Testing the theory of immune selection in cancers that break the rules of transplantation

Modification of cancer cells likely to reduce their immunogenicity, including loss or down-regulation of MHC molecules, is now well documented and has become the main support for the concept of immune surveillance. The evidence that these modifications, in fact, result from selection by the immune system is less clear, since the possibility that they may result from reorganized metabolism associated with proliferation or from cell de-differentiation remains. Here, we (a) survey old and new transplantation experiments that test the possibility of selection and (b) survey how transmissible tumours of dogs and Tasmanian devils provide naturally evolved tests of immune surveillance

Point prevalence of surgical checklist use in Europe: relationship with hospital mortality

Background The prevalence of use of the World Health Organization surgical checklist is unknown. The clinical effectiveness of this intervention in improving postoperative outcomes is debated. Methods We undertook a retrospective analysis of data describing surgical checklist use from a 7 day cohort study of surgical outcomes in 28 European nations (European Surgical Outcomes Study, EuSOS). The analysis included hospitals recruiting >10 patients and excluding outlier hospitals above the 95th centile for mortality. Multivariate logistic regression and three-level hierarchical generalized mixed models were constructed to explore the relationship between surgical checklist use and hospital mortality. Findings are presented as crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Results A total of 45 591 patients from 426 hospitals were included in the analysis. A surgical checklist was used in 67.5% patients, with marked variation across countries (0-99.6% of patients). Surgical checklist exposure was associated with lower crude hospital mortality (OR 0.84, CI 0.75-0.94; P=0.002). This effect remained after adjustment for baseline risk factors in a multivariate model (adjusted OR 0.81, CI 0.70-0.94; P<0.005) and strengthened after adjusting for variations within countries and hospitals in a three-level generalized mixed model (adjusted OR 0.71, CI 0.58-0.85; P<0.001). Conclusions The use of surgical checklists varies across European nations. Reported use of a checklist was associated with lower mortality. This observation may represent a protective effect of the surgical checklist itself, or alternatively, may be an indirect indicator of the quality of perioperative care. Clinical trial registration The European Surgical Outcomes Study is registered with ClinicalTrials.gov, number NCT0120360

Rule-based modelling provides an extendable framework for comparing candidate mechanisms underpinning clathrin polymerisation

Abstract Polymerisation of clathrin is a key process that underlies clathrin-mediated endocytosis. Clathrin-coated vesicles are responsible for cell internalization of external substances required for normal homeostasis and life –sustaining activity. There are several hypotheses describing formation of closed clathrin structures. According to one of the proposed mechanisms cage formation may start from a flat lattice buildup on the cellular membrane, which is later transformed into a curved structure. Creation of the curved surface requires rearrangement of the lattice, induced by additional molecular mechanisms. Different potential mechanisms require a modeling framework that can be easily modified to compare between them. We created an extendable rule-based model that describes polymerisation of clathrin molecules and various scenarios of cage formation. Using Global Sensitivity Analysis (GSA) we obtained parameter sets describing clathrin pentagon closure and the emergence/production and closure of large-size clathrin cages/vesicles. We were able to demonstrate that the model can reproduce budding of the clathrin cage from an initial flat array

Males and Females Contribute Unequally to Offspring Genetic Diversity in the Polygynandrous Mating System of Wild Boar

The maintenance of genetic diversity across generations depends on both the number of reproducing males and females. Variance in reproductive success, multiple paternity and litter size can all affect the relative contributions of male and female parents to genetic variation of progeny. The mating system of the wild boar (Sus scrofa) has been described as polygynous, although evidence of multiple paternity in litters has been found. Using 14 microsatellite markers, we evaluated the contribution of males and females to genetic variation in the next generation in independent wild boar populations from the Iberian Peninsula and Hungary. Genetic contributions of males and females were obtained by distinguishing the paternal and maternal genetic component inherited by the progeny. We found that the paternally inherited genetic component of progeny was more diverse than the maternally inherited component. Simulations showed that this finding might be due to a sampling bias. However, after controlling for the bias by fitting both the genetic diversity in the adult population and the number of reproductive individuals in the models, paternally inherited genotypes remained more diverse than those inherited maternally. Our results suggest new insights into how promiscuous mating systems can help maintain genetic variation

Forty years on: clathrin-coated pits continue to fascinate

Clathrin mediated endocytosis (CME) is a fundamental process in cell biology and has been extensively investigated throughout the last several decades. Every cell biologist learns about it at some point during their education and the beauty of this process has led many of us to go deeper and make it the topic of our own research. Great progress has been made towards elucidating the mechanisms of CME and the field is becoming increasingly complex with several hundred new publications every year. This makes it easy to get lost in the vast amount of literature and to forget about the fundamentals of the field, based on the careful interpretation of simple observations made over 40 years ago. A study performed by Anderson, Brown and Goldstein in 1977 (Anderson et al., 1977) is a prime example of this. We therefore want to take a step back and examine how this seminal study was pivotal to our understanding of CME and its progression into ever increasing complexity over the last four decades

Biotechnology and the Politics of Truth : From the Green Revolution to an Evergreen Revolution

This paper investigates why and how issues around the diffusion of GM technologies and products to developing countries have become so central to a debate which has shifted away from technical issues of cost-benefit optimisation in a context of uniform mass production and consumption in the North, to the moral case for GM crops to feed the hungry and aid ‘development’ in the South. Using comparison between agricultural biotechnology and the ‘Green Revolution’ as a cross cutting theme, the contributions of this paper are threefold. Firstly, by analysing biotechnology as a set of overlapping frames within a discursive formation, four frames are identified which summarise key challenges presented by biotechnology era. Secondly, the use of Foucault's concept of bio-power to synthesise key themes from the frame analysis illuminates the ‘revolutionary’ nature of the biotech revolution. Thirdly, the potential of actor-network theory to provide a tools for the empirical study of processes of (re)negotiation of nature/society relations in the context of agricultural biotechnology controversies is explored

Patient-directed self-management of pain (PaDSMaP) compared to treatment as usual following total knee replacement; a randomised controlled trial

Background Self-administration of medicines by patients whilst in hospital is being increasingly promoted despite little evidence to show the risks and benefits. Pain control after total knee replacement (TKR) is known to be poor. The aim of the study was to determine if patients operated on with a TKR who self-medicate their oral analgesics in the immediate post-operative period have better pain control than those who receive their pain control by nurse-led drug rounds (Treatment as Usual (TAU)). Methods A prospective, parallel design, open-label, randomised controlled trial comparing pain control in patient-directed self-management of pain (PaDSMaP) with nurse control of oral analgesia (TAU) after a TKR. Between July 2011 and March 2013, 144 self-medicating adults were recruited at a secondary care teaching hospital in the UK. TAU patients (n = 71) were given medications by a nurse after their TKR. PaDSMaP patients (n = 73) took oral medications for analgesia and co-morbidities after two 20 min training sessions reinforced with four booklets. Primary outcome was pain (100 mm visual analogue scale (VAS)) at 3 days following TKR surgery or at discharge (whichever came soonest). Seven patients did not undergo surgery for reasons unrelated to the study and were excluded from the intention-to-treat (ITT) analysis. Results ITT analysis did not detect any significant differences between the two groups’ pain scores. A per protocol (but underpowered) analysis of the 60% of patients able to self-medicate found reduced pain compared to the TAU group at day 3/discharge, (VAS -9.9 mm, 95% CI -18.7, − 1.1). One patient in the self-medicating group over-medicated but suffered no harm. Conclusion Self-medicating patients did not have better (lower) pain scores compared to the nurse-managed patients following TKR. This cohort of patients were elderly with multiple co-morbidities and may not be the ideal target group for self-medication

Fatal meningitis in a previously healthy young adult caused by Streptococcus pneumoniae serotype 38: an emerging serotype?

BACKGROUND: In December 2001, a fatal case of pneumococcal meningitis in a Marine Corps recruit was identified. As pneumococcal vaccine usage in recruit populations is being considered, an investigation was initiated into the causative serotype. CASE PRESENTATION: Traditional and molecular methods were utilized to determine the serotype of the infecting pneumococcus. The pneumococcal isolate was identified as serotype 38 (PS38), a serotype not covered by current vaccine formulations. The global significance of this serotype was explored in the medical literature, and found to be a rare but recognized cause of carriage and invasive disease. CONCLUSION: The potential of PS38 to cause severe disease is documented in this report. Current literature does not support the hypothesis that this serotype is increasing in incidence. However, as we monitor the changing epidemiology of pneumococcal illness in the US in this conjugate era, PS38 might find a more prominent and concerning niche as a replacement serotype