Epigenomic profiling by chromatin immunoprecipitation coupled with massively parallel DNA sequencing (ChIP-seq) is a prevailing methodology used to investigate chromatin-based regulation in ...biological systems such as human disease, but the lack of an empirical methodology to enable normalization among experiments has limited the precision and usefulness of this technique. Here, we describe a method called ChIP with reference exogenous genome (ChIP-Rx) that allows one to perform genome-wide quantitative comparisons of histone modification status across cell populations using defined quantities of a reference epigenome. ChIP-Rx enables the discovery and quantification of dynamic epigenomic profiles across mammalian cells that would otherwise remain hidden using traditional normalization methods. We demonstrate the utility of this method for measuring epigenomic changes following chemical perturbations and show how reference normalization of ChIP-seq experiments enables the discovery of disease-relevant changes in histone modification occupancy.
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•ChIP-seq is a prevailing methodology to investigate and compare epigenomic states•Lack of an empirical normalization strategy has limited the usefulness of ChIP-seq•ChIP-Rx allows genome-wide quantitative comparisons of histone modification status•ChIP-Rx identifies graded epigenomic changes following chemical perturbations
The lack of an empirical methodology to enable normalization among chromatin immunoprecipitation coupled with massively parallel DNA sequencing (ChIP-seq) experiments has limited the precision and comparative utility of this technique. Orlando et al. describe a method, called ChIP with reference exogenous genome (ChIP-Rx), that allows one to perform genome-wide quantitative comparisons of histone modification status across cell populations using defined quantities of a reference epigenome. They use the method to detect disease-relevant epigenomic changes following drug treatment.
The popular media has reported an increase in the use of social networking sites (SNSs) such as Facebook by hiring managers and human resource professionals attempting to find more detailed ...information about job applicants. Within the peer-reviewed literature, cursory empirical evidence exists indicating that others' judgments of characteristics or attributes of an individual based on information obtained from SNSs may be accurate. Although this predictor method provides a potentially promising source of applicant information on predictor constructs of interest, it is also fraught with potential limitations and legal challenges. The level of publicly available data obtainable by employers is highly unstandardized across applicants, as some applicants will choose not to use SNSs at all while those choosing to use SNSs customize the degree to which information they share is made public to those outside of their network. It is also unclear how decision makers are currently utilizing the available information. Potential discrimination may result through employer's access to publicly available pictures, videos, biographical information, or other shared information that often allows easy identification of applicant membership to a protected class. For the practice to progress in a positive direction, evidence for the validity and job-relevance of information obtained from SNSs needs to be established. Organizational researchers and practitioners also need to promote awareness and attempt to create safeguards against the potential negative outcomes related to misuse of SNSs by employers.
Clinical trials of resveratrol Patel, Ketan R.; Scott, Edwina; Brown, Victoria A. ...
Annals of the New York Academy of Sciences,
01/2011, Letnik:
1215, Številka:
1
Journal Article
Recenzirano
Odprti dostop
An expanding body of preclinical evidence suggests resveratrol has the potential to impact a variety of human diseases. To translate encouraging experimental findings into human benefits, information ...is first needed on the safety, pharmacokinetics, pharmacodynamics, and, ultimately, clinical efficacy of resveratrol. Published clinical trials have largely focused on characterizing the pharmacokinetics and metabolism of resveratrol. Recent studies have also evaluated safety and potential mechanisms of activity following multiple dosing, and have found resveratrol to be safe and reasonably well‐tolerated at doses of up to 5 g/day. However, the occurrence of mild to moderate side effects is likely to limit the doses employed in future trials to significantly less than this amount. This review describes the available clinical data, outlines how it supports the continuing development of resveratrol, and suggests what additional information is needed to increase the chances of success in future clinical trials.
Resveratrol, a naturally occurring polyphenol, has cancer chemopreventive properties in preclinical models. It has been shown to downregulate the levels of insulin-like growth factor-1 (IGF-I) in ...rodents. The purpose of the study was to assess its safety, pharmacokinetics, and effects on circulating levels of IGF-I and IGF-binding protein-3 (IGFBP-3) after repeated dosing. Forty healthy volunteers ingested resveratrol at 0.5, 1.0, 2.5, or 5.0 g daily for 29 days. Levels of resveratrol and its metabolites were measured by high performance liquid chromatography-UV in plasma obtained before and up to 24 hours after a dose between days 21 and 28. IGF-I and IGFBP-3 were measured by ELISA in plasma taken predosing and on day 29. Resveratrol was safe, but the 2.5 and 5 g doses caused mild to moderate gastrointestinal symptoms. Resveratrol-3-O-sulfate, resveratrol-4'-O-glucuronide, and resveratrol-3-O-glucuronide were major plasma metabolites. Maximal plasma levels and areas under the concentration versus time curve for the metabolites dramatically exceeded those for resveratrol, in the case of areas under the concentration versus time curve, by up to 20.3-fold. Compared with predosing values, the ingestion of resveratrol caused a decrease in circulating IGF-I and IGFBP-3 (P<0.04 for both), respectively, in all volunteers. The decrease was most marked at the 2.5 g dose level. The results suggest that repeated administration of high doses of resveratrol generates micromolar concentrations of parent and much higher levels of glucuronide and sulfate conjugates in the plasma. The observed decrease in circulating IGF-I and IGFBP-3 might contribute to cancer chemopreventive activity.
Objectives
As general practice increasingly moves towards large group practices, there is debate about the relative benefits, safety and sustainability of different care delivery models. This study ...investigates the performance of single-handed practices compared to practices with multiple doctors in England, UK.
Methods
Practices in England with more than 1000 patients were included. Workforce data and a quality control process classified practices as single-handed or multiple-handed. Outcomes were (i) GP patient survey scores measuring access, continuity, confidence in health professional and overall satisfaction; (ii) reported diabetes and hypertension outcomes; and (iii) emergency department presentation rates and cancer detection (percentage of cancers diagnosed by a 2-week wait). Generalised linear models, controlling for patient and practice characteristics, compared outcomes in single and multiple-handed practices and assessed the effect of GP age in single-handed practices.
Results
Single-handed practices were more commonly found in areas of high deprivation (41% compared to 20% of multiple-handed practices). Single-handed practices had higher patient-reported access, continuity and overall satisfaction but slightly lower diabetes management and cancer detection rates. Emergency department presentations were higher when controlling for patient characteristics in single-handed practices but not when also controlling for practice rurality and size. Increased deprivation was associated with lower performance in seven out of eight outcomes.
Conclusions
We found single-handed practices to be associated with high patient satisfaction while performing slightly less well on selected clinical outcomes. Further research is required to better understand the association between practice size, including increasing multidisciplinary working, on patient experience and outcomes.
Resveratrol is a phytochemical with chemopreventive activity in preclinical rodent models of colorectal carcinogenesis. Antiproliferation is one of the many chemopreventive modes of action it has ...been shown to engage in. Concentrations of resveratrol, which can be achieved in human tissues after p.o. administration, have not yet been defined. The purpose of this study was to measure concentrations of resveratrol and its metabolites in the colorectal tissue of humans who ingested resveratrol. Twenty patients with histologically confirmed colorectal cancer consumed eight daily doses of resveratrol at 0.5 or 1.0 g before surgical resection. Resveratrol was found to be well tolerated. Normal and malignant biopsy tissue samples were obtained before dosing. Parent compound plus its metabolites resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-O-sulfate, resveratrol sulfate glucuronide, and resveratrol disulfate were identified by high-performance liquid chromatography (HPLC) with UV or mass spectrometric detection in colorectal resection tissue. Quantitation was achieved by HPLC/UV. Cell proliferation, as reflected by Ki-67 staining, was compared in preintervention and postintervention tissue samples. Resveratrol and resveratrol-3-O-glucuronide were recovered from tissues at maximal mean concentrations of 674 and 86.0 nmol/g, respectively. Levels of resveratrol and its metabolites were consistently higher in tissues originating in the right side of the colon compared with the left. Consumption of resveratrol reduced tumor cell proliferation by 5% (P = 0.05). The results suggest that daily p.o. doses of resveratrol at 0.5 or 1.0 g produce levels in the human gastrointestinal tract of an order of magnitude sufficient to elicit anticarcinogenic effects. Resveratrol merits further clinical evaluation as a potential colorectal cancer chemopreventive agent.
Reactivity to smoking-related cues may be an important factor that precipitates relapse in smokers who are trying to quit. The neurobiology of smoking cue reactivity has been investigated in several ...fMRI studies. We combined the results of these studies using activation likelihood estimation, a meta-analytic technique for fMRI data. Results of the meta-analysis indicated that smoking cues reliably evoke larger fMRI responses than neutral cues in the extended visual system, precuneus, posterior cingulate gyrus, anterior cingulate gyrus, dorsal and medial prefrontal cortex, insula, and dorsal striatum. Subtraction meta-analyses revealed that parts of the extended visual system and dorsal prefrontal cortex are more reliably responsive to smoking cues in deprived smokers than in non-deprived smokers, and that short-duration cues presented in event-related designs produce larger responses in the extended visual system than long-duration cues presented in blocked designs. The areas that were found to be responsive to smoking cues agree with theories of the neurobiology of cue reactivity, with two exceptions. First, there was a reliable cue reactivity effect in the precuneus, which is not typically considered a brain region important to addiction. Second, we found no significant effect in the nucleus accumbens, an area that plays a critical role in addiction, but this effect may have been due to technical difficulties associated with measuring fMRI data in that region. The results of this meta-analysis suggest that the extended visual system should receive more attention in future studies of smoking cue reactivity.
► Meta-analysis of 11 fMRI studies of cigarette cue reactivity. ► Compared cigarette and neutral cues, deprived and non-deprived smokers. ► Larger responses to cigarette cues in posterior parietal cortex and cingulate gyrus. ► Deprived smokers had larger responses in dorsal prefrontal cortex. ► These areas may be important neuroanatomical substrates of tobacco addiction.
International student mobility to the United States (US) has increased over the past two decades. Despite the increase in numbers, international students may experience racism, nativism, and other ...forms of discrimination within the US context. Much of the existing literature focus on how international students can assimilate and cope with these issues rather than interrogating the systems of oppression that create negative student experiences. Thus, we utilized critical race theory (CRT) as a framework for interrogating how international student experiences are portrayed in current literature. Although CRT is grounded in US-based legal theory, we argue that CRT must move beyond the rigid confinement within US borders and expand to consider how transnationalism and global exchange contributes to the fluidity and applicability of this theory. We also provide recommendations for critical race praxis, with an emphasis on implications for practice, theory, and future research.
Background
Musculoskeletal conditions require particular management skills. Identification of interventions which are effective in equipping general practitioners (GPs) with such necessary skills ...could translate to improved health outcomes for patients and reduced healthcare and societal costs.
Objectives
To determine the effectiveness of professional interventions for GPs that aim to improve the management of musculoskeletal conditions in primary care.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), 2010, Issue 2; MEDLINE, Ovid (1950 ‐ October 2013); EMBASE, Ovid (1980 ‐ Ocotber 2013); CINAHL, EbscoHost (1980 ‐ November 2013), and the EPOC Specialised Register. We conducted cited reference searches using ISI Web of Knowledge and Google Scholar; and handsearched selected issues of Arthritis and Rheumatism and Primary Care‐Clinics in Office Practice. The latest search was conducted in November 2013.
Selection criteria
We included randomised controlled trials (RCTs), non‐randomised controlled trials (NRCTs), controlled before‐and‐after studies (CBAs) and interrupted time series (ITS) studies of professional interventions for GPs, taking place in a community setting, aiming to improve the management (including diagnosis and treatment) of musculoskeletal conditions and reporting any objective measure of GP behaviour, patient or economic outcomes. We considered professional interventions of any length, duration, intensity and complexity compared with active or inactive controls.
Data collection and analysis
Two review authors independently ed all data. We calculated the risk difference (RD) and risk ratio (RR) of compliance with desired practice for dichotomous outcomes, and the mean difference (MD) and standardised mean difference (SMD) for continuous outcomes. We investigated whether the direction of the targeted behavioural change affects the effectiveness of interventions.
Main results
Thirty studies met our inclusion criteria.
From 11 studies on osteoporosis, meta‐analysis of five studies (high‐certainty evidence) showed that a combination of a GP alerting system on a patient's increased risk of osteoporosis and a patient‐directed intervention (including patient education and a reminder to see their GP) improves GP behaviour with regard to diagnostic bone mineral density (BMD) testing and osteoporosis medication prescribing (RR 4.44; (95% confidence interval (CI) 3.54 to 5.55; 3 studies; 3,386 participants)) for BMD and RR 1.71 (95% CI 1.50 to 1.94; 5 studies; 4,223 participants) for osteoporosis medication. Meta‐analysis of two studies showed that GP alerting on its own also probably improves osteoporosis guideline‐consistent GP behaviour (RR 4.75 (95% CI 3.62 to 6.24; 3,047 participants)) for BMD and RR 1.52 (95% CI 1.26 to 1.84; 3.047 participants) for osteoporosis medication) and that adding the patient‐directed component probably does not lead to a greater effect (RR 0.94 (95% CI 0.81 to 1.09; 2,995 participants)) for BMD and RR 0.93 (95% CI 0.79 to 1.10; 2,995 participants) for osteoporosis medication.
Of the 10 studies on low back pain, seven showed that guideline dissemination and educational opportunities for GPs may lead to little or no improvement with regard to guideline‐consistent GP behaviour. Two studies showed that the combination of guidelines and GP feedback on the total number of investigations requested may have an effect on GP behaviour and result in a slight reduction in the number of tests, while one of these studies showed that the combination of guidelines and GP reminders attached to radiology reports may result in a small but sustained reduction in the number of investigation requests.
Of the four studies on osteoarthritis, one study showed that using educationally influential physicians may result in improvement in guideline‐consistent GP behaviour. Another study showed slight improvements in patient outcomes (pain control) after training GPs on pain management.
Of three studies on shoulder pain, one study reported that there may be little or no improvement in patient outcomes (functional capacity) after GP education on shoulder pain and injection training.
Of two studies on other musculoskeletal conditions, one study on pain management showed that there may be worse patient outcomes (pain control) after GP training on the use of validated assessment scales.
The 12 remaining studies across all musculoskeletal conditions showed little or no improvement in GP behaviour and patient outcomes.
The direction of the targeted behaviour (i.e. increasing or decreasing a behaviour) does not seem to affect the effectiveness of an intervention. The majority of the studies did not investigate the potential adverse effects of the interventions and only three studies included a cost‐effectiveness analysis.
Overall, there were important methodological limitations in the body of evidence, with just a third of the studies reporting adequate allocation concealment and blinded outcome assessments. While our confidence in the pooled effect estimate of interventions for improving diagnostic testing and medication prescribing in osteoporosis is high, our confidence in the reported effect estimates in the remaining studies is low.
Authors' conclusions
There is good‐quality evidence that a GP alerting system with or without patient‐directed education on osteoporosis improves guideline‐consistent GP behaviour, resulting in better diagnosis and treatment rates.
Interventions such as GP reminder messages and GP feedback on performance combined with guideline dissemination may lead to small improvements in guideline‐consistent GP behaviour with regard to low back pain, while GP education on osteoarthritis pain and the use of educationally influential physicians may lead to slight improvement in patient outcomes and guideline‐consistent behaviour respectively. However, further studies are needed to ascertain the effectiveness of such interventions in improving GP behaviour and patient outcomes.
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