were estimated through a quantification matrix developed by local stakeholders. The expansion of urban and forest areas from 7% to 40% and from 43% to 55%, respectively, mostly through the occupation of agriculture fields (reduced from 48% to 4%), together with changes in the type of forest area (from mixed to commercial broad-leaved), led to a 73% reduction in the ESs potential supply. This reduction was driven by major losses in regulation but also provisioning services. Catchment management and urban planning should be supported by ESs assessment in order to mitigate the negative impacts on regulation, provisioning and cultural services provided by the ecosystems, and thus maximize the benefits for society.
Display omitted
•Urbanization has adverse impacts on the potential supply of ecosystem services (ESs)•The conversion of forest into urban land-use has more detrimental impacts on ESs than the occupation of agriculture fields•The expansion of forestry can partially compensate the impacts of urbanization on ESs•Wildfire has a major impact on ESs potential supply than discontinuous urbanization•Mapping ESs should integrate urban planning to achieve sustainable development
Objective
In current management paradigms of rheumatoid arthritis (RA), patient global assessment (PGA) is crucial to decide whether a patient has attained remission (target) or needs reinforced ...therapy. We investigated whether the clinical and psychological determinants of PGA are appropriate to support this important role.
Methods
This was a cross‐sectional, single‐center study including consecutive ambulatory RA patients. Data collection comprised swollen 28‐joint count (SJC28), tender 28‐joint count (TJC28), C‐reactive protein (CRP) level, PGA, pain, fatigue, function, anxiety, depression, happiness, personality traits, and comorbidities. Remission was categorized using American College of Rheumatology/European League Against Rheumatism Boolean‐based criteria: remission, near‐remission (only PGA >1), and nonremission. A binary definition without PGA (3v‐remission) was also studied. Univariable and multivariable analyses were used to identify explanatory variables of PGA in each remission state.
Results
A total of 309 patients were included (remission 9.4%, near‐remission 37.2%, and nonremission 53.4%). Patients in near‐remission were indistinguishable from remission regarding disease activity, but described a disease impact similar to those in nonremission. In multivariable analyses, PGA in near‐remission was explained (R2adjusted = 0.50) by fatigue, pain, anxiety, and function. Fatigue and pain had no relationship with disease activity measures.
Conclusion
In RA, a consensually acceptable level of disease activity (SJC28, TJC28, and CRP level ≤1) does not equate to low disease impact: a large proportion of these patients are considered in nonremission solely due to PGA. PGA mainly reflects fatigue, pain, function, and psychological domains, which are inadequate to define the target for immunosuppressive therapy. This consideration suggests that clinical practice should be guided by 2 separate remission targets: inflammation (3v‐remission) and disease impact.
Efflux pumps of the ATP-binding cassette transporters superfamily (ABC transporters) are frequently involved in the multidrug-resistance (MDR) phenomenon in cancer cells. Herein, we describe a new ...atomistic model for the MDR-related ABCG2 efflux pump, also named breast cancer resistance protein (BCRP), based on the recently published crystallographic structure of the ABCG5/G8 heterodimer sterol transporter, a member of the ABCG family involved in cholesterol homeostasis. By means of molecular dynamics simulations and molecular docking, a far-reaching characterization of the ABCG2 homodimer was obtained. The role of important residues and motifs in the structural stability of the transporter was comprehensively studied and was found to be in good agreement with the available experimental data published in literature. Moreover, structural motifs potentially involved in signal transmission were identified, along with two symmetrical drug-binding sites that are herein described for the first time, in a rational attempt to better understand how drug binding and recognition occurs in ABCG2 homodimeric transporters.
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