306 research outputs found
Applying refinement to the use of mice and rats in rheumatoid arthritis research
Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research
Src Dependent Pancreatic Acinar Injury Can Be Initiated Independent of an Increase in Cytosolic Calcium
Several deleterious intra-acinar phenomena are simultaneously triggered on initiating acute pancreatitis. These culminate in acinar injury or inflammatory mediator generation in vitro and parenchymal damage in vivo. Supraphysiologic caerulein is one such initiator which simultaneously activates numerous signaling pathways including non-receptor tyrosine kinases such as of the Src family. It also causes a sustained increase in cytosolic calcium- a player thought to be crucial in regulating deleterious phenomena. We have shown Src to be involved in caerulein induced actin remodeling, and caerulein induced changes in the Golgi and post-Golgi trafficking to be involved in trypsinogen activation, which initiates acinar cell injury. However, it remains unclear whether an increase in cytosolic calcium is necessary to initiate acinar injury or if injury can be initiated at basal cytosolic calcium levels by an alternate pathway. To study the interplay between tyrosine kinase signaling and calcium, we treated mouse pancreatic acinar cells with the tyrosine phosphatase inhibitor pervanadate. We studied the effect of the clinically used Src inhibitor Dasatinib (BMS-354825) on pervanadate or caerulein induced changes in Src activation, trypsinogen activation, cell injury, upstream cytosolic calcium, actin and Golgi morphology. Pervanadate, like supraphysiologic caerulein, induced Src activation, redistribution of the F-actin from its normal location in the sub-apical area to the basolateral areas, and caused antegrade fragmentation of the Golgi. These changes, like those induced by supraphysiologic caerulein, were associated with trypsinogen activation and acinar injury, all of which were prevented by Dasatinib. Interestingly, however, pervanadate did not cause an increase in cytosolic calcium, and the caerulein induced increase in cytosolic calcium was not affected by Dasatinib. These findings suggest that intra-acinar deleterious phenomena may be initiated independent of an increase in cytosolic calcium. Other players resulting in acinar injury along with the Src family of tyrosine kinases remain to be explored. © 2013 Mishra et al
Diabetes prevalence and diagnosis in US states: analysis of health surveys
This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens
Antidepressant Response in Major Depressive Disorder: A Meta-Regression Comparison of Randomized Controlled Trials and Observational Studies
To compare response to antidepressants between randomized controlled trials
(RCTs) and observational trials.Published and unpublished studies (from 1989 to 2009) were searched for by 2
reviewers on Medline, the Cochrane library, Embase, clinicaltrials.gov,
Current Controlled Trial, bibliographies and by mailing key organisations
and researchers. RCTs and observational studies on fluoxetine or venlafaxine
in first-line treatment for major depressive disorder reported in English,
French or Spanish language were included in the main analysis. Studies
including patients from a wider spectrum of depressive disorders (anxious
depression, minor depressive episode, dysthymia) were added in a second
analysis. The main outcome was the pre-/post-treatment difference on
depression scales standardised to 100 (17-item or 21-item Hamilton Rating
Scale for Depression or Montgomery and Åsberg Rating Scale) in each
study arm. A meta-regression was conducted to adjust the comparison between
observational studies and RCTs on treatment type, study characteristics and
average patient characteristics. 12 observational studies and 109 RCTs
involving 6757 and 11035 patients in 12 and 149 arms were included in the
main analysis. Meta-regression showed that the standardised treatment
response in RCTs is greater by a magnitude of 4.59 (2.61 to 6.56). Study
characteristics were related to standardised treatment response, positively
(study duration, number of follow-up assessments, outpatients versus
inpatients, per protocol analysis versus intention to treat analysis) or
negatively (blinded design, placebo design). At patient level, response
increased with baseline severity and decreased with age. Results of the
second analysis were consistent with this.Response to antidepressants is greater in RCTs than in observational studies.
Observational studies should be considered as a necessary complement to
RCTs
Nut production in Bertholletia excelsa across a logged forest mosaic: implications for multiple forest use
Although many examples of multiple-use forest management may be found in tropical smallholder systems, few studies provide empirical support for the integration of selective timber harvesting with non-timber forest product (NTFP) extraction. Brazil nut (Bertholletia excelsa, Lecythidaceae) is one of the world’s most economically-important NTFP species extracted almost entirely from natural forests across the Amazon Basin. An obligate out-crosser, Brazil nut flowers are pollinated by large-bodied bees, a process resulting in a hard round fruit that takes up to 14 months to mature. As many smallholders turn to the financial security provided by timber, Brazil nut fruits are increasingly being harvested in logged forests. We tested the influence of tree and stand-level covariates (distance to nearest cut stump and local logging intensity) on total nut production at the individual tree level in five recently logged Brazil nut concessions covering about 4000 ha of forest in Madre de Dios, Peru. Our field team accompanied Brazil nut harvesters during the traditional harvest period (January-April 2012 and January-April 2013) in order to collect data on fruit production. Three hundred and ninety-nine (approximately 80%) of the 499 trees included in this study were at least 100 m from the nearest cut stump, suggesting that concessionaires avoid logging near adult Brazil nut trees. Yet even for those trees on the edge of logging gaps, distance to nearest cut stump and local logging intensity did not have a statistically significant influence on Brazil nut production at the applied logging intensities (typically 1–2 timber trees removed per ha). In one concession where at least 4 trees ha-1 were removed, however, the logging intensity covariate resulted in a marginally significant (0.09) P value, highlighting a potential risk for a drop in nut production at higher intensities. While we do not suggest that logging activities should be completely avoided in Brazil nut rich forests, when a buffer zone cannot be observed, low logging intensities should be implemented. The sustainability of this integrated management system will ultimately depend on a complex series of socioeconomic and ecological interactions. Yet we submit that our study provides an important initial step in understanding the compatibility of timber harvesting with a high value NTFP, potentially allowing for diversification of forest use strategies in Amazonian Perù
Hyperspectral phasor analysis enables multiplexed 5D in vivo imaging
Time-lapse imaging of multiple labels is challenging for biological imaging as noise, photobleaching and phototoxicity compromise signal quality, while throughput can be limited by processing time. Here, we report software called Hyper-Spectral Phasors (HySP) for denoising and unmixing multiple spectrally overlapping fluorophores in a low signal-to-noise regime with fast analysis. We show that HySP enables unmixing of seven signals in time-lapse imaging of living zebrafish embryos
Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner
OBJECTIVE: Primary
sclerosing cholangitis (PSC) is the classical hepatobiliary
manifestation of IBD. This clinical association is linked pathologically
to the recruitment of mucosal T cells to the liver, via vascular
adhesion protein (VAP)-1-dependent enzyme activity. Our aim was to
examine the expression, function and enzymatic activation of the
ectoenzyme VAP-1 in patients with PSC.DESIGN: We
examined VAP-1 expression in patients with PSC, correlated levels with
clinical characteristics and determined the functional consequences of
enzyme activation by specific enzyme substrates on hepatic endothelium.RESULTS: The
intrahepatic enzyme activity of VAP-1 was elevated in PSC versus
immune-mediated disease controls and non-diseased liver (p<0.001).
The adhesion of gut-tropic α4β7+lymphocytes to hepatic
endothelial cells in vitro under flow was attenuated by 50% following
administration of the VAP-1 inhibitor semicarbazide (p<0.01). Of a
number of natural VAP-1 substrates tested, cysteamine-which can be
secreted by inflamed colonic epithelium and gut bacteria-was the most
efficient (yielded the highest enzymatic rate) and efficacious in its
ability to induce expression of functional mucosal addressin cell
adhesion molecule-1 on hepatic endothelium. In a prospectively evaluated
patient cohort with PSC, elevated serum soluble (s)VAP-1 levels
predicted poorer transplant-free survival for patients, independently
(HR: 3.85, p=0.003) and additively (HR: 2.02, p=0.012) of the presence
of liver cirrhosis.CONCLUSIONS: VAP-1
expression is increased in PSC, facilitates adhesion of gut-tropic
lymphocytes to liver endothelium in a substrate-dependent manner, and
elevated levels of its circulating form predict clinical outcome in
patients.</p
Determination of Edema in Porcine Coronary Arteries by T2 Weighted Cardiovascular Magnetic Resonance
Chemoradiation for advanced hypopharyngeal carcinoma: a retrospective study on efficacy, morbidity and quality of life
Chemoradiation (CRT) is a valuable treatment option for advanced hypopharyngeal squamous cell cancer (HSCC). However, long-term toxicity and quality of life (QOL) is scarcely reported. Therefore, efficacy, acute and long-term toxic effects, and long-term QOL of CRT for advanced HSCC were evaluated,using retrospective study and post-treatment quality of life questionnaires. in a tertiary hospital setting. Analysis was performed of 73 patients that had been treated with CRT. Toxicity was rated using the CTCAE score list. QOL questionnaires EORTC QLQ-C30, QLQ-H&N35, and VHI were analyzed. The most common acute toxic effects were dysphagia and mucositis. Dysphagia and xerostomia remained problematic during long-term follow-up. After 3 years, the disease-specific survival was 41%, local disease control was 71%, and regional disease control was 97%. The results indicated that CRT for advanced HSCC is associated with high locoregional control and disease-specific survival. However, significant acute and long-term toxic effects occur, and organ preservation appears not necessarily equivalent to preservation of function and better QOL
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