R2P from Below: Does the British Public View Humanitarian Interventions as Ethical and Effective?

One of the major barriers to the implementation of the Responsibility to Protect principle is the lack of a political will. Public attitudes towards intervention will have a crucial impact on elite willingness to prevent mass atrocities, yet we have little understanding of the factors that influence those attitudes. This article provides the first examination of UK public perceptions about the moral justifiability and effectiveness of humanitarian interventions. The article shows that decisions about justifiability and effectiveness are very different. Attitudes towards justification were more easily explained suggesting that judgements about effectiveness are more contextual and less easily accounted for by individuals’ background characteristics and attitudes. Experiences with both Iraq and Afghanistan have contaminated public perceptions of both the ethics and effectiveness of humanitarian interventions. Although the public is broadly supportive about the justifiability of humanitarian interventions they are extremely sceptical about the likelihood that those interventions will be successful

Post-depositional fracturing and subsidence of pumice flow deposits: Lascar Volcano, Chile

Unconsolidated pyroclastic flow deposits of the 1993 eruption of Lascar Volcano, Chile, have, with time, become increasingly dissected by a network of deeply penetrating fractures. The fracture network comprises orthogonal sets of decimeter-wide linear voids that form a pseudo-polygonal grid visible on the deposit surface. In this work, we combine shallow surface geophysical imaging tools with remote sensing observations and direct field measurements of the deposit to investigate these fractures and their underlying causal mechanisms. Based on ground penetrating radar images, the fractures are observed to have propagated to depths of up to 10 m. In addition, orbiting radar interferometry shows that deposit subsidence of up to 1 cm/year occurred between 1993 and 1996 with continued subsidence occurring at a slower rate thereafter. In situ measurements show that 1 m below the surface, the 1993 deposits remain 5°C to 15°C hotter, 18 years after emplacement, than adjacent deposits. Based on the observed subsidence as well as estimated cooling rates, the fractures are inferred to be the combined result of deaeration, thermal contraction, and sedimentary compaction in the months to years following deposition. Significant environmental factors, including regional earthquakes in 1995 and 2007, accelerated settling at punctuated moments in time. The spatially variable fracture pattern relates to surface slope and lithofacies variations as well as substrate lithology. Similar fractures have been reported in other ignimbrites but are generally exposed only in cross section and are often attributed to formation by external forces. Here we suggest that such interpretations should be invoked with caution, and deformation including post-emplacement subsidence and fracturing of loosely packed ash-rich deposits in the months to years postemplacement is a process inherent in the settling of pyroclastic material

Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines

Introduction: Overexpression of the receptor tyrosine kinase HER2 has been reported in around 25% of human breast cancers, usually indicating a poor prognosis. As a result, HER2 has become a popular target for therapy. However, despite recent advances in HER2 targeted therapy, many patients still experience primary and secondary resistance to such treatments. It is therefore important to understand the underlying mechanism of resistance and to develop more effective therapeutic interventions for breast cancer. Methods: The sensitivity of a panel of seven breast cancer cell lines to treatment with various types HER-family inhibitors alone, or in combination with a selection of other tyrosine kinase inhibitors (TKIs) or chemotherapeutic agents was determined using the Sulforhodamine B colorimetric assay. Receptor expression, cell-cycle distribution, cell signalling and cell migration were determined using flow cytometry, Western blot and Incucyte Zoom Live-Cell Analysis System respectively. Results: Overall, breast cancer cells were more sensitive to treatment with the irreversible pan-HER family inhibitors, particularly afatinib and neratinib, than treatment with the first-generation reversible inhibitors. Of three HER-2 overexpressing cell lines in this panel, SKBr3 and BT474 were highly sensitive to treatment with HER-family inhibitors (IC50s as low as 3 nM), while MDA-MB-453 was relatively resistant (lowest IC50 = 0.11 μM). When the HER-family inhibitors were combined with other agents such as NVP-AEW541 (an IGF-1R inhibitor), dasatinib (a Src inhibitor) or crizotinib (a c-Met/ALK inhibitor), such combination produced synergistic effects in some of the cell lines examined. Interestingly, co-targeting of Src and HER-family members in MDA-MB-453 cells led to synergistic growth inhibition, suggesting the importance of Src in mediating resistance to HER2-targeting agents. Finally, treatment with the irreversible HER family blockers and dasatinib were also most effective at inhibiting the migration of breast cancer cells. Conclusion: We concluded that the irreversible inhibitors of HER-family members are generally more effective at inhibiting growth, downstream signalling and migration compared with reversible inhibitors, and that combining HER-family inhibitors with other TKIs such as dasatinib may have therapeutic advantages in certain breast cancer subtypes and warrants further investigation

New Pharmacological Agents to Aid Smoking Cessation and Tobacco Harm Reduction: What has been Investigated and What is in the Pipeline?

A wide range of support is available to help smokers to quit and aid attempts at harm reduction, including three first-line smoking cessation medications: nicotine replacement therapy, varenicline and bupropion. Despite the efficacy of these, there is a continual need to diversify the range of medications so that the needs of tobacco users are met. This paper compares the first-line smoking cessation medications to: 1) two variants of these existing products: new galenic formulations of varenicline and novel nicotine delivery devices; and 2) twenty-four alternative products: cytisine (novel outside of central and eastern Europe), nortriptyline, other tricyclic antidepressants, electronic cigarettes, clonidine (an anxiolytic), other anxiolytics (e.g. buspirone), selective 5-hydroxytryptamine (5-HT) reuptake inhibitors, supplements (e.g. St John’s wort), silver acetate, nicobrevin, modafinil, venlafaxine, monoamine oxidase inhibitors (MAOI), opioid antagonist, nicotinic acetylcholine receptors (nAChR) antagonists, glucose tablets, selective cannabinoid type 1 receptor antagonists, nicotine vaccines, drugs that affect gamma-aminobutyric acid (GABA) transmission, drugs that affect N-methyl-D-aspartate receptors (NMDA), dopamine agonists (e.g. levodopa), pioglitazone (Actos; OMS405), noradrenaline reuptake inhibitors, and the weight management drug lorcaserin. Six criteria are used: relative efficacy, relative safety, relative cost, relative use (overall impact of effective medication use), relative scope (ability to serve new groups of patients), and relative ease of use (ESCUSE). Many of these products are in the early stages of clinical trials, however, cytisine looks most promising in having established efficacy and safety and being of low cost. Electronic cigarettes have become very popular, appear to be efficacious and are safer than smoking, but issues of continued dependence and possible harms need to be considered

CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammation.

BACKGROUND: Defining the presence of acute and chronic brain inflammation remains a challenge to clinicians due to the heterogeneity of clinical presentations and aetiologies. However, defining the presence of neuroinflammation, and monitoring the effects of therapy is important given its reversible and potentially damaging nature. We investigated the utility of CSF metabolites in the diagnosis of primary neuroinflammatory disorders such as encephalitis and explored the potential pathogenic role of inflammation in epilepsy. METHODS: Cerebrospinal fluid (CSF) collected from 341 paediatric patients (169 males, median age 5.8 years, range 0.1-17.1) were examined. The patients were separated into a primary inflammatory disorder group (n = 90) and epilepsy group (n = 80), who were compared with three control groups including neurogenetic and structural (n = 76), neurodevelopmental disorders, psychiatric and functional neurological disorders (n = 63), and headache (n = 32). FINDINGS: There were statistically significant increases of CSF neopterin, kynurenine, quinolinic acid and kynurenine/tryptophan ratio (KYN/TRP) in the inflammation group compared to all control groups (all p < 0.0003). As biomarkers, at thresholds with 95% specificity, CSF neopterin had the best sensitivity for defining neuroinflammation (82%, CI 73-89), then quinolinic acid (57%, CI 47-67), KYN/TRP ratio (47%, CI 36-56) and kynurenine (37%, CI 28-48). CSF pleocytosis had sensitivity of 53%, CI 42-64). The area under the receiver operating characteristic curve (ROC AUC) of CSF neopterin (94.4% CI 91.0-97.7%) was superior to that of CSF pleocytosis (84.9% CI 79.5-90.4%) (p = 0.005). CSF kynurenic acid/kynurenine ratio (KYNA/KYN) was statistically decreased in the epilepsy group compared to all control groups (all p ≤ 0.0003), which was evident in most epilepsy subgroups. INTERPRETATION: Here we show that CSF neopterin, kynurenine, quinolinic acid and KYN/TRP are useful diagnostic and monitoring biomarkers of neuroinflammation. These findings provide biological insights into the role of inflammatory metabolism in neurological disorders and provide diagnostic and therapeutic opportunities for improved management of neurological diseases. FUNDING: Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, University of Sydney, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP 1176660 and Macquarie University

Cyclin D1, cyclin E, and p21 have no apparent prognostic value in anal carcinomas treated by radiotherapy with or without chemotherapy

The purpose of this study was to assess the potential prognostic and/or predictive value of the expression of cyclin D1, cyclin E, and p21 protein in a series of 98 anal carcinomas (T1-4, N0-3) treated by radiotherapy with (51) or without (47) chemotherapy in one institution. Correlation with Mib1 index and p53 expression was also investigated. Median follow-up for surviving patients was 124 months (range: 30-266). Immunohistochemical staining was performed on pretreatment biopsies, applying a standard ABC technique for cyclin D1 (clone DSC6, DAKO, 1 : 300), cyclin E (clone 13A3, Novocastra, 1 : 100), p21(WAF/CIP1) (clone SX118, DAKO, 1 : 50), p53 (clone DO7, DAKO, 1 : 200), and Mib1 (Ki-67, Dianova, 1 : 20). Tumours were classified into low- or high-expression groups according to the expression level of the protein considered. High expression was found in 51% of tumours for cyclin E, in 33.7% for cyclin D1, and in 65% for p21. None of those factors were significantly associated with clinical variables such as advanced T or N categories. In a monovariate analysis, advanced T and N categories and longer overall treatment time were the only variables that correlated significantly with low rate of local control (LC) and disease-free survival. However, in a subgroup analysis, high p21 expression correlated with a trend for significantly higher 5-year LC (87 vs 68%, P=0.07) in the N0 patients. The results of this study suggest that the cell-cycle proteins investigated are unlikely to be clinically useful in predicting treatment response or prognosis in patients with anal carcinomas

Can teaching agenda-setting skills to physicians improve clinical interaction quality? A controlled intervention

<p>Abstract</p> <p>Background</p> <p>Physicians and medical educators have repeatedly acknowledged the inadequacy of communication skills training in the medical school curriculum and opportunities to improve these skills in practice. This study of a controlled intervention evaluates the effect of teaching practicing physicians the skill of "agenda-setting" on patients' experiences with care. The agenda-setting intervention aimed to engage clinicians in the practice of initiating patient encounters by eliciting the full set of concerns from the patient's perspective and using that information to prioritize and negotiate which clinical issues should most appropriately be dealt with and which (if any) should be deferred to a subsequent visit.</p> <p>Methods</p> <p>Ten physicians from a large physician organization in California with baseline patient survey scores below the statewide 25th percentile participated in the agenda-setting intervention. Eleven physicians matched on baseline scores, geography, specialty, and practice size were selected as controls. Changes in survey summary scores from pre- and post-intervention surveys were compared between the two groups. Multilevel regression models that accounted for the clustering of patients within physicians and controlled for respondent characteristics were used to examine the effect of the intervention on survey scale scores.</p> <p>Results</p> <p>There was statistically significant improvement in intervention physicians' ability to "explain things in a way that was easy to understand" (p = 0.02) and marginally significant improvement in the overall quality of physician-patient interactions (p = 0.08) compared to control group physicians. Changes in patients' experiences with organizational access, care coordination, and office staff interactions did not differ by experimental group.</p> <p>Conclusion</p> <p>A simple and modest behavioral training for practicing physicians has potential to positively affect physician-patient relationship interaction quality. It will be important to evaluate the effect of more extensive trainings, including those that work with physicians on a broader set of communication techniques.</p

Stress corrosion cracking: Characteristics, Mechanisms and Experimental study

Stress corrosion cracking (SCC) is a phenomenon in which the cracking of a metal alloy usually results from the combined action of a corrodent and tensile stress. Stresses that cause cracking can be residual or may be applied during service. A degree of mechanistic understanding of SCC will enable most metallic engineering materials to operate safely though stress corrosion cracking failures still continue to occur unexpectedly in industry. In this paper, the characteristics, mechanisms and methods of SCC prevention are reviewed. The results of experimental studies on alpha brass are also reported of which the failure mode conformed with the film-rupture and anodic dissolution mechanism

Discovery and functional characterisation of a luqin-type neuropeptide signalling system in a deuterostome

The results presented in this paper have not been published previously in whole or in part. The work reported in this paper was supported by grants from the BBSRC awarded to M.R.E (BB/M001644/1) and J.H.S. (BB/M001032/1). L.A.Y.G is supported by a PhD studentship awarded by the Mexican Council of Science and Technology (CONACyT studentship no. 418612) and Queen Mary University of London. We are grateful to Philipp Bauknecht and Gáspár Jékely (Max Planck Institute for Developmental Biology, Tübingen, Germany) for providing the Gα16 plasmid and the CHO-G5A cells, which were originally generated by Baubet et al. (Proc Natl Acad Sci USA 97:7260–7265). We are also grateful to Phil Edwards for his help with collecting starfish, Paul Fletcher for maintaining our seawater aquarium and Maria Eugenia Guerra for creating the silhouettes of animals used in Figure 7