Recognition of skin malignancy by general practitioners: observational study using data from a population-based randomised controlled trial

Skin malignancy is an important cause of mortality in the United Kingdom and is rising in incidence every year. Most skin cancer presents in primary care, and an important determinant of outcome is initial recognition and management of the lesion. Here we present an observational study of interobserver agreement using data from a population-based randomised controlled trial of minor surgery. Trial participants comprised patients presenting in primary care and needing minor surgery in whom recruiting doctors felt to be able to offer treatment themselves or to be able to refer to a colleague in primary care. They are thus relatively unselected. The skin procedures undertaken in the randomised controlled trial generated 491 lesions with a traceable histology report: 36 lesions (7%) from 33 individuals were malignant or pre-malignant. Chance-corrected agreement (κ) between general practitioner (GP) diagnosis of malignancy and histology was 0.45 (0.36–0.54) for lesions and 0.41 (0.32–0.51) for individuals affected with malignancy. Sensitivity of GPs for the detection of malignant lesions was 66.7% (95% confidence interval (CI), 50.3–79.8) for lesions and 63.6% (95% CI, 46.7–77.8) for individuals affected with malignancy. The safety of patients is of paramount importance and it is unsafe to leave the diagnosis and treatment of potential skin malignancy in the hands of doctors who have limited training and experience. However, the capacity to undertake all of the minor surgical demand works demanded in hospitals does not exist. If the capacity to undertake it is present in primary care, then the increased costs associated with enhanced training for general medical practitioners (GPs) must be borne

Population policies and education: exploring the contradictions of neo-liberal globalisation

The world is increasingly characterised by profound income, health and social inequalities (Appadurai, 2000). In recent decades development initiatives aimed at reducing these inequalities have been situated in a context of increasing globalisation with a dominant neo-liberal economic orthodoxy. This paper argues that neo-liberal globalisation contains inherent contradictions regarding choice and uniformity. This is illustrated in this paper through an exploration of the impact of neo-liberal globalisation on population policies and programmes. The dominant neo-liberal economic ideology that has influenced development over the last few decades has often led to alternative global visions being overlooked. Many current population and development debates are characterised by polarised arguments with strongly opposing aims and views. This raises the challenge of finding alternatives situated in more middle ground that both identify and promote the socially positive elements of neo-liberalism and state intervention, but also to limit their worst excesses within the population field and more broadly. This paper concludes with a discussion outling the positive nature of middle ground and other possible alternatives

‘I arranged my own marriage': arranged marriages and post-colonial feminism

This article looks at the practice of arranged marriage among women of Indian, Pakistani and Bangladeshi origin resident in Britain. It examines the conflation of arranged marriages with forced marriages and the assumption that arranged marriages are examples of cultural practices that thwart individual agency. Drawing upon original empirical data, this article will argue that in the practice of arranged marriage, some South Asian women are able to exercise agency while choosing their marriage partner. They adapt traditional arranged marriage practices to navigate their way around strict cultural expectations and to negotiate with their family members the choice of a match that is favourable for them. It provides a corrective account of arranged marriages by challenging the stereotype of the ‘oppressed third world women' and their experiences of such marriages. The article will do this by employing the idea of post-colonial feminism and by highlighting two long-standing issues in feminist debates: the idea of agency and the conception and role of power in the struggle for women's rights. It will make a case for a post-colonial approach to feminism as one way of reconciling feminism with the politics of multiculturalism

Secondary mineral formation associated with respiration of nontronite, NAu-1 by iron reducing bacteria

Experimental batch and miscible-flow cultures were studied in order to determine the mechanistic pathways of microbial Fe(III) respiration in ferruginous smectite clay, NAu-1. The primary purpose was to resolve if alteration of smectite and release of Fe precedes microbial respiration. Alteration of NAu-1, represented by the morphological and mineralogical changes, occurred regardless of the extent of microbial Fe(III) reduction in all of our experimental systems, including those that contained heat-killed bacteria and those in which O(2), rather than Fe(III), was the primary terminal electron acceptor. The solid alteration products observed under transmission electron microscopy included poorly crystalline smectite with diffuse electron diffraction signals, discrete grains of Fe-free amorphous aluminosilicate with increased Al/Si ratio, Fe-rich grains, and amorphous Si globules in the immediate vicinity of bacterial cells and extracellular polymeric substances. In reducing systems, Fe was also found as siderite. The small amount of Fe partitioned to the aqueous phase was primarily in the form of dissolved Fe(III) species even in the systems in which Fe(III) was the primary terminal electron acceptor for microbial respiration. From these observations, we conclude that microbial respiration of Fe(III) in our laboratory systems proceeded through the following: (1) alteration of NAu-1 and concurrent release of Fe(III) from the octahedral sheets of NAu-1; and (2) subsequent microbial respiration of Fe(III)

The SR Protein B52/SRp55 Is Required for DNA Topoisomerase I Recruitment to Chromatin, mRNA Release and Transcription Shutdown

DNA- and RNA-processing pathways are integrated and interconnected in the eukaryotic nucleus to allow efficient gene expression and to maintain genomic stability. The recruitment of DNA Topoisomerase I (Topo I), an enzyme controlling DNA supercoiling and acting as a specific kinase for the SR-protein family of splicing factors, to highly transcribed loci represents a mechanism by which transcription and processing can be coordinated and genomic instability avoided. Here we show that Drosophila Topo I associates with and phosphorylates the SR protein B52. Surprisingly, expression of a high-affinity binding site for B52 in transgenic flies restricted localization, not only of B52, but also of Topo I to this single transcription site, whereas B52 RNAi knockdown induced mis-localization of Topo I in the nucleolus. Impaired delivery of Topo I to a heat shock gene caused retention of the mRNA at its site of transcription and delayed gene deactivation after heat shock. Our data show that B52 delivers Topo I to RNA polymerase II-active chromatin loci and provide the first evidence that DNA topology and mRNA release can be coordinated to control gene expression

Effects of Engineered Nanoparticles on the Assembly of Exopolymeric Substances from Phytoplankton

The unique properties of engineered nanoparticles (ENs) that make their industrial applications so attractive simultaneously raise questions regarding their environmental safety. ENs exhibit behaviors different from bulk materials with identical chemical compositions. Though the nanotoxicity of ENs has been studied intensively, their unintended environmental impacts remain largely unknown. Herein we report experimental results of EN interactions with exopolymeric substances (EPS) from three marine phytoplankton species: Amphora sp., Ankistrodesmus angustus and Phaeodactylum tricornutum. EPS are polysaccharide-rich anionic colloid polymers released by various microorganisms that can assemble into microgels, possibly by means of hydrophobic and ionic mechanisms. Polystyrene nanoparticles (23 nm) were used in our study as model ENs. The effects of ENs on EPS assembly were monitored with dynamic laser scattering (DLS). We found that ENs can induce significant acceleration in Amphora sp. EPS assembly; after 72 hours EN-EPS aggregation reached equilibrium, forming microscopic gels of ∼4–6 µm in size. In contrast, ENs only cause moderate assembly kinetic acceleration for A. angustus and P. tricornutum EPS samples. Our results indicate that the effects of ENs on EPS assembly kinetics mainly depend on the hydrophobic interactions of ENs with EPS polymers. The cycling mechanism of EPS is complex. Nonetheless, the change of EPS assembly kinetics induced by ENs can be considered as one potential disturbance to the marine carbon cycle

Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins

Delivery is a stressful and risky event menacing the newborn. The mother-dependent respiration has to be replaced by autonomous pulmonary breathing immediately after delivery. If delayed, it may lead to deficient oxygen supply compromising survival and development of the central nervous system. Lack of oxygen availability gives rise to depletion of NAD+ tissue stores, decrease of ATP formation, weakening of the electron transport pump and anaerobic metabolism and acidosis, leading necessarily to death if oxygenation is not promptly re-established. Re-oxygenation triggers a cascade of compensatory biochemical events to restore function, which may be accompanied by improper homeostasis and oxidative stress. Consequences may be incomplete recovery, or excess reactions that worsen the biological outcome by disturbed metabolism and/or imbalance produced by over-expression of alternative metabolic pathways. Perinatal asphyxia has been associated with severe neurological and psychiatric sequelae with delayed clinical onset. No specific treatments have yet been established. In the clinical setting, after resuscitation of an infant with birth asphyxia, the emphasis is on supportive therapy. Several interventions have been proposed to attenuate secondary neuronal injuries elicited by asphyxia, including hypothermia. Although promising, the clinical efficacy of hypothermia has not been fully demonstrated. It is evident that new approaches are warranted. The purpose of this review is to discuss the concept of sentinel proteins as targets for neuroprotection. Several sentinel proteins have been described to protect the integrity of the genome (e.g. PARP-1; XRCC1; DNA ligase IIIα; DNA polymerase β, ERCC2, DNA-dependent protein kinases). They act by eliciting metabolic cascades leading to (i) activation of cell survival and neurotrophic pathways; (ii) early and delayed programmed cell death, and (iii) promotion of cell proliferation, differentiation, neuritogenesis and synaptogenesis. It is proposed that sentinel proteins can be used as markers for characterising long-term effects of perinatal asphyxia, and as targets for novel therapeutic development and innovative strategies for neonatal care

Potential biological role of poly (ADP-ribose) polymerase (PARP) in male gametes

Maintaining the integrity of sperm DNA is vital to reproduction and male fertility. Sperm contain a number of molecules and pathways for the repair of base excision, base mismatches and DNA strand breaks. The presence of Poly (ADP-ribose) polymerase (PARP), a DNA repair enzyme, and its homologues has recently been shown in male germ cells, specifically during stage VII of spermatogenesis. High PARP expression has been reported in mature spermatozoa and in proven fertile men. Whenever there are strand breaks in sperm DNA due to oxidative stress, chromatin remodeling or cell death, PARP is activated. However, the cleavage of PARP by caspase-3 inactivates it and inhibits PARP's DNA-repairing abilities. Therefore, cleaved PARP (cPARP) may be considered a marker of apoptosis. The presence of higher levels of cPARP in sperm of infertile men adds a new proof for the correlation between apoptosis and male infertility. This review describes the possible biological significance of PARP in mammalian cells with the focus on male reproduction. The review elaborates on the role played by PARP during spermatogenesis, sperm maturation in ejaculated spermatozoa and the potential role of PARP as new marker of sperm damage. PARP could provide new strategies to preserve fertility in cancer patients subjected to genotoxic stresses and may be a key to better male reproductive health

Effects of DNA supercoiling on chromatin architecture

Disruptions in chromatin structure are necessary for the regulation of eukaryotic genomes, from remodelling of nucleosomes at the base pair level through to large-scale chromatin domains that are hundreds of kilobases in size. RNA polymerase is a powerful motor which, prevented from turning with the tight helical pitch of the DNA, generates over-wound DNA ahead of itself and under-wound DNA behind. Mounting evidence supports a central role for transcription-dependent DNA supercoiling in disrupting chromatin structure at all scales. This supercoiling changes the properties of the DNA helix in a manner that substantially alters the binding specificity of DNA binding proteins and complexes, including nucleosomes, polymerases, topoisomerases and transcription factors. For example, transient over-wound DNA destabilises nucleosome core particles ahead of a transcribing polymerase, whereas under-wound DNA facilitates pre-initiation complex formation, transcription factor binding and nucleosome core particle association behind the transcribing polymerase. Importantly, DNA supercoiling can also dissipate through DNA, even in a chromatinised context, to influence both local elements and large chromatin domains. We propose a model in which changes in unconstrained DNA supercoiling influences higher levels of chromatin organisation through the additive effects of DNA supercoiling on both DNA-protein and DNA-nucleosome interactions. This model links small-scale changes in DNA and chromatin to the higher-order fibre and large-scale chromatin structures, providing a mechanism relating gene regulation to chromatin architecture in vivo

A prospective randomised comparison of minor surgery in primary and secondary care. The MiSTIC trial

Objective: To determine whether there is equivalence in the competence of GPs and hospital doctors to perform a range of elective minor surgical procedures, in terms of the safety, quality and cost of care.Design: A prospective randomised controlled equivalence trial was undertaken in consenting patients presenting at general practices and needing minor surgery.Setting: The study was conducted in the south of England. Participants: Consenting patients presenting at general practices who needed minor surgery in specified categories for whom the recruiting doctor felt able to offer treatment or to be able to refer to a colleague in primary care.Interventions: On presentation to their GP, patients were randomised to either treatment within primary care or treatment at their local hospital. Evaluation was by assessment of clinical quality and safety of outcome, supplemented by examination of patient satisfaction and cost-effectiveness.Main outcome measures: Two independent observers assessed surgical quality by blinded assessment of wound appearance, between 6 and 8 weeks postsurgery, from photographs of wounds. Other measures included satisfaction with care, safety of surgery in terms of recognition of and appropriate treatment of skin malignancies, and resource use and implications.Results: The 568 patients recruited ( 284 primary care, 284 hospital) were randomised by 82 GPs. In total, 637 skin procedures plus 17 ingrowing toenail procedures were performed ( 313 primary care, 341 hospital) by 65 GPs and 60 hospital doctors. Surgical quality was assessed for 273 ( 87%) primary care and 316 ( 93%) hospital lesions. Mean visual analogue scale score in hospital was significantly higher than that in primary care [ mean difference = 5.46 on 100- point scale; 95% confidence interval ( CI) 0.925 to 9.99], but the clinical importance of the difference was uncertain. Hospital doctors were better at achieving complete excision of malignancies, with a difference that approached statistical significance [ 7/ 16 GP ( 44%) versus 15/20 hospital ( 75%), chi(2) = 3.65, p = 0.056]. The proportion of patients with post-operative complications was similar in both groups. The mean cost for hospital-based minor surgery was pound 1222.24 and for primary care pound 449.74. Using postoperative complications as an outcome, both effectiveness and costs of the alternative interventions are uncertain. Using completeness of excision of malignancy as an outcome, hospital minor surgery becomes more cost-effective. The 705 skin procedures undertaken in this trial generated 491 lesions with a traceable histology report: 36 lesions ( 7%) from 33 individuals were malignant or premalignant. Chance-corrected agreement ( kappa) between GP diagnosis of malignancy and histology was 0.45 ( 95% CI 0.36 to 0.54) for lesions and 0.41 ( 95% CI 0.32 to 0.51) for individuals affected by malignancy. Sensitivity of GPs for detection of malignant lesions was 66.7% ( 95% CI 50.3 to 79.8) for lesions and 63.6% ( 95% CI 46.7 to 77.8) for individuals affected by malignancy.Conclusions: The quality of minor surgery carried out in general practice is not as high as that carried out in hospital, using surgical quality as the primary outcome, although the difference is not large. Patients are more satisfied if their procedure is performed in primary care, largely because of convenience. However, there are clear deficiencies in GPs' ability to recognise malignant lesions, and there may be differences in completeness of excision when compared with hospital doctors. The safety of patients is of paramount importance and this study does not demonstrate that minor surgery carried out in primary care is safe as it is currently practised. There are several alternative models of minor surgery provision worthy of consideration, including ones based in primary care that require all excised tissue to be sent for histological examination, or that require further training of GPs to undertake the necessary work. The results of this study suggest that a hospital-based service is more cost-effective. It must be concluded that it is unsafe to leave minor surgery in the hands of doctors who have never been trained to do it. Further work is required to determine GPs' management of a range of skin conditions (including potentially life-threatening malignancies), rather than just their recognition of them. Further economic modelling work is required to look at the potential costs of training sufficient numbers of GPs and GPs with special interests to meet the demand for minor surgery safely in primary care, and of the alternative of transferring minor surgery large-scale to the hospital sector. Different models of provision need thorough testing before widespread introduction