Refining the role of laparoscopy and laparoscopic ultrasound in the staging of presumed pancreatic head and ampullary tumours

Laparoscopy and laparoscopic ultrasound have been validated previously as staging tools for pancreatic cancer. The aim of this study was to identify if assessment of vascular involvement with abdominal computed tomography (CT) would allow refinement of the selection criteria for laparoscopy and laparoscopic ultrasound (LUS). The details of patients staged with LUS and abdominal CT were obtained from the unit's pancreatic cancer database. A CT grade (O, A-F) of vascular involvement was recorded by a single radiologist. Of 152 patients, who underwent a LUS, 56 (37%) had unresectable disease. Three of 26 (12%) patients with CT grade O, 27 of 88 (31%) patients with CT grade A to D, 17 of 29 (59%) patients with CT grade E and all nine patients with CT grade F were found to have unresectable disease. In all, 24% of patients with tumours <3 cm were found to have unresectable disease. In those patients with tumours considered unresectable, local vascular involvement was found in 56% of patients and vascular involvement with metastatic disease in 17%, while 20% of patients had liver metastases alone and 5% had isolated peritoneal metastases. The remaining patient was deemed unfit for resection. Selective use of laparoscopic ultrasound is indicated in the staging of periampullary tumours with CT grades A to D

Diurnal Rhythms Result in Significant Changes in the Cellular Protein Complement in the Cyanobacterium Cyanothece 51142

Cyanothece sp. ATCC 51142 is a diazotrophic cyanobacterium notable for its ability to perform oxygenic photosynthesis and dinitrogen fixation in the same single cell. Previous transcriptional analysis revealed that the existence of these incompatible cellular processes largely depends on tightly synchronized expression programs involving ∼30% of genes in the genome. To expand upon current knowledge, we have utilized sensitive proteomic approaches to examine the impact of diurnal rhythms on the protein complement in Cyanothece 51142. We found that 250 proteins accounting for ∼5% of the predicted ORFs from the Cyanothece 51142 genome and 20% of proteins detected under alternating light/dark conditions exhibited periodic oscillations in their abundances. Our results suggest that altered enzyme activities at different phases during the diurnal cycle can be attributed to changes in the abundance of related proteins and key compounds. The integration of global proteomics and transcriptomic data further revealed that post-transcriptional events are important for temporal regulation of processes such as photosynthesis in Cyanothece 51142. This analysis is the first comprehensive report on global quantitative proteomics in a unicellular diazotrophic cyanobacterium and uncovers novel findings about diurnal rhythms

Prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability

Prostacyclin (PGI2) modulates platelet activation to regulate haemostasis. Evidence has emerged to suggest that thrombi are dynamic structures with distinct areas of differing platelet activation. It was hypothesised that PGI2 could reverse platelet spreading by actin cytoskeletal modulation, leading to reduced capability of platelet aggregates to withstand a high shear environment. Our data demonstrates that post-flow of PGI2 over activated and spread platelets on fibrinogen, identified a significant reduction in platelet surface area under high shear. Exploration of the molecular mechanisms underpinning this effect revealed that PGI2 reversed stress fibre formation in adherent platelets, reduced platelet spreading, whilst simultaneously promoting actin nodule formation. The effects of PGI2 on stress fibres were mimicked by the adenylyl cyclase activator forskolin and prevented by inhibitors of protein kinase A (PKA). Stress fibre formation is a RhoA dependent process and we found that treatment of adherent platelets with PGI2 caused inhibitory phosphorylation of RhoA, reduced RhoA GTP-loading and reversal of myosin light chain phosphorylation. Phospho-RhoA was localised in actin nodules with PKA type II and a number of other phosphorylated PKA substrates. This study demonstrates that PGI2 can reverse key platelet functions after their initial activation and identifies a novel mechanism for controlling thrombosis

Persistence of SARS-CoV-2 antibodies over 18 months following infection: UK Biobank COVID-19 Serology Study

Background Little is known about the persistence of antibodies after the first year following SARS-CoV-2 infection. We aimed to determine the proportion of individuals that maintain detectable levels of SARS-CoV-2 antibodies over an 18-month period following infection. Methods Population-based prospective study of 20 000 UK Biobank participants and their adult relatives recruited in May 2020. The proportion of SARS-CoV-2 cases testing positive for immunoglobulin G (IgG) antibodies against the spike protein (IgG-S), and the nucleocapsid protein (IgG-N), was calculated at varying intervals following infection. Results Overall, 20 195 participants were recruited. Their median age was 56 years (IQR 39–68), 56% were female and 88% were of white ethnicity. The proportion of SARS-CoV-2 cases with IgG-S antibodies following infection remained high (92%, 95% CI 90%–93%) at 6 months after infection. Levels of IgG-N antibodies following infection gradually decreased from 92% (95% CI 88%–95%) at 3 months to 72% (95% CI 70%–75%) at 18 months. There was no strong evidence of heterogeneity in antibody persistence by age, sex, ethnicity or socioeconomic deprivation. Conclusion This study adds to the limited evidence on the long-term persistence of antibodies following SARS-CoV-2 infection, with likely implications for waning immunity following infection and the use of IgG-N in population surveys

Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs

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The incredible years therapeutic dinosaur programme to build social and emotional competence in welsh primary schools: study protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>School interventions such as the Incredible Years <it>Classroom </it>Dinosaur Programme targets pupil behaviour across whole classrooms, yet for some children a more intense approach is needed. The Incredible Years <it>Therapeutic </it>Dinosaur Programme is effective for clinically referred children by enhancing social, problem-solving skills, and peer relationship-building skills when delivered in a clinical setting in small groups.</p> <p>The aim of this trial is to evaluate the effectiveness of the Therapeutic Programme, delivered with small groups of children at high-risk of developing conduct disorder, delivered in schools already implementing the Classroom Programme.</p> <p>Methods/Design</p> <p>This is a pragmatic, parallel, randomised controlled trial.</p> <p>Two hundred and forty children (aged 4-8 years) rated by their teacher as above the 'borderline cut-off' for concern on the Strengths and Difficulties Questionnaire, and their parents, will be recruited.</p> <p>Randomisation is by individual within blocks (schools); 1:1 ratio, intervention to waiting list control.</p> <p>Twenty schools will participate in two phases. Two teachers per school will deliver the programme to six intervention children for 2-hours/week for 18 weeks between baseline and first follow-up. The control children will receive the intervention after first follow up.</p> <p>Phase 1 comprises three data collection points - baseline and two follow-ups eight months apart. Phase 2 includes baseline and first follow-up.</p> <p>The Therapeutic Programme includes elements on; Learning school rules; understanding, identifying, and articulating feelings; problem solving; anger management; how to be friendly; how to do your best in school.</p> <p>Primary outcomes are; change in child social, emotional and behavioural difficulties. Secondary outcomes are; teacher and parent mental wellbeing, child academic attainment, child and teacher school attendance. Intervention delivery will be assessed for fidelity.</p> <p>Intention to treat analyses will be conducted. ANCOVA, effect sizes, mediator and moderator analyses will be applied to establish differences between conditions, and for whom the intervention works best for and why.</p> <p>Discussion</p> <p>This trial will provide information on the delivery and effectiveness of a child centred, school-based intervention delivered in small groups of children, at risk of developing more severe conduct problems. The effects on child behaviour in school and home environments, academic attainment, peer interactions, parent and teacher mental health will be assessed.</p> <p>Trial Registration</p> <p>UK Clinical Research Network UKCRNID8615</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN96803379">ISRCTN96803379</a></p

A polymorphism in the CTGF promoter region associated with systemic sclerosis

BackgroundSystemic sclerosis (scleroderma) is a life-threatening autoimmune disease that is characterized by the presence of specific autoantibodies and fibrosis of the skin and major internal organs.MethodsWe genotyped a polymorphism (G-945C) in the promoter of the connective-tissue growth factor (CTGF) gene in 1000 subjects in two groups: group 1, consisting of 200 patients with systemic sclerosis and 188 control subjects; and group 2, consisting of 300 patients with systemic sclerosis and 312 control subjects. The combined groups represented an estimated 10% of patients with systemic sclerosis in the United Kingdom. We tested the effect of the polymorphism on the transcription of CTGF.ResultsThe GG genotype was significantly more common in patients with systemic sclerosis than in control subjects in both groups, with an odds ratio for the combined group of 2.2 (95% confidence interval [CI], 1.5 to 3.2; P<0.001 for trend). Analysis of the combined group of patients with systemic sclerosis showed a significant association between homozygosity for the G allele and the presence of anti-topoisomerase I antibodies (odds ratio, 3.3; 95% CI, 2.0 to 5.6; P<0.001) and fibrosing alveolitis (odds ratio, 3.1; 95% CI, 1.9 to 5.0; P<0.001). We observed that the substitution of cytosine for guanine created a binding site of the transcriptional regulators Sp1 and Sp3. The C allele has high affinity for Sp3 and is associated with severely reduced transcriptional activity. A chromatin immunoprecipitation assay showed a marked shift in the ratio of Sp1 to Sp3 binding at this region, demonstrating functional relevance in vivo.ConclusionsThe G-945C substitution represses CTGF transcription, and the -945G allele is significantly associated with susceptibility to systemic sclerosis