Untangling the ATR-CHEK1 network for prognostication, prediction and therapeutic target validation in breast cancer

Background: ATR-Chk1 signalling network is critical for genomic stability. ATR-Chk1 may be deregulated in breast cancer and have prognostic, predictive and therapeutic significance. Patients and methods: We investigated ATR and phosphorylated CHK1Ser345 protein (pChk1) expression in 1712 breast cancers (Nottingham Tenovus series). ATR and Chk1 mRNA were evaluated in 1950 breast cancers (METABRIC cohort). Pre-clinically, biological consequences of ATR gene knockdown or ATR inhibition by small molecule inhibitor (VE-821) were investigated in MCF-7 and MDA-MB-231 breast cancer cell lines and in non-tumorigenic breast epithelial cells (MCF10A). Results: High ATR and high cytoplasmic pChk1 expression was significantly associated with higher tumour stage, higher mitotic index, pleomorphism and lymphovascular invasion. In univariate analysis, high ATR and high cytoplasmic pChk1 protein expression was associated with shorter breast cancer specific survival (BCSS). In multivariate analysis, high ATR remains an independent predictor of adverse outcome. At the mRNA level, high Chk1 remains associated with aggressive phenotypes including lymph node positivity, high grade, Her-2 overexpression, triple-negative phenotype and molecular classes associated with aggressive behaviour and shorter survival.. Pre-clinically, Chk1 phosphorylation at serine 345 following replication stress (induced by gemcitabine or hydroxyurea treatment) was impaired in ATR knockdown and in VE-821 treated breast cancer cells. Doxycycline inducible knockdown of ATR suppressed growth, which was restored when ATR was re-expressed. Similarly, VE-821 treatment resulted in a dose dependent suppression of cancer cell growth and survival (MCF7 and MDA-MB-231) but had no effect on non-tumorigenic breast epithelial cells (MCF10A). Conclusions: We provides evidence that ATR and Chk1 are promising biomarkers and rational drug target for personalized therapy in breast cancer

The effect of head-up tilt upon markers of heart rate variability in patients with atrial fibrillation

BACKGROUND: Heart rate variability (HRV) analysis is uncommonly undertaken in patients with atrial fibrillation (AF) due to an assumption that ventricular response is random. We sought to determine the effects of head-up tilt (HUT), a stimulus known to elicit an autonomic response, on HRV in patients with AF; we contrasted the findings with those of patients in sinus rhythm (SR). METHODS: Consecutive, clinically indicated tilt tests were examined for 207 patients: 176 in SR, 31 in AF. Patients in AF were compared to an age-matched SR cohort (n = 69). Five minute windows immediately before and after tilting were analyzed using time-domain, frequency-domain and nonlinear HRV parameters. Continuous, noninvasive assessment of blood pressure, heart rate and stroke volume were available in the majority of patients. RESULTS: There were significant differences at baseline in all HRV parameters between AF and age matched SR. HUT produced significant hemodynamic changes, regardless of cardiac rhythm. Coincident with these hemodynamic changes, patients in AF had a significant increase in median [quartile 1, 2] DFA-α2 (+0.14 [-0.03, 0.32], p < .005) and a decrease in sample entropy (-0.17 [-0.50, -0.01], p < .005). CONCLUSION: In the SR cohort, increasing age was associated with fewer HRV changes on tilting. Patients with AF had blunted HRV responses to tilting, mirroring those seen in an age matched SR group. It is feasible to measure HRV in patients with AF and the changes observed on HUT are comparable to those seen in patients in sinus rhythm

Wetlands In a Changing Climate: Science, Policy and Management

Part 1 of this review synthesizes recent research on status and climate vulnerability of freshwater and saltwater wetlands, and their contribution to addressing climate change (carbon cycle, adaptation, resilience). Peatlands and vegetated coastal wetlands are among the most carbon rich sinks on the planet sequestering approximately as much carbon as do global forest ecosystems. Estimates of the consequences of rising temperature on current wetland carbon storage and future carbon sequestration potential are summarized. We also demonstrate the need to prevent drying of wetlands and thawing of permafrost by disturbances and rising temperatures to protect wetland carbon stores and climate adaptation/resiliency ecosystem services. Preventing further wetland loss is found to be important in limiting future emissions to meet climate goals, but is seldom considered. In Part 2, the paper explores the policy and management realm from international to national, subnational and local levels to identify strategies and policies reflecting an integrated understanding of both wetland and climate change science. Specific recommendations are made to capture synergies between wetlands and carbon cycle management, adaptation and resiliency to further enable researchers, policy makers and practitioners to protect wetland carbon and climate adaptation/resiliency ecosystem services

Squirrelpox virus: assessing prevalence, transmission and environmental degradation

Red squirrels (Sciurus vulgaris) declined in Great Britain and Ireland during the last century, due to habitat loss and the introduction of grey squirrels (Sciurus carolinensis), which competitively exclude the red squirrel and act as a reservoir for squirrelpox virus (SQPV). The disease is generally fatal to red squirrels and their ecological replacement by grey squirrels is up to 25 times faster where the virus is present. We aimed to determine: (1) the seropositivity and prevalence of SQPV DNA in the invasive and native species at a regional scale; (2) possible SQPV transmission routes; and, (3) virus degradation rates under differing environmental conditions. Grey (n = 208) and red (n = 40) squirrel blood and tissues were sampled. Enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qPCR) techniques established seropositivity and viral DNA presence, respectively. Overall 8% of squirrels sampled (both species combined) had evidence of SQPV DNA in their tissues and 22% were in possession of antibodies. SQPV prevalence in sampled red squirrels was 2.5%. Viral loads were typically low in grey squirrels by comparison to red squirrels. There was a trend for a greater number of positive samples in spring and summer than in winter. Possible transmission routes were identified through the presence of viral DNA in faeces (red squirrels only), urine and ectoparasites (both species). Virus degradation analyses suggested that, after 30 days of exposure to six combinations of environments, there were more intact virus particles in scabs kept in warm (25°C) and dry conditions than in cooler (5 and 15°C) or wet conditions. We conclude that SQPV is present at low prevalence in invasive grey squirrel populations with a lower prevalence in native red squirrels. Virus transmission could occur through urine especially during warm dry summer conditions but, more notably, via ectoparasites, which are shared by both species

FORM: An Australian method for formulating and grading recommendations in evidence-based clinical guidelines

Extent: 8p.BACKGROUND: Clinical practice guidelines are an important element of evidence-based practice. Considering an often complicated body of evidence can be problematic for guideline developers, who in the past may have resorted to using levels of evidence of individual studies as a quasi-indicator for the strength of a recommendation. This paper reports on the production and trial of a methodology and associated processes to assist Australian guideline developers in considering a body of evidence and grading the resulting guideline recommendations. METHODS: In recognition of the complexities of clinical guidelines and the multiple factors that influence choice in health care, a working group of experienced guideline consultants was formed under the auspices of the Australian National Health and Medical Research Council (NHMRC) to produce and pilot a framework to formulate and grade guideline recommendations. Consultation with national and international experts and extensive piloting informed the process. RESULTS: The FORM framework consists of five components (evidence base, consistency, clinical impact, generalisability and applicability) which are used by guideline developers to structure their decisions on how to convey the strength of a recommendation through wording and grading via a considered judgement form. In parallel (but separate from the grading process) guideline developers are asked to consider implementation implications for each recommendation. CONCLUSIONS: The framework has now been widely adopted by Australian guideline developers who find it to be a logical and intuitive way to formulate and grade recommendations in clinical practice guidelines.Susan Hillier, Karen Grimmer-Somers, Tracy Merlin, Philippa Middleton, Janet Salisbury, Rebecca Tooher and Adele Westo

Diagnostic accuracy of ultrasonography compared to unenhanced CT for stone and obstruction in patients with renal failure

BACKGROUND: To determine accuracy of ultrasound (US) kidney, ureter and bladder (KUB) compared to un-enhanced helical CT (UHCT) in patients with renal failure in the diagnosis of stone and obstruction. METHODS: This is a case controlled study conducted in the period from June 2000 to July 2003 at a university hospital. All patients had both US and UHCT scan. Patients with serum creatinine ≥ 1.8 mg/dl were included in the study. Only direct visualization of stone was considered as confirmatory. In both the studies, UHCT and US, presence of stone and obstruction were noted. The relevant biochemicals, radiological and clinical records of all the patients were analyzed. Data was analyzed using commercially available software. RESULTS: During the period of study 864 patients had UHCT for evaluation of the urinary tract in patients presenting with flank pain. Out of these 34 patients had both UHCT and US done within a span of one day and had serum creatinine of ≥1.8 mg/dl. Mean age was 48 ±15.8 years and 59% of patients were males. UHCT identified renal stones in 21 (62%), whereas 17 of these were identified on US, with a sensitivity of 81%. Of the four patients with renal stones missed on US, three were identified on plain x-ray; the mean size of stones missed was 6.3 mm. Of the 22 (65%) patients with ureteric stone on UHCT, US could only identify 10; a further 7 were identified on x-ray KUB, giving a sensitivity of 45% (US alone) and 77% (US with x-ray KUB). CONCLUSIONS: US is sensitive and specific for renal stones, 81% and 100% and for hydronephrosis, 93% and 100%, respectively. Its sensitivity to pick ureteric stone (46%) and to identify hydroureter (50%) is low. Addition of x-ray KUB abdomen increases the sensitivity for ureteric stones to 77%

Monitoring Cognitive and Emotional Processes Through Pupil and Cardiac Response During Dynamic Versus Logical Task

The paper deals with the links between physiological measurements and cognitive and emotional functioning. As long as the operator is a key agent in charge of complex systems, the definition of metrics able to predict his performance is a great challenge. The measurement of the physiological state is a very promising way but a very acute comprehension is required; in particular few studies compare autonomous nervous system reactivity according to specific cognitive processes during task performance and task related psychological stress is often ignored. We compared physiological parameters recorded on 24 healthy subjects facing two neuropsychological tasks: a dynamic task that require problem solving in a world that continually evolves over time and a logical task representative of cognitive processes performed by operators facing everyday problem solving. Results showed that the mean pupil diameter change was higher during the dynamic task; conversely, the heart rate was more elevated during the logical task. Finally, the systolic blood pressure seemed to be strongly sensitive to psychological stress. A better taking into account of the precise influence of a given cognitive activity and both workload and related task-induced psychological stress during task performance is a promising way to better monitor operators in complex working situations to detect mental overload or pejorative stress factor of error

Recent advances on information transmission and storage assisted by noise

The interplay between nonlinear dynamic systems and noise has proved to be of great relevance in several application areas. In this presentation, we focus on the areas of information transmission and storage. We review some recent results on information transmission through nonlinear channels assisted by noise. We also present recent proposals of memory devices in which noise plays an essential role. Finally, we discuss new results on the influence of noise in memristors.Comment: To be published in "Theory and Applications of Nonlinear Dynamics: Model and Design of Complex Systems", Proceedings of ICAND 2012 (Springer, 2014

Popliteal block with transfibular approach in ankle arthrodesis: a case series

<p>Abstract</p> <p>Introduction</p> <p>Ankle arthrodesis is primarily undertaken to control severe pain in the ankle joint. Immediate postoperative pain is usually treated using oral analgesics, intravenous opiates and regional anaesthesia. The outcomes of ankle fusion, including patient satisfaction studies, are well documented in the literature. However, the advantage of popliteal block in the management of early postoperative pain after ankle fusion for osteoarthritis has not been widely reported. This study aims to determine the role of popliteal block using ankle fusion in the management of ankle osteoarthritis.</p> <p>Case presentation</p> <p>Ankle arthrodeses were performed in 27 patients over a five-year period. Eighteen patients were males (one had bilateral arthrodesis) and eight were females. Their mean age was 56 years and they were all Caucasians. The notes and radiographs of the patients were reviewed in retrospect for the duration of their hospital admission, time to union and complications.</p> <p>Conclusion</p> <p>Popliteal block is a safe and effective technique for postoperative analgesia in ankle arthrodesis. By using this technique, we achieved a significant reduction in the duration of hospital stay for our patients after ankle arthrodesis. The resultant cost saving was GBP717 for each patient.</p

HGF Mediates the Anti-inflammatory Effects of PRP on Injured Tendons

Platelet-rich plasma (PRP) containing hepatocyte growth factor (HGF) and other growth factors are widely used in orthopaedic/sports medicine to repair injured tendons. While PRP treatment is reported to decrease pain in patients with tendon injury, the mechanism of this effect is not clear. Tendon pain is often associated with tendon inflammation, and HGF is known to protect tissues from inflammatory damages. Therefore, we hypothesized that HGF in PRP causes the anti-inflammatory effects. To test this hypothesis, we performed in vitro experiments on rabbit tendon cells and in vivo experiments on a mouse Achilles tendon injury model. We found that addition of PRP or HGF decreased gene expression of COX-1, COX-2, and mPGES-1, induced by the treatment of tendon cells in vitro with IL-1β. Further, the treatment of tendon cell cultures with HGF antibodies reduced the suppressive effects of PRP or HGF on IL-1β-induced COX-1, COX-2, and mPGES-1 gene expressions. Treatment with PRP or HGF almost completely blocked the cellular production of PGE2 and the expression of COX proteins. Finally, injection of PRP or HGF into wounded mouse Achilles tendons in vivo decreased PGE2 production in the tendinous tissues. Injection of platelet-poor plasma (PPP) however, did not reduce PGE2 levels in the wounded tendons, but the injection of HGF antibody inhibited the effects of PRP and HGF. Further, injection of PRP or HGF also decreased COX-1 and COX-2 proteins. These results indicate that PRP exerts anti-inflammatory effects on injured tendons through HGF. This study provides basic scientific evidence to support the use of PRP to treat injured tendons because PRP can reduce inflammation and thereby reduce the associated pain caused by high levels of PGE2. © 2013 Zhang et al