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

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

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

Factors underlying age-related changes in discrete aiming

Age has a clear impact on one’s ability to make accurate goal-directed aiming movements. Older adults seem to plan slower and shorter-ranged initial pulses towards the target, and rely more on sensory feedback to ensure endpoint accuracy. Despite the fact that these age-related changes in manual aiming have been observed consistently, the underlying mechanism remains speculative. In an attempt to isolate four commonly suggested underlying factors, young and older adults were instructed to make discrete aiming movements under varying speed and accuracy constraints. Results showed that older adults were physically able to produce fast primary submovements and that they demonstrated similar movement-programming capacities as young adults. On the other hand, considerable evidence was found supporting a decreased visual feedback-processing efficiency and the implementation of a play-it-safe strategy in older age. In conclusion, a combination of the latter two factors seems to underlie the age-related changes in manual aiming behaviour

Visual attention and action: How cueing, direct mapping, and social interactions drive orienting

Despite considerable interest in both action perception and social attention over the last 2 decades, there has been surprisingly little investigation concerning how the manual actions of other humans orient visual attention. The present review draws together studies that have measured the orienting of attention, following observation of another’s goal-directed action. Our review proposes that, in line with the literature on eye gaze, action is a particularly strong orienting cue for the visual system. However, we additionally suggest that action may orient visual attention using mechanisms, which gaze direction does not (i.e., neural direct mapping and corepresentation). Finally, we review the implications of these gaze-independent mechanisms for the study of attention to action. We suggest that our understanding of attention to action may benefit from being studied in the context of joint action paradigms, where the role of higher level action goals and social factors can be investigated

Angiostatin generating capacity and anti-tumour effects of D-penicillamine and plasminogen activators

BACKGROUND: Upregulation of endogenous angiostatin levels may constitute a novel anti-angiogenic, and therefore anti-tumor therapy. In vitro, angiostatin generation is a two-step process, starting with the conversion of plasminogen to plasmin by plasminogen activators (PAs). Next, plasmin excises angiostatin from other plasmin molecules, a process requiring a donor of a free sulfhydryl group. In previous studies, it has been demonstrated that administration of PA in combination with the free sulfhydryl donor (FSD) agents captopril or N-acetyl cysteine, resulted in angiostatin generation, and anti-angiogenic and anti-tumour activity in murine models. METHODS: In this study we have investigated the angiostatin generating capacities of several FSDs. D-penicillamine proved to be most efficient in supporting the conversion of plasminogen to angiostatin in vitro. Next, from the optimal concentrations of tPA and D-penicillamine in vitro, equivalent dosages were administered to healthy Balb/c mice to explore upregulation of circulating angiostatin levels. Finally, anti-tumor effects of treatment with tPA and D-penicillamine were determined in a human melanoma xenograft model. RESULTS: Surprisingly, we found that despite the superior angiostatin generating capacity of D-penicillamine in vitro, both in vivo angiostatin generation and anti-tumour effects of tPA/D-penicillamine treatment were impaired compared to our previous studies with tPA and captopril. CONCLUSION: Our results indicate that selecting the most appropriate free sulfhydryl donor for anti-angiogenic therapy in a (pre)clinical setting should be performed by in vivo rather than by in vitro studies. We conclude that D-penicillamine is not suitable for this type of therapy

Levels and Determinants of Inflammatory Biomarkers in a Swiss Population-Based Sample (CoLaus Study)

OBJECTIVE: to assess the levels and determinants of interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α and C-reactive protein (CRP) in a healthy Caucasian population. METHODS: population sample of 2884 men and 3201 women aged 35 to 75. IL-1β, IL-6 and TNF-α were assessed by a multiplexed particle-based flow cytometric assay and CRP by an immunometric assay. RESULTS: Spearman rank correlations between duplicate cytokine measurements (N = 80) ranged between 0.89 and 0.96; intra-class correlation coefficients ranged between 0.94 and 0.97, indicating good reproducibility. Among the 6085 participants, 2289 (37.6%), 451 (7.4%) and 43 (0.7%) had IL-1β, IL-6 and TNF-α levels below detection limits, respectively. Median (interquartile range) for participants with detectable values were 1.17 (0.48-3.90) pg/ml for IL-1β; 1.47 (0.71-3.53) pg/ml for IL-6; 2.89 (1.82-4.53) pg/ml for TNF-α and 1.3 (0.6-2.7) ng/ml for CRP. On multivariate analysis, greater age was the only factor inversely associated with IL-1β levels. Male sex, increased BMI and smoking were associated with greater IL-6 levels, while no relationship was found for age and leisure-time PA. Male sex, greater age, increased BMI and current smoking were associated with greater TNF-α levels, while no relationship was found with leisure-time PA. CRP levels were positively related to age, BMI and smoking, and inversely to male sex and physical activity. CONCLUSION: Population-based levels of several cytokines were established. Increased age and BMI, and to a lesser degree sex and smoking, significantly and differentially impact cytokine levels, while leisure-time physical activity has little effect