Using the collaborative evidence based practice model : a systematic review and uptake of chlorhexidine-impregnated sponge dressings on central venous access devices in a tertiary cancer centre

Background: Greater research utilisation in cancer nursing practice is needed, in order to provide well-informed and effective nursing care to people affected by cancer. This paper aims to report on the implementation of evidence-based practice in a tertiary cancer centre. Methods: Using a case report design, this paper reports on the use of the Collaborative Model for Evidence Based Practice (CMEBP) in an Australian tertiary cancer centre. The clinical case is the uptake of routine application of chlorhexidine-impregnated sponge dressings for preventing centrally inserted catheter-related bloodstream infections. In this case report, a number of processes that resulted in a service-wide practice change are described. Results: This model was considered a feasible method for successful research utilisation. In this case report, chlorhexidine-impregnated sponge dressings were proposed and implemented in the tertiary cancer centre with an aim of reducing the incidence of centrally inserted catheter-related bloodstream infections and potentially improving patient health outcomes. Conclusion: The CMEBP is feasible and effective for implementing clinical evidence into cancer nursing practice. Cancer nurses and health administrators need to ensure a supportive infrastructure and environment for clinical inquiry and research utilisation exists, in order to enable successful implementation of evidence-based practice in their cancer centres.

Drugs and the respiratory system

17.1 Drugs for bronchial asthma and Chronic Obstructive Pulmonary Disease (COPD) 17.1.1 Introduction to asthma 17.1.2 Introduction to COPD 17.1.3 Drug delivery by inhalation 17.1.4 Drugs to treat 17.1.4.1 β2-adrenoceptor agonists 17.1.4.2 Muscarinic receptor antagonists 17.1.4.3 Leukotriene receptor antagonists 17.1.4.4 Theophylline 17.1.4.5 Oxygen for COPD 17.1.5 Drugs to prevent asthma 31.5.1 Glucocorticoids 31.5.2 Cromolyn sodium 17.1.6 Combination to treat and prevent asthma 17.1.7 Drug for allergic asthma – omalizumab 17.1.8 Emergency treatment of asthma 17.2. Expectorants, mucolytics, cough and oxygen 17.2.1 Introduction to expectorants and mucolytics 17.2.2 Expectorants 17.2.3 Mucolytics 17.2.4 Cough 17.2.5 Oxygen 17.3. Drugs for rhinitis and rhinorrea 17.3.1 Introduction 17.3.2 Histamine and H1-receptor antagonists 17.3.3 Sympathomimetic 17.3.4 Muscarinic receptor antagonists 17.3.4 Cromolyn sodium 17.3.5 Glucocorticoids

XIAP downregulation accompanies mebendazole growth inhibition in melanoma xenografts

Mebendazole (MBZ) was identified as a promising therapeutic on the basis of its ability to induce apoptosis in melanoma cell lines through a B-cell lymphoma 2 (BCL2)-dependent mechanism. We now show that in a human xenograft melanoma model, oral MBZ is as effective as the current standard of care temozolomide in reducing tumor growth. Inhibition of melanoma growth in vivo is accompanied by phosphorylation of BCL2 and decreased levels of X-linked inhibitor of apoptosis (XIAP). Reduced expression of XIAP on treatment with MBZ is partially mediated by its proteasomal degradation. Furthermore, exposure of melanoma cells to MBZ promotes the interaction of SMAC/DIABLO with XIAP, thereby alleviating XIAP's inhibition on apoptosis. XIAP expression on exposure to MBZ is indicative of sensitivity to MBZ as MBZ-resistant cells do not show reduced levels of XIAP after treatment. Resistance to MBZ can be reversed partially by siRNA knockdown of cellular levels of XIAP. Our data indicate that MBZ is a promising antimelanoma agent on the basis of its effects on key antiapoptotic proteins.

Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status

BACKGROUND: Melanoma is the most lethal form of skin cancer, but recent advances in molecularly targeted agents against the Ras/Raf/MAPK pathway demonstrate promise as effective therapies. Despite these advances, resistance remains an issue, as illustrated recently by the clinical experience with vemurafenib. Such acquired resistance appears to be the result of parallel pathway activation, such as PI3K, to overcome single-agent inhibition. In this report, we describe the cytotoxicity and anti-tumour activity of the novel MEK inhibitor, E6201, in a broad panel of melanoma cell lines (n = 31) of known mutational profile in vitro and in vivo. We further test the effectiveness of combining E6201 with an inhibitor of PI3K (LY294002) in overcoming resistance in these cell lines. RESULTS: The majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201. This sensitivity correlated with wildtype PTEN and mutant BRAF status, whereas mutant RAS and PI3K pathway activation were associated with resistance. Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA. Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested. E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro. In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1. CONCLUSIONS: Our data demonstrate that E6201 elicits a predominantly cytocidal effect in vitro and in vivo in melanoma cells of diverse mutational background. Resistance to E6201 was associated with disruption of PTEN and activation of downstream PI3K signalling. In keeping with these data we demonstrate that co-inhibition of MAPK and PI3K is effective in overcoming resistance inherent in melanoma.

Setting up a platform for plant-based influenza virus vaccine production in South Africa

Background During a global influenza pandemic, the vaccine requirements of developing countries can surpass their supply capabilities, if these exist at all, compelling them to rely on developed countries for stocks that may not be available in time. There is thus a need for developing countries in general to produce their own pandemic and possibly seasonal influenza vaccines. Here we describe the development of a plant-based platform for producing influenza vaccines locally, in South Africa. Plant-produced influenza vaccine candidates are quicker to develop and potentially cheaper than egg-produced influenza vaccines, and their production can be rapidly upscaled. In this study, we investigated the feasibility of producing a vaccine to the highly pathogenic avian influenza A subtype H5N1 virus, the most generally virulent influenza virus identified to date. Two variants of the haemagglutinin (HA) surface glycoprotein gene were synthesised for optimum expression in plants: these were the full-length HA gene (H5) and a truncated form lacking the transmembrane domain (H5tr). The genes were cloned into a panel of Agrobacterium tumefaciens binary plant expression vectors in order to test HA accumulation in different cell compartments. The constructs were transiently expressed in tobacco by means of agroinfiltration. Stable transgenic tobacco plants were also generated to provide seed for stable storage of the material as a pre-pandemic strategy. Results For both transient and transgenic expression systems the highest accumulation of full-length H5 protein occurred in the apoplastic spaces, while the highest accumulation of H5tr was in the endoplasmic reticulum. The H5 proteins were produced at relatively high concentrations in both systems. Following partial purification, haemagglutination and haemagglutination inhibition tests indicated that the conformation of the plant-produced HA variants was correct and the proteins were functional. The immunisation of chickens and mice with the candidate vaccines elicited HA-specific antibody responses. Conclusions We managed, after synthesis of two versions of a single gene, to produce by transient and transgenic expression in plants, two variants of a highly pathogenic avian influenza virus HA protein which could have vaccine potential. This is a proof of principle of the potential of plant-produced influenza vaccines as a feasible pandemic response strategy for South Africa and other developing countries.

Inhibition of maize streak virus (MSV) replication by transient and transgenic expression of MSV replication-associated protein mutants

Maize streak disease is a severe agricultural problem in Africa and the development of maize genotypes resistant to the causal agent, Maize streak virus (MSV), is a priority. A transgenic approach to engineering MSV-resistant maize was developed and tested in this study. A pathogen-derived resistance strategy was adopted by using targeted deletions and nucleotide-substitution mutants of the multifunctional MSV replication-associated protein gene (rep). Various rep gene constructs were tested for their efficacy in limiting replication of wild-type MSV by co-bombardment of maize suspension cells together with an infectious genomic clone of MSV and assaying replicative forms of DNA by quantitative PCR. Digitaria sanguinalis, an MSV-sensitive grass species used as a model monocot, was then transformed with constructs that had inhibited virus replication in the transient-expression system. Challenge experiments using leafhopper-transmitted MSV indicated significant MSV resistance - from highly resistant to immune - in regenerated transgenic D. sanguinalis lines. Whereas regenerated lines containing a mutated full-length rep gene displayed developmental and growth defects, those containing a truncated rep gene both were fertile and displayed no growth defects, making the truncated gene a suitable candidate for the development of transgenic MSV-resistant maize. © 2007 SGM.

The causes of sinuous crustal-scale deformation patterns in hot orogens: Evidence from scaled analogue experiments and the southern Central Andes

The cause of upper-crustal segmentation into rhomb-shaped, shear zone-bound domains associated with contractional sedimentary basins in hot, wide orogens is not well understood. Here we use scaled multilayered analogue experiments to investigate the role of an orogen-parallel crustal-strength gradient on the formation of such structures. We show that the aspect ratio and size of domains, the sinuous character and abundance of transpressional shear zones vary with the integrated mechanical strength of crust. Upper-crustal deformation patterns and the degree of strain localization in the experiments are controlled by the ratio between the brittle and ductile strength in the model crust as well as gradients in tectonic and buoyancy forces. The experimental results match the first-order kinematic and structural characteristics of the southern Central Andes and provide insight on the dynamics of underlying deformation patterns in hot, wide orogens.

NOS1AP is associated with increased severity of PTSD and depression in untreated combat veterans

Background Post traumatic stress disorder (PTSD) and depressive disorder are over represented in combat veterans. Veterans with both disorders have an increased risk of suicide. The nitric oxide synthase 1 adaptor protein (NOS1AP) gene, which modulates stress-evoked N-methyl-D-aspartate (NMDA) activity, was investigated in combat veterans. Methods A comprehensive genetic analysis of NOS1AP and its association with PTSD was investigated in Vietnam combat veterans with PTSD (n=121) and a group of healthy control individuals (n=237). PTSD patients were assessed for symptom severity and level of depression using the Mississippi Scale for Combat-Related PTSD and the Beck Depression Inventory-II (BDI). Results The G allele of NOS1AP SNP rs386231 was significantly associated with PTSD (p = 0.002). Analysis of variance revealed significant differences in BDI-II and Mississippi scores between genotypes for rs386231 with the GG genotype associated with increased severity of depression (p = 0.002 F = 6.839) and higher Mississippi Scale for Combat-Related PTSD scores (p = 0.033). Haplotype analysis revealed that the C/G haplotype (rs451275/rs386231) was significantly associated with PTSD (p = 0.001). Limitations The sample sizes in our study were not sufficient to detect SNP associations with very small effects. In addition the study was limited by its cross sectional design. Conclusions This is the first study reporting that a variant of the NOS1AP gene is associated with PTSD. Our data also suggest that a genetic variant in NOS1AP may increase the susceptibility to severe depression in patients with PTSD and increased risk for suicide.

KPNA3 variation is associated with schizophrenia, major depression, opiate dependence and alcohol dependence

KPNA3 is a gene that has been linked to schizophrenia susceptibility. In this study we investigated the possible association between KPNA3 variation and schizophrenia. To investigate a wider role of KPNA3 across psychiatric disorders we also analysed major depression, PTSD, nicotine dependent, alcohol dependent and opiate dependent cohorts. Using a haplotype block-based gene-tagging approach we genotyped six KPNA3 single nucleotide polymorphisms (SNPs) in 157 schizophrenia patients, 121 post-traumatic stress disorder patients, 120 opiate dependent patients, 231 alcohol dependent patients, 147 nicotine dependent patients and 266 major depression patients. One SNP rs2273816 was found to be significantly associated with schizophrenia, opiate dependence and alcohol dependence at the genotype and allele level. Major depression was also associated with rs2273816 but only at the allele level. Our study suggests that KPNA3 may contribute to the genetic susceptibility to schizophrenia as well as other psychiatric disorders.

Serine protease inhibition and mitochondrial dysfunction associated with cisplatin resistance in human tumor cell lines : targets for therapy

Indicators of mitochondrial function were studied in two different cell culture models of cis-diamminedichloroplatinum-II (CDDP) resistance: the intrinsically resistant human ovarian cancer cell line CI-80-13S, and resistant clones (HeLa-S1a and HeLa-S1b) generated by stable expression of the serine protease inhibitor—plasminogen activator inhibitor type-2 (PAI-2), in the human cervical cancer cell line HeLa. In both models, CDDP resistance was associated with sensitivity to killing by adriamycin, etoposide, auranofin, bis[1,2-bis(diphenylphosphino)ethane]gold(I) chloride {[Au(DPPE)2]Cl}, CdCl2 and the mitochondrial inhibitors rhodamine-123 (Rhl23), dequalinium chloride (DeCH), tetraphenylphosphonium (TPP), and ethidium bromide (EtBr) and with lower constitutive levels of ATP. Unlike the HeLa clones, CI-80-13S cells were additionally sensitive to chloramphenicol, 1-methyl-4-phenylpyridinium ion (MPP+), rotenone, thenoyltrifluoroacetone (TTFA), and antimycin A, and showed poor reduction of 1-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), suggesting a deficiency in NADH dehydrogenase and/or succinate dehydrogenase activities. Total platinum uptake and DNA-bound platinum were slightly lower in CI-80-13S than in sensitive cells. The HeLa-S1a and HeLa-S1b clones, on the other hand, showed poor reduction of triphenyltetrazolium chloride (TTC), indicative of low cytochrome c oxidase activity. Total platinum uptake by HeLa-S1a was similar to HeLa, but DNA-bound platinum was much lower than for the parent cell line. The mitochondria of CI-80-13S and HeLa-S1a showed altered morphology and were fewer in number than those of JAM and HeLa. In both models, CDDP resistance was associated with less platinum accumulation and with mitochondrial and membrane defects, brought about one case with expression of a protease inhibitor which is implicated in tumor progression. Such markers may identify tumors suitable for treatment with gold phosphine complexes or other mitochondrial inhibitors.

Dietetic confidence working with clients with depression/anxiety is associated with client-focused practic and advocacy skills

Confidence in a professional role is a key element in the successful transition to competent practice. New graduate dietitians report that whilst they are confident about their general dietetic ability, they are not as confident when working with clients experiencing depression and anxiety. This study aimed to develop and validate a scale which measured confidence about working with clients with depression/anxiety. The 21-item Dietetics Collaborative Practice Scale was developed using research about dietetic practice in mental health, coping self-efficacy literature and collaboration with industry experts. A convenience sample of 189 Australian dietitians completed the questionnaire. Exploratory factor analysis suggests that dietetic confidence is best represented by a two dimensional solution consisting of (a) Client –focused practice (CFP, 50.8% variance) and (b) Advocacy for self and client care (ASC, 9.7% variance). The alpha coefficient of both dimensions (CFP ɑ=0.95, ASC ɑ=0.84) demonstrated the internal consistency of components. Combined, these two components account for 60.5% of variance. The scale components were not related to years of practice or working with mental health clients but were significantly related to overall dietetic confidence (ODC). Correlation coefficients between ODC and CFP were 0.501 (p<0.01), ODC and ASC were correlated at 0.465 (p<0.01) and CFP and number of years as a dietitian were weakly correlated at 0.24 (p<0.05). Results have implications for dietetic training and professional development. Client focus and advocacy for self and client appear to be important factors in overall confidence as a dietitian.

Lineage-specific biomarkers predict response to FGFR inhibition

In this issue of Cancer Discovery, Guagnano and colleagues use a large and diverse annotated collection of cancer cell lines, the Cancer Cell Line Encyclopedia, to correlate whole-genome expression and genomic alteration datasets with cell line sensitivity data to the novel pan-fibroblast growth factor receptor (FGFR) inhibitor NVP-BGJ398. Their findings underscore not only the preclinical use of such cell line panels in identifying predictive biomarkers, but also the emergence of the FGFRs as valid therapeutic targets, across an increasingly broad range of malignancies.

The impact of anxiety on processing efficiency : implications for the attentional control theory

The Attentional Control Theory (ACT) proposes that high-anxious individuals maintain performance effectiveness (accuracy) at the expense of processing efficiency (response time), in particular, the two central executive functions of inhibition and shifting. In contrast, research has generally failed to consider the third executive function which relates to the function of updating. In the current study, seventy-five participants completed the Parametric Go/No-Go and n-back tasks, as well as the State-Trait Anxiety Inventory in order to explore the effects of anxiety on attention. Results indicated that anxiety lead to decay in processing efficiency, but not in performance effectiveness, across all three Central Executive functions (inhibition, set-shifting and updating). Interestingly, participants with high levels of trait anxiety also exhibited impaired performance effectiveness on the n-back task designed to measure the updating function. Findings are discussed in relation to developing a new model of ACT that also includes the role of preattentive processes and dual-task coordination when exploring the effects of anxiety on task performance.

Increased sedation requirements in patients receiving extracorporeal membrane oxygenation for respiratory and cardiorespiratory failure

Critically ill patients receiving extracorporeal membrane oxygenation (ECMO) are often noted to have increased sedation requirements. However, data related to sedation in this complex group of patients is limited. The aim of our study was to characterise the sedation requirements in adult patients receiving ECMO for cardiorespiratory failure. A retrospective chart review was performed to collect sedation data for 30 consecutive patients who received venovenous or venoarterial ECMO between April 2009 and March 2011. To test for a difference in doses over time we used a regression model. The dose of midazolam received on ECMO support increased by an average of 18 mg per day (95% confidence interval 8, 29 mg, P=0.001), while the dose of morphine increased by 29 mg per day (95% confidence interval 4, 53 mg, P=0.021) The venovenous group received a daily midazolam dose that was 157 mg higher than the venoarterial group (95% confidence interval 53, 261 mg, P=0.005). We did not observe any significant increase in fentanyl doses over time (95% confidence interval 1269, 4337 µg, P=0.94). There is a significant increase in dose requirement for morphine and midazolam during ECMO. Patients on venovenous ECMO received higher sedative doses as compared to patients on venoarterial ECMO. Future research should focus on mechanisms behind these changes and also identify drugs that are most suitable for sedation during ECMO.