2,295 research outputs found
Revising ethical guidance for the evaluation of programmes and interventions not initiated by researchers
Public health and service delivery programmes, interventions and policies (collectively, “programmes)” are typically developed and implemented for the primary purpose of effecting change rather than generating knowledge. Nonetheless, evaluations of these programmes may produce valuable learning that helps to determine effectiveness and costs as well as informing design and implementation of future programmes. Such studies might be termed “opportunistic evaluations”, since they are responsive to emergent opportunities rather than being studies of interventions that are initiated or designed by researchers. However, current ethical guidance and registration procedures make little allowance for scenarios where researchers have played no role in the development or implementation of a programme, but nevertheless plan to conduct a prospective evaluation. We explore the limitations of the guidance and procedures with respect to opportunistic evaluations, providing a number of examples. We propose that the key missing distinction in current guidance is that moral responsibility: researchers can only be held accountable for those aspects of a study over which they have control. We argue that requiring researchers to justify an intervention, programme or policy that would occur regardless of their involvement prevents or hinders research in the public interest without providing any further protections to research participants. We recommend that trial consent and ethics procedures allow for a clear separation of responsibilities for the intervention and the evaluation.SIW and RJL are funded by the NIHR Global Health Research Unit on Improving Health in Slums. CT, PJC and RJL are also supported by the National Institute for Health Research (NIHR) Collaboration for Leadership for Applied Health Research Care (CLAHRC) West Midlands initiative. EBW and ELD are employed by Partners In Health. MD-W is supported by the Health Foundation’s grant to the University of Cambridge for The Healthcare Improvement Studies (THIS) Institute. THIS Institute is supported by the Health Foundation - an independent charity committed to bringing about better health and health care for people in the UK. This work was also supported by MDW’s Wellcome Trust Investigator award WT09789. MDW is a National Institute for Health Research (NIHR) Senior Investigator. This paper presents independent research and the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Healt
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A novel cell culture model for studying differentiation and apoptosis in the mouse mammary gland.
BACKGROUND: This paper describes the derivation and characterization of a novel, conditionally immortal mammary epithelial cell line named KIM-2. These cells were derived from mid-pregnant mammary glands of a mouse harbouring one to two copies of a transgene comprised of the ovine beta-lactoglobulin milk protein gene promoter, driving expression of a temperature-sensitive variant of simian virus-40 (SV40) large T antigen (T-Ag). RESULTS: KIM-2 cells have a characteristic luminal epithelial cell morphology and a stable, nontransformed phenotype at the semipermissive temperature of 37 degrees C. In contrast, at the permissive temperature of 33 degrees C the cells have an elongated spindle-like morphology and become transformed after prolonged culture. Differentiation of KIM-2 cells at 37 degrees C, in response to lactogenic hormones, results in the formation of polarized dome-like structures with tight junctions. This is accompanied by expression of the milk protein genes that encode beta-casein and whey acidic protein (WAP), and activation of the prolactin signalling molecule, signal transducer and activator of transcription (STAT)5. Fully differentiated KIM-2 cultures at 37 degrees C become dependent on lactogenic hormones for survival and undergo extensive apoptosis upon hormone withdrawal, as indicated by nuclear morphology and flow cytometric analysis. KIM-2 cells can be genetically modified by stable transfection and clonal lines isolated that retain the characteristics of untransfected cells. CONCLUSION: KIM-2 cells are a valuable addition, therefore, to currently available lines of mammary epithelial cells. Their capacity for extensive differentiation in the absence of exogenously added basement membrane, and ability to undergo apoptosis in response to physiological signals will provide an invaluable model system for the study of signal transduction pathways and transcriptional regulatory mechanisms that control differentiation and involution in the mammary gland
Harnack inequality for fractional sub-Laplacians in Carnot groups
In this paper we prove an invariant Harnack inequality on
Carnot-Carath\'eodory balls for fractional powers of sub-Laplacians in Carnot
groups. The proof relies on an "abstract" formulation of a technique recently
introduced by Caffarelli and Silvestre. In addition, we write explicitly the
Poisson kernel for a class of degenerate subelliptic equations in product-type
Carnot groups
Interactions between the Nse3 and Nse4 Components of the SMC5-6 Complex Identify Evolutionarily Conserved Interactions between MAGE and EID Families
The SMC5-6 protein complex is involved in the cellular response to DNA damage. It is composed of 6-8 polypeptides, of which Nse1, Nse3 and Nse4 form a tight sub-complex. MAGEG1, the mammalian ortholog of Nse3, is the founding member of the MAGE (melanoma-associated antigen) protein family and Nse4 is related to the EID (E1A-like inhibitor of differentiation) family of transcriptional repressors.Using site-directed mutagenesis, protein-protein interaction analyses and molecular modelling, we have identified a conserved hydrophobic surface on the C-terminal domain of Nse3 that interacts with Nse4 and identified residues in its N-terminal domain that are essential for interaction with Nse1. We show that these interactions are conserved in the human orthologs. Furthermore, interaction of MAGEG1, the mammalian ortholog of Nse3, with NSE4b, one of the mammalian orthologs of Nse4, results in transcriptional co-activation of the nuclear receptor, steroidogenic factor 1 (SF1). In an examination of the evolutionary conservation of the Nse3-Nse4 interactions, we find that several MAGE proteins can interact with at least one of the NSE4/EID proteins.We have found that, despite the evolutionary diversification of the MAGE family, the characteristic hydrophobic surface shared by all MAGE proteins from yeast to humans mediates its binding to NSE4/EID proteins. Our work provides new insights into the interactions, evolution and functions of the enigmatic MAGE proteins
The impact of genetic counselling on risk perception and mental health in women with a family history of breast cancer
The present study investigated: (1) perception of genetic risk and, (2) the psychological effects of genetic counselling in women with a family history of breast cancer. Using a prospective design, with assessment pre- and post-genetic counselling at clinics and by postal follow-up at 1, 6 and 12 months, attenders at four South London genetic clinics were assessed. Participants included 282 women with a family history of breast cancer. Outcome was measured in terms of mental health, cancer-specific distress and risk perception. High levels of cancer-specific distress were found pre-genetic counselling, with 28% of participants reporting that they worried about breast cancer ‘frequently or constantly’ and 18% that worry about breast cancer was ‘a severe or definite problem’. Following genetic counselling, levels of cancer-specific distress were unchanged. General mental health remained unchanged over time (33% psychiatric cases detected pre-genetic counselling, 27% at 12 months after genetic counselling). Prior to their genetics consultation, participants showed poor knowledge of their lifetime risk of breast cancer since there was no association between their perceived lifetime risk (when they were asked to express this as a 1 in x odds ratio) and their actual risk, when the latter was calculated by the geneticist at the clinic using the CASH model. In contrast, women were more accurate about their risk of breast cancer pre-genetic counselling when this was assessed in broad categorical terms (i.e. very much lower/very much higher than the average woman) with a significant association between this rating and the subsequently calculated CASH risk figure (P= 0.001). Genetic counselling produced a modest shift in the accuracy of perceived lifetime risk, expressed as an odds ratio, which was maintained at 12 months' follow-up. A significant minority failed to benefit from genetic counselling; 77 women continued to over-estimate their risk and maintain high levels of cancer-related worry. Most clinic attenders were inaccurate in their estimates of the population risk of breast cancer with only 24% able to give the correct figure prior to genetic counselling and 36% over-estimating this risk. There was some improvement following genetic counselling with 62% able to give the correct figure, but this information was poorly retained and this figure had dropped to 34% by the 1-year follow-up. The study showed that women attending for genetic counselling are worried about breast cancer, with 34% indicating that they had initiated the referral to the genetic clinic themselves. This anxiety is not alleviated by genetic counselling, although women reported that it was less of a problem at follow-up. Women who continue to over-estimate their risk and worry about breast cancer are likely to go on seeking unnecessary screening if they are not reassured. © 1999 Cancer Research Campaig
The Chinese version of the Obsessive-Compulsive Inventory-Revised scale: Replication and extension to non-clinical and clinical individuals with OCD symptoms
<p>Abstract</p> <p>Background</p> <p>The Obsessive-Compulsive Inventory-Revised (OCI-R) was designed to evaluate the severity of obsessive-compulsive symptoms in both clinical and non-clinical samples. The aim of the study was to evaluate the psychometric properties of a Chinese version of this scale.</p> <p>Methods</p> <p>The Chinese version of the OCI-R was administered to both a non-clinical sample (209 undergraduate students) and a clinical sample (56 obsessive-compulsive disorder (OCD) patients). Confirmatory factor analysis was conducted to examine the construct validity of the OCI-R in the non-clinical sample. The internal consistency at baseline and test-retest reliabilities at 4-week interval was examined in both the non-clinical and clinical samples.</p> <p>Results</p> <p>The confirmatory factor analysis of the non-clinical sample confirmed a 6-factor model suggested by the original authors of the instrument (df = 120, RMSEA = 0.068, CFI = 0.88, NNFI = 0.85, GFI = 0.89). The internal consistency and test-retest reliability were at an acceptable range for both the non-clinical and clinical samples. The OCI-R also showed good clinical discrimination for patients with OCD from healthy controls.</p> <p>Conclusions</p> <p>The Chinese version of the OCI-R is a valid and reliable instrument for measuring OCD symptoms in the Chinese context.</p
Zircon ages in granulite facies rocks: decoupling from geochemistry above 850 °C?
Granulite facies rocks frequently show a large spread in their zircon ages, the interpretation of which raises questions: Has the isotopic system been disturbed? By what process(es) and conditions did the alteration occur? Can the dates be regarded as real ages, reflecting several growth episodes? Furthermore, under some circumstances of (ultra-)high-temperature metamorphism, decoupling of zircon U–Pb dates from their trace element geochemistry has been reported. Understanding these processes is crucial to help interpret such dates in the context of the P–T history. Our study presents evidence for decoupling in zircon from the highest grade metapelites (> 850 °C) taken along a continuous high-temperature metamorphic field gradient in the Ivrea Zone (NW Italy). These rocks represent a well-characterised segment of Permian lower continental crust with a protracted high-temperature history. Cathodoluminescence images reveal that zircons in the mid-amphibolite facies preserve mainly detrital cores with narrow overgrowths. In the upper amphibolite and granulite facies, preserved detrital cores decrease and metamorphic zircon increases in quantity. Across all samples we document a sequence of four rim generations based on textures. U–Pb dates, Th/U ratios and Ti-in-zircon concentrations show an essentially continuous evolution with increasing metamorphic grade, except in the samples from the granulite facies, which display significant scatter in age and chemistry. We associate the observed decoupling of zircon systematics in high-grade non-metamict zircon with disturbance processes related to differences in behaviour of non-formula elements (i.e. Pb, Th, U, Ti) at high-temperature conditions, notably differences in compatibility within the crystal structure
Reading between Eye Saccades
Background: Skilled adult readers, in contrast to beginners, show no or little increase in reading latencies as a function of the number of letters in words up to seven letters. The information extraction strategy underlying such efficiency in word identification is still largely unknown, and methods that allow tracking of the letter information extraction through time between eye saccades are needed to fully address this question. Methodology/Principal Findings: The present study examined the use of letter information during reading, by means of the Bubbles technique. Ten participants each read 5,000 five-letter French words sampled in space-time within a 200 ms window. On the temporal dimension, our results show that two moments are especially important during the information extraction process. On the spatial dimension, we found a bias for the upper half of words. We also show for the first time that letter positions four, one, and three are particularly important for the identification of five-letter words. Conclusions/Significance: Our findings are consistent with either a partially parallel reading strategy or an optimal serial reading strategy. We show using computer simulations that this serial reading strategy predicts an absence of a wordlength effect for words from four- to seven letters in length. We believe that the Bubbles technique will play an importan
Identification of the initial molecular changes in response to circulating angiogenic cells-mediated therapy in critical limb ischemia
BackgroundCritical limb ischemia (CLI) constitutes the most aggressive form of peripheral arterial occlusive disease, characterized by the blockade of arteries supplying blood to the lower extremities, significantly diminishing oxygen and nutrient supply. CLI patients usually undergo amputation of fingers, feet, or extremities, with a high risk of mortality due to associated comorbidities.Circulating angiogenic cells (CACs), also known as early endothelial progenitor cells, constitute promising candidates for cell therapy in CLI due to their assigned vascular regenerative properties. Preclinical and clinical assays with CACs have shown promising results. A better understanding of how these cells participate in vascular regeneration would significantly help to potentiate their role in revascularization.Herein, we analyzed the initial molecular mechanisms triggered by human CACs after being administered to a murine model of CLI, in order to understand how these cells promote angiogenesis within the ischemic tissues.MethodsBalb-c nude mice (n:24) were distributed in four different groups: healthy controls (C, n:4), shams (SH, n:4), and ischemic mice (after femoral ligation) that received either 50 mu l physiological serum (SC, n:8) or 5x10(5) human CACs (SE, n:8). Ischemic mice were sacrificed on days 2 and 4 (n:4/group/day), and immunohistochemistry assays and qPCR amplification of Alu-human-specific sequences were carried out for cell detection and vascular density measurements. Additionally, a label-free MS-based quantitative approach was performed to identify protein changes related.ResultsAdministration of CACs induced in the ischemic tissues an increase in the number of blood vessels as well as the diameter size compared to ischemic, non-treated mice, although the number of CACs decreased within time. The initial protein changes taking place in response to ischemia and more importantly, right after administration of CACs to CLI mice, are shown.ConclusionsOur results indicate that CACs migrate to the injured area; moreover, they trigger protein changes correlated with cell migration, cell death, angiogenesis, and arteriogenesis in the host. These changes indicate that CACs promote from the beginning an increase in the number of vessels as well as the development of an appropriate vascular network.Institute of Health Carlos III, ISCIII; Junta de Andaluci
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