Regulation of expression of the interleukin-2 receptor alpha chain (CD25) in human tonsillar B lymphocytes

The Interleukin-2 Receptor α chain (IL-2Rα or CD25) plays an important role in B cell activation since it allows formation of the high affinity IL-2 Receptor and thus permits the B cell to respond to physiological concentrations of IL-2. IL-4 appears to be the sole cytokine which can induce IL-2Rα in human tonsillar B cells. In addition, polyvalent anti-lmmunoglobulin antibodies and anti-CD40 antibodies can cause up-regulation of IL- 2Rα (Burlinson et al 1995). However, although anti-lg, anti-CD40 and IL-4 can increase IL-2Rα expression, this elevation in IL-2Rα levels does not necessarily facilitate subsequent B cell proliferation in the presence of IL-2. Of the three, only anti-Ig antibodies, in combination with IL-2, could cause resting B cells to proliferate to a significant level. Stimulation of human tonsillar B cells with polyvalent anti-lg antibodies resulted in more than 80% of them acquiring an IL-2Rα -positive phenotype. IL-2Rα expression on different subsets of B cells present within the tonsillar population was studied by stimulating the cells with isotype-specific antibodies; anti-μ, anti-δ or anti-γ antibodies. Low concentrations of anti-μ antibodies up-regulated expression of IL-2Rα as did all concentrations of anti-γ antibodies. However, high doses of anti-μ antibodies and any dose of anti-δ antibodies failed to up-regulate IL-2Rα. It is possible that the failure of B cells to respond to high doses of anti-μ antibodies or to anti-δ antibodies by increasing IL-2Rα expression may cause these cells to become tolerised and thus prevent them from causing an auto-immune response. Expression of IL-2Rα on the cell surface can be related to events taking place at the promoter region of the IL-2Rα gene. There are at least three positive regulatory regions (PRRI-PRRIII) and two negative regulatory regions (NRE I and NRE II) within the promoter region and we chose to study PRR, and NREI because these regions are believed to be involved in the induction of IL-2Rα. It was found that an, as yet, unidentified protein, NRE-BP, which binds to NRE I plays a major role in controlling IL- 2Rα transcription when cells are stimulated via their sIgM receptors. NRE-BP appears to be involved in the silencing of the IL-2Rα gene and remains bound to the promoter when the B cells are stimulated with high concentrations of anti-μ antibodies. At low concentration of anti-μ antibodies, binding of NRE-BP to NRE I is attenuated. Although anti-γ antibodies up-regulate expression of IL-2Rα on the cell surface, anti-γ antibodies have no effect on the binding of NRE-BP to the promoter. Previous studies have discovered differences in signalling through the sIgM and slgG complexes. Now we have determined that sIgM and sIgG appear to act differently in the regulation of IL-2Rα and that the binding of NRE-BP to NRE I is important in this variation

Comment on: Randomized controlled trial of plain English and visual abstracts for disseminating surgical research via social media

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Should pregnant women know their individual risk of future pelvic floor dysfunction? A qualitative study

Background The study aimed to explore: • pregnant women’s and healthcare professionals’ perspectives on provision of individual risk scores for future Pelvic Floor Dysfunction (PFD), • the feasibility of providing this during routine maternity care, • actions women might take as a result of knowing their PFD risk. Methods Qualitative study. Setting: UK NHS Health Board. Participants: Pregnant women (n = 14), obstetricians (n = 6), midwives (n = 8) and physiotherapists (n = 3). A purposive sample of pregnant women and obstetric healthcare professionals were introduced to the UR-CHOICE calculator, which estimates a woman’s PFD risk, and were shown examples of low, medium and high-risk women. Data were collected in 2019 by semi-structured interview and focus group and analysed using the Framework Approach. Results Women’s PFD knowledge was limited, meaning they were unlikely to raise PFD risk with healthcare professionals. Women believed it was important to know their individual PFD risk and that knowledge would motivate them to undertake preventative activities. Healthcare professionals believed it was important to discuss PFD risk, however limited time and concerns over increased caesarean section rates prevented this in all but high-risk women or those that expressed concerns. Conclusion Women want to know their PFD risk. As part of an intervention based within a pregnant woman/ maternity healthcare professional consultation, the UR-CHOICE calculator could support discussion to consider preventative PFD activities and to enable women to be more prepared should PFD occur. A randomised controlled trial is needed to test the effectiveness of an intervention which includes the UR-CHOICE calculator in reducing PFD

Antenatal care trial interventions: a systematic scoping review and taxonomy development of care models

BACKGROUND: Antenatal care models vary widely around the world, reflecting local contexts, drivers and resources. Randomised controlled trials (RCTs) have tested the impact of multi-component antenatal care interventions on service delivery and outcomes in many countries since the 1980s. Some have applied entirely new schemes, while others have modified existing care delivery approaches. Systematic reviews (SRs) indicate that some specific antenatal interventions are more effective than others; however the causal mechanisms leading to better outcomes are poorly understood, limiting implementation and future research. As a first step in identifying what might be making the difference we conducted a scoping review of interventions tested in RCTs in order to establish a taxonomy of antenatal care models. METHODS: A protocol-driven systematic search was undertaken of databases for RCTs and SRs reporting antenatal care interventions. Results were unrestricted by time or locality, but limited to English language. Key characteristics of both experimental and control interventions in the included trials were mapped using SPIO (Study design; Population; Intervention; Outcomes) criteria and the intervention and principal outcome measures were described. Commonalities and differences between the components that were being tested in each study were identified by consensus, resulting in a comprehensive description of emergent models for antenatal care interventions. RESULTS: Of 13,050 articles retrieved, we identified 153 eligible articles including 130 RCTs in 34 countries. The interventions tested in these trials varied from the number of visits to the location of care provision, and from the content of care to the professional/lay group providing that care. In most studies neither intervention nor control arm was well described. Our analysis of the identified trials of antenatal care interventions produced the following taxonomy: Universal provision model (for all women irrespective of health state or complications); Restricted 'lower-risk'-based provision model (midwifery-led or reduced/flexible visit approach for healthy women); Augmented provision model (antenatal care as in Universal provision above but augmented by clinical, educational or behavioural intervention); Targeted 'higher-risk'-based provision model (for woman with defined clinical or socio-demographic risk factors). The first category was most commonly tested in low-income countries (i.e. resource-poor settings), particularly in Asia. The other categories were tested around the world. The trials included a range of care providers, including midwives, nurses, doctors, and lay workers. CONCLUSIONS: Interventions can be defined and described in many ways. The intended antenatal care population group proved the simplest and most clinically relevant way of distinguishing trials which might otherwise be categorised together. Since our review excluded non-trial interventions, the taxonomy does not represent antenatal care provision worldwide. It offers a stable and reproducible approach to describing the purpose and content of models of antenatal care which have been tested in a trial. It highlights a lack of reported detail of trial interventions and usual care processes. It provides a baseline for future work to examine and test the salient characteristics of the most effective models, and could also help decision-makers and service planners in planning implementation

Robotics and Automated Systems for Environmental Sustainability: Monitoring Terrestrial Biodiversity

It is critical to protect Earth’s biodiversity, not just for its own intrinsic value, but also for the ecosystem services it underpins. Yet biodiversity is in crisis, with up to 1 million animal and plant species at risk of extinction, many within decades. This dire projection has captured world attention and triggered major mitigation efforts, but we are faced with problems in assessing global trends in biodiversity – which species, taxa, habitats and ecosystems are suffering the greatest declines? Are current mitigation measures having any positive impact? To answer key questions such as these, ecologists are seeking the help of robotics and automated systems (RAS) experts in the monumental task of attempting to monitor the state of biodiversity.In this White Paper, we have surveyed recent literature and consulted more than 120 international expert ecologists and engineers working in the fields of biodiversity and robotics. We have done this to evaluate the potential for developing robotic and autonomous systems that could massively extend the scope of terrestrial biodiversity monitoring across habitats globally. The complexities of biodiversity itself, and the many barriers and challenges that must be overcome in monitoring it, are formidable. We assess each of these barriers in turn, highlighting currently available RAS solutions, as well as nascent technologies that may be relevant to future RAS for biodiversity (RAS-BD) monitoring. Using this information, we have drawn up a roadmap of actions needed to address the barriers that should be easiest to overcome. Encouragingly, we find that a variety of existing RAS capabilities may be transferable to a biodiversity monitoring context. Beyond these are the harder barriers, where promising novel ideas being researched at UK universities and research institutes may, in time, become integral parts of future RAS-BD monitoring technology. We believe that RAS-BD technology has great potential to complement and considerably extend the field survey work undertaken by expert human observers. In the UK, we are fortunate in having particular strengths in both biodiversity and robotics research; as a nation we are in an ideal position to integrate them and become a leading force in the development and application of RAS-BD monitoring. To this end, we propose these recommendations that we hope will guide future government strategy in an area that is vital to the future of humanity:● The creation and funding of an integrated multidisciplinary task force, including academics and industry specialists with expertise in RAS and biodiversity, to support technological research and development.● Future UK funding and focus should be prioritised to utilise existing RAS capabilities to develop first generation RAS-BD technology for monitoring biodiversity.● Relevant nascent technologies being researched by numerous UK academic teams need increased and accelerated research and development funding to turn pioneering concepts into enhanced RAS-BD technology suited to overcoming the hardest monitoring barriers that ecologists encounter.● Education strategies should be developed to foster links between aspiring engineers, biologists andcomputer technologists, both in the curriculum of schools, and at later stages in universities and research facilities

Microbial nitrogen limitation in the mammalian large intestine

Resource limitation is a fundamental factor governing the composition and function of ecological communities. However, the role of resource supply in structuring the intestinal microbiome has not been established and represents a challenge for mammals that rely on microbial symbionts for digestion: too little supply might starve the microbiome while too much might starve the host. We present evidence that microbiota occupy a habitat that is limited in total nitrogen supply within the large intestines of 30 mammal species. Lowering dietary protein levels in mice reduced their faecal concentrations of bacteria. A gradient of stoichiometry along the length of the gut was consistent with the hypothesis that intestinal nitrogen limitation results from host absorption of dietary nutrients. Nitrogen availability is also likely to be shaped by host-microbe interactions: levels of host-secreted nitrogen were altered in germ-free mice and when bacterial loads were reduced via experimental antibiotic treatment. Single-cell spectrometry revealed that members of the phylum Bacteroidetes consumed nitrogen in the large intestine more readily than other commensal taxa did. Our findings support a model where nitrogen limitation arises from preferential host use of dietary nutrients. We speculate that this resource limitation could enable hosts to regulate microbial communities in the large intestine. Commensal microbiota may have adapted to nitrogen-limited settings, suggesting one reason why excess dietary protein has been associated with degraded gut-microbial ecosystems

A case report of bilateral synovial chondromatosis of the ankle

<p>Abstract</p> <p>Background</p> <p>Synovial chondromatosis is a rare, generally benign condition which affects synovial membranes. It most commonly involves large joints such as the knee, hip, and elbow, but its presence in smaller joints has also been reported. The diagnosis of synovial chondromatosis is commonly made following a thorough history, physical examination, and radiographic examination. Patients may report pain and swelling within a joint which is often aggravated with physical activity.</p> <p>Case presentation</p> <p>A rare case of bilateral synovial chondromatosis of the ankle is reviewed. A 26 year-old male presented with chronic bilateral ankle pain. Physical examination suggested and imaging confirmed multiple synovial chondromatoses bilaterally, likely secondary to previous trauma.</p> <p>Conclusion</p> <p>The clinical and imaging findings, along with potential differential diagnoses, are described. Since this condition tends to be progressive but self-limiting, indications for surgery depend on the level of symptomatic presentation in addition to the functional demands of the patient. Following a surgical consultation, it was decided that it was not appropriate to pursue surgery at the present time.</p

Length of carotid stenosis predicts peri-procedural stroke or death and restenosis in patients randomized to endovascular treatment or endarterectomy.

BACKGROUND: The anatomy of carotid stenosis may influence the outcome of endovascular treatment or carotid endarterectomy. Whether anatomy favors one treatment over the other in terms of safety or efficacy has not been investigated in randomized trials. METHODS: In 414 patients with mostly symptomatic carotid stenosis randomized to endovascular treatment (angioplasty or stenting; n = 213) or carotid endarterectomy (n = 211) in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), the degree and length of stenosis and plaque surface irregularity were assessed on baseline intraarterial angiography. Outcome measures were stroke or death occurring between randomization and 30 days after treatment, and ipsilateral stroke and restenosis ≥50% during follow-up. RESULTS: Carotid stenosis longer than 0.65 times the common carotid artery diameter was associated with increased risk of peri-procedural stroke or death after both endovascular treatment [odds ratio 2.79 (1.17-6.65), P = 0.02] and carotid endarterectomy [2.43 (1.03-5.73), P = 0.04], and with increased long-term risk of restenosis in endovascular treatment [hazard ratio 1.68 (1.12-2.53), P = 0.01]. The excess in restenosis after endovascular treatment compared with carotid endarterectomy was significantly greater in patients with long stenosis than with short stenosis at baseline (interaction P = 0.003). Results remained significant after multivariate adjustment. No associations were found for degree of stenosis and plaque surface. CONCLUSIONS: Increasing stenosis length is an independent risk factor for peri-procedural stroke or death in endovascular treatment and carotid endarterectomy, without favoring one treatment over the other. However, the excess restenosis rate after endovascular treatment compared with carotid endarterectomy increases with longer stenosis at baseline. Stenosis length merits further investigation in carotid revascularisation trials

Midwifery-led antenatal care models: mapping a systematic review to an evidence-based quality framework to identify key components and characteristics of care.

BACKGROUND: Implementing effective antenatal care models is a key global policy goal. However, the mechanisms of action of these multi-faceted models that would allow widespread implementation are seldom examined and poorly understood. In existing care model analyses there is little distinction between what is done, how it is done, and who does it. A new evidence-informed quality maternal and newborn care (QMNC) framework identifies key characteristics of quality care. This offers the opportunity to identify systematically the characteristics of care delivery that may be generalizable across contexts, thereby enhancing implementation. Our objective was to map the characteristics of antenatal care models tested in Randomised Controlled Trials (RCTs) to a new evidence-based framework for quality maternal and newborn care; thus facilitating the identification of characteristics of effective care. METHODS: A systematic review of RCTs of midwifery-led antenatal care models. Mapping and evaluation of these models' characteristics to the QMNC framework using data extraction and scoring forms derived from the five framework components. Paired team members independently extracted data and conducted quality assessment using the QMNC framework and standard RCT criteria. RESULTS: From 13,050 citations initially retrieved we identified 17 RCTs of midwifery-led antenatal care models from Australia (7), the UK (4), China (2), and Sweden, Ireland, Mexico and Canada (1 each). QMNC framework scores ranged from 9 to 25 (possible range 0-32), with most models reporting fewer than half the characteristics associated with quality maternity care. Description of care model characteristics was lacking in many studies, but was better reported for the intervention arms. Organisation of care was the best-described component. Underlying values and philosophy of care were poorly reported. CONCLUSIONS: The QMNC framework facilitates assessment of the characteristics of antenatal care models. It is vital to understand all the characteristics of multi-faceted interventions such as care models; not only what is done but why it is done, by whom, and how this differed from the standard care package. By applying the QMNC framework we have established a foundation for future reports of intervention studies so that the characteristics of individual models can be evaluated, and the impact of any differences appraised

The safety profile of a cationic lipid-mediated cystic fibrosis gene transfer agent following repeated monthly aerosol administration to sheep

Clinically effective gene therapy for Cystic Fibrosis has been a goal for over 20 years. A plasmid vector (pGM169) that generates persistent expression and reduced host inflammatory responses in mice has raised prospects for translation to the clinic. The UK CF Gene Therapy Consortium is currently evaluating long-term repeated delivery of pGM169 complexed with the cationic lipid GL67A in a large Multidose Trial. This regulatory-compliant evaluation of aerosol administration of nine doses of pGM169/GL67A at monthly intervals, to the sheep lung, was performed in preparation for the Multidose Trial. All sheep tolerated treatment well with no adverse effects on haematology, serum chemistry, lung function or histopathology. Acute responses were observed in relation to bronchoalveolar cellularity comprising increased neutrophils and macrophage numbers 1 day post-delivery but these increases were transient and returned to baseline. Importantly there was no cumulative inflammatory effect or lung remodelling with successive doses. Molecular analysis confirmed delivery of pGM169 DNA to the airways and pGM169-specific mRNA was detected in bronchial brushing samples at day 1 following doses 1, 5 and 9. In conclusion, nine doses of pGM169/GL67A were well tolerated with no significant evidence of toxicity that would preclude adoption of a similar strategy in CF patients