27 research outputs found
Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control
DNA replication stress is a source of genomic instability. Here we identify âchanged mutation rate 1 (âCmr1) as a factor involved in the response to DNA replication stress in Saccharomyces cerevisiae and show that âCmr1âtogether with âMrc1/âClaspin, âPph3, the chaperonin containing âTCP1 (CCT) and 25 other proteinsâdefine a novel intranuclear quality control compartment (INQ) that sequesters misfolded, ubiquitylated and sumoylated proteins in response to genotoxic stress. The diversity of proteins that localize to INQ indicates that other biological processes such as cell cycle progression, chromatin and mitotic spindle organization may also be regulated through INQ. Similar to âCmr1, its human orthologue âWDR76 responds to proteasome inhibition and DNA damage by relocalizing to nuclear foci and physically associating with CCT, suggesting an evolutionarily conserved biological function. We propose that âCmr1/âWDR76 plays a role in the recovery from genotoxic stress through regulation of the turnover of sumoylated and phosphorylated proteins
The role of inflammation in epilepsy.
Epilepsy is the third most common chronic brain disorder, and is characterized by an enduring predisposition to generate seizures. Despite progress in pharmacological and surgical treatments of epilepsy, relatively little is known about the processes leading to the generation of individual seizures, and about the mechanisms whereby a healthy brain is rendered epileptic. These gaps in our knowledge hamper the development of better preventive treatments and cures for the approximately 30% of epilepsy cases that prove resistant to current therapies. Here, we focus on the rapidly growing body of evidence that supports the involvement of inflammatory mediators-released by brain cells and peripheral immune cells-in both the origin of individual seizures and the epileptogenic process. We first describe aspects of brain inflammation and immunity, before exploring the evidence from clinical and experimental studies for a relationship between inflammation and epilepsy. Subsequently, we discuss how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death. Further insight into the complex role of inflammation in the generation and exacerbation of epilepsy should yield new molecular targets for the design of antiepileptic drugs, which might not only inhibit the symptoms of this disorder, but also prevent or abrogate disease pathogenesis
Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)
Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic
Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases
The production of peroxide and superoxide is an inevitable consequence of
aerobic metabolism, and while these particular "reactive oxygen species" (ROSs)
can exhibit a number of biological effects, they are not of themselves
excessively reactive and thus they are not especially damaging at physiological
concentrations. However, their reactions with poorly liganded iron species can
lead to the catalytic production of the very reactive and dangerous hydroxyl
radical, which is exceptionally damaging, and a major cause of chronic
inflammation. We review the considerable and wide-ranging evidence for the
involvement of this combination of (su)peroxide and poorly liganded iron in a
large number of physiological and indeed pathological processes and
inflammatory disorders, especially those involving the progressive degradation
of cellular and organismal performance. These diseases share a great many
similarities and thus might be considered to have a common cause (i.e.
iron-catalysed free radical and especially hydroxyl radical generation). The
studies reviewed include those focused on a series of cardiovascular, metabolic
and neurological diseases, where iron can be found at the sites of plaques and
lesions, as well as studies showing the significance of iron to aging and
longevity. The effective chelation of iron by natural or synthetic ligands is
thus of major physiological (and potentially therapeutic) importance. As
systems properties, we need to recognise that physiological observables have
multiple molecular causes, and studying them in isolation leads to inconsistent
patterns of apparent causality when it is the simultaneous combination of
multiple factors that is responsible. This explains, for instance, the
decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference
'Best for everyone concerned' or 'Only as a last resort'? Views of Australian doctors about sterilisation of men and women with intellectual disability
Backgroundâ Doctors have the potential to influence opportunities for normative life experiences in the area of sexuality for individuals with intellectual disability (ID). Methodâ In Study One, 106 doctors completed the Attitudes to Sexuality Questionnaire (Individuals with an Intellectual Disability). In Study Two, 97 doctors completed a modified form of the questionnaire that included additional questions designed to assess their views about sterilisation. Resultsâ Attitudes were less positive about parenting than about other aspects of sexuality, and less sexual freedom was seen as desirable for adults with ID. A surprising number of doctors agreed that sterilisation was a desirable practice. Study Two provided data about the conditions under which sterilisation was endorsed. Most doctors reported they had not been approached to perform sterilisations. Only 12% believed medical practitioners receive sufficient training in the area of disability and sexuality. Conclusionsâ The findings have implications for training and professional development for doctors
Safety profile of BG00012, all oral formulation of dimethyl fumarate for patients with relapsing MS
The efficacy of BG00012 in patients with relapsing-remitting multiple sclerosis: Subgroup analyses from the phase 2B study
Where can I get free? Everyday Bordering, Everyday Incarceration
This paper draws on the growing body of geographical literature on carceral spaces and carcerality to explore alternatives sites of incarceration in everyday life and also to look beyond the state as a carceral actor and agent. In particular, it focuses on âunfreedomâ and the punitive elements of UK immigration controls from the perspective of those who have left violent domestic situations and in doing so have been forced to apply for leave to remain in the country. The paper highlights the ways in which, in enacting the spatial violence of immigration policies and controls, everyday actors, such as sales assistants and landlords, become agents in the âcontinuum of unfreedoms.â The discussion, therefore, seeks to define carcerality beyond the institution as not only linked to institutional carceralities but as existing in and of itself in and around us in everyday life. In particular, it is argued that from a feminist perspective there is a need to better understand these everyday carceralities in the process of seeking asylum, as women are less likely to be incarcerated in state institutions. The paper also demonstrates the complex roles of non and quasiâstate actors in shaping the âunfreedomsâ of everyday life for those seeking leave to remain in the UK as a result of domestic violence