Laparoscopic versus open colectomy for colon cancer in an older population: a cohort study

<p>Abstract</p> <p>Background</p> <p>Laparoscopic colectomy for colon cancer has been compared with open colectomy in randomized controlled trials, but these studies may not be generalizable because of strict enrollment and exclusion criteria which may explicitly or inadvertently exclude older individuals due to associated comorbidities. Previous studies of older patients undergoing laparoscopic colectomy have generally focused on short-term outcomes. The goals of this cohort study were to identify predictors of laparoscopic colectomy in an older population in the United States and to compare short-term and long-term outcomes.</p> <p>Methods</p> <p>Patients aged 65 years or older with incident colorectal cancer diagnosed 1996-2002 who underwent colectomy within 6 months of cancer diagnosis were identified from the linked Surveillance, Epidemiology, and End Results-Medicare database. Laparoscopic and open colectomy patients were compared with respect to length of stay, blood transfusion requirements, intensive care unit monitoring, complications, 30-day mortality, and long-term survival. We adjusted for potential selection bias in surgical approach with propensity score matching.</p> <p>Results</p> <p>Laparoscopic colectomy cases were associated with left-sided tumors; areas with higher population density, income, and education level; areas in the western United States; and National Cancer Institute-designated cancer centers. Laparoscopic colectomy cases had shorter length of stay and less intensive care unit monitoring. Although laparoscopic colectomy patients (n = 424) had fewer complications (21.5% versus 26.3%), lower 30-day mortality (3.3% versus 5.8%), and longer median survival (6.6 versus 4.8 years) compared with open colectomy patients (n = 27,012), after propensity score matching these differences disappeared.</p> <p>Conclusions</p> <p>In this older population, laparoscopic colectomy practice patterns were associated with factors which likely correlate with tertiary referral centers. Although short-term and long-term survival are comparable, laparoscopic colectomy offers shorter hospitalizations and less intensive care.</p

Metabolic manipulation in chronic heart failure: study protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Heart failure is a major cause of morbidity and mortality in society. Current medical therapy centres on neurohormonal modulation with angiotensin converting enzyme inhibitors and β-blockers. There is growing evidence for the use of metabolic manipulating agents as adjunctive therapy in patients with heart failure. We aim to determine the effect of perhexiline on cardiac energetics and alterations in substrate utilisation in patients with non-ischaemic dilated cardiomyopathy.</p> <p>Methods</p> <p>A multi-centre, prospective, randomised double-blind, placebo-controlled trial of 50 subjects with non-ischaemic dilated cardiomyopathy recruited from University Hospital Birmingham NHS Foundation Trust and Cardiff and Vale NHS Trust. Baseline investigations include magnetic resonance spectroscopy to assess cardiac energetic status, echocardiography to assess left ventricular function and assessment of symptomatic status. Subjects are then randomised to receive 200 mg perhexiline maleate or placebo daily for 4 weeks with serum drug level monitoring. All baseline investigations will be repeated at the end of the treatment period. A subgroup of patients will undergo invasive investigations with right and left heart catheterisation to calculate respiratory quotient, and mechanical efficiency. The primary endpoint is an improvement in the phosphocreatine to adenosine triphosphate ratio at 4 weeks. Secondary end points are: i) respiratory quotient; ii) mechanical efficiency; iii) change in left ventricular (LV) function.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00841139">NCT00841139</a></p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN2887836">ISRCTN2887836</a></p

Pogostick: A New Versatile piggyBac Vector for Inducible Gene Over-Expression and Down-Regulation in Emerging Model Systems

Non-traditional model systems need new tools that will enable them to enter the field of functional genetics. These tools should enable the exploration of gene function, via knock-downs of endogenous genes, as well as over-expression and ectopic expression of transgenes.We constructed a new vector called Pogostick that can be used to over-express or down-regulate genes in organisms amenable to germ line transformation by the piggyBac transposable element. Pogostick can be found at www.addgene.org, a non-profit plasmid repository. The vector currently uses the heat-shock promoter Hsp70 from Drosophila to drive transgene expression and, as such, will have immediate applicability to organisms that can correctly interpret this promotor sequence. We detail how to clone candidate genes into this vector and test its functionality in Drosophila by targeting a gene coding for the fluorescent protein DsRed. By cloning a single DsRed copy into the vector, and generating transgenic lines, we show that DsRed mRNA and protein levels are elevated following heat-shock. When cloning a second copy of DsRed in reverse orientation into a flanking site, and transforming flies constitutively expressing DsRed in the eyes, we show that endogenous mRNA and protein levels drop following heat-shock. We then test the over-expression vector, containing the complete cDNA of Ultrabithorax (Ubx) gene, in an emerging model system, Bicyclus anynana. We produce a transgenic line and show that levels of Ubx mRNA expression rise significantly following a heat-shock. Finally, we show how to obtain genomic sequence adjacent to the Pogostick insertion site and to estimate transgene copy number in genomes of transformed individuals.This new vector will allow emerging model systems to enter the field of functional genetics with few hurdles

Assessing internet-based information used to aid patient decision-making about surgery for perianal Crohn's fistula.

BACKGROUND: Decision-making in perianal Crohn's fistula (pCD) is preference sensitive. Patients use the internet to access healthcare information. The aim of this study was to assess the online information and patient decision aids relating to surgery for pCD. METHODS: A search of Google™ and the Decision Aids Library Inventory (DALI) was performed using a predefined search strategy. Patient-focussed sources providing information about pCD surgery were included in the analysis. Written health information was assessed using the International Patient Decision Aids Standards (IPDAS) and DISCERN criteria. The readability of the source content was assessed using the Flesch-Kincaid score. RESULTS: Of the 201 sources found, 187 were excluded, leaving 14 sources for analysis. Three sources were dedicated to pCD, and six sources mentioned pCD-specific outcomes. The most common surgical intervention reported was seton insertion (n = 13). The least common surgical intervention reported was proctectomy (n = 1). The mean IPDAS and DISCERN scores were 4.43 ± 1.65 out of 12 (range = 2-8) and 2.93 ± 0.73 out of 5 (range = 1-5), respectively. The mean reading ease was US college standard. CONCLUSIONS: We found no patient decision aids relating to surgery for pCD. The online sources relating to surgery for pCD are few, and their quality is poor, as seen in the low IPDAS and DISCERN scores. Less than half of the sources mentioned pCD-specific outcomes, and three sources were solely dedicated to providing information on pCD. Healthcare professionals should look to create a patient tool to assist decision-making in pCD

Identification of metabolic engineering targets through analysis of optimal and sub-optimal routes

Identification of optimal genetic manipulation strategies for redirecting substrate uptake towards a desired product is a challenging task owing to the complexity of metabolic networks, esp. in terms of large number of routes leading to the desired product. Algorithms that can exploit the whole range of optimal and suboptimal routes for product formation while respecting the biological objective of the cell are therefore much needed. Towards addressing this need, we here introduce the notion of structural flux, which is derived from the enumeration of all pathways in the metabolic network in question and accounts for the contribution towards a given biological objective function. We show that the theoretically estimated structural fluxes are good predictors of experimentally measured intra-cellular fluxes in two model organisms, namely, Escherichia coli and Saccharomyces cerevisiae. For a small number of fluxes for which the predictions were poor, the corresponding enzyme-coding transcripts were also found to be distinctly regulated, showing the ability of structural fluxes in capturing the underlying regulatory principles. Exploiting the observed correspondence between in vivo fluxes and structural fluxes, we propose an in silico metabolic engineering approach, iStruF, which enables the identification of gene deletion strategies that couple the cellular biological objective with the product flux while considering optimal as well as sub-optimal routes and their efficiency.This work was supported by the Portuguese Science Foundation [grant numbers MIT-Pt/BS-BB/0082/2008, SFRH/BPD/44180/2008 to ZS] (http://www.fct.pt/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Evaluation of a group based cognitive behavioural therapy programme for menstrual pain management in young women with intellectual disabilities: protocol for a mixed methods controlled clinical trial

BACKGROUND: Menstrual pain which is severe enough to impact on daily activities is very common amongst menstruating females. Research suggests that menstrual pain which impacts on daily functioning may be even more prevalent amongst those with intellectual disabilities. Despite this, little research attention has focused on pain management programmes for those with intellectual disabilities. The aims of this pilot study were to develop and evaluate a theory-based cognitive behavioural therapy (CBT) programme for menstrual pain management in young women with intellectual disabilities. METHODS/DESIGN: The study utilised a mixed methods controlled clinical trial to evaluate elements from a CBT programme called Feeling Better (McGuire & McManus, 2010). The Feeling Better programme is a modular, manualised intervention designed for people with an intellectual disability and their carers. The programme was delivered to 36 young women aged 12 – 30 years who have a Mild - Moderate Intellectual Disability, split between two conditions. The treatment group received the Feeling Better intervention and the control group received treatment as usual. To evaluate the effectiveness of the programme, measures were taken of key pain variables including impact, knowledge, self-efficacy and coping. Process evaluation was conducted to examine which elements of the programme were most successful in promoting change. DISCUSSION: Participants in the intervention group were expected to report the use of a greater number of coping strategies and have greater knowledge of pain management strategies following participation in the intervention and at three month follow-up, when compared to control group participants. A significant advantage of the study was the use of mixed methods and inclusion of process evaluation to determine which elements of a cognitive behavioural therapy programme work best for individuals with intellectual disabilities. TRIAL REGISTRATION: Current Controlled Trials ISRCTN7556775

Reconstruction and analysis of genome-scale metabolic model of a photosynthetic bacterium

<p>Abstract</p> <p>Background</p> <p><it>Synechocystis </it>sp. PCC6803 is a cyanobacterium considered as a candidate photo-biological production platform - an attractive cell factory capable of using CO₂and light as carbon and energy source, respectively. In order to enable efficient use of metabolic potential of <it>Synechocystis </it>sp. PCC6803, it is of importance to develop tools for uncovering stoichiometric and regulatory principles in the <it>Synechocystis </it>metabolic network.</p> <p>Results</p> <p>We report the most comprehensive metabolic model of <it>Synechocystis </it>sp. PCC6803 available, <it>i</it>Syn669, which includes 882 reactions, associated with 669 genes, and 790 metabolites. The model includes a detailed biomass equation which encompasses elementary building blocks that are needed for cell growth, as well as a detailed stoichiometric representation of photosynthesis. We demonstrate applicability of <it>i</it>Syn669 for stoichiometric analysis by simulating three physiologically relevant growth conditions of <it>Synechocystis </it>sp. PCC6803, and through <it>in silico </it>metabolic engineering simulations that allowed identification of a set of gene knock-out candidates towards enhanced succinate production. Gene essentiality and hydrogen production potential have also been assessed. Furthermore, <it>i</it>Syn669 was used as a transcriptomic data integration scaffold and thereby we found metabolic hot-spots around which gene regulation is dominant during light-shifting growth regimes.</p> <p>Conclusions</p> <p><it>i</it>Syn669 provides a platform for facilitating the development of cyanobacteria as microbial cell factories.</p

Factors predicting hospital length-of-stay and readmission after colorectal resection: a population-based study of elective and emergency admissions

<p>Abstract</p> <p>Background</p> <p>The impact of developments in colorectal cancer surgery on length-of-stay (LOS) and re-admission have not been well described. In a population-based analysis, we investigated predictors of LOS and emergency readmission after the initial surgery episode.</p> <p>Methods</p> <p>Incident colorectal cancers (ICD-O2: C18-C20), diagnosed 2002-2008, were identified from the National Cancer Registry Ireland, and linked to hospital in-patient episodes. For those who underwent colorectal resection, the associated hospital episode was identified. Factors predicting longer LOS (upper-quartile, > 24 days) for elective and emergency admissions separately, and whether LOS predicted emergency readmission within 28 days of discharge, were investigated using logistic regression.</p> <p>Results</p> <p>8197 patients underwent resection, 63% (n = 5133) elective and 37% (n = 3063) emergency admissions. Median LOS was 14 days (inter-quartile range (IQR) = 11-20) for elective and 21 (15-33) for emergency admissions. For both emergency and elective admissions, likelihood of longer LOS was significantly higher in patients who were older, had co-morbidities and were unmarried; it was reduced for private patients. For emergency patients only the likelihood of longer LOS was lower for patients admitted to higher-volume hospitals. Longer LOS was associated with increased risk of emergency readmission.</p> <p>Conclusions</p> <p>One quarter of patients stay in hospital for at least 25 days following colorectal resection. Over one third of resected patients are emergency admissions and these have a significantly longer median LOS. Patient- and health service-related factors were associated with prolonged LOS. Longer LOS was associated with increased risk of emergency readmission. The cost implications of these findings are significant.</p

Tumor Endothelial Marker 8 Amplifies Canonical Wnt Signaling in Blood Vessels

Tumor Endothelial Marker 8/Anthrax Toxin Receptor 1 (TEM8/ANTXR1) expression is induced in the vascular compartment of multiple tumors and therefore, is a candidate molecule to target tumor therapies. This cell surface molecule mediates anthrax toxin internalization, however, its physiological function in blood vessels remains largely unknown. We identified the chicken chorioallantoic membrane (CAM) as a model system to study the endogenous function of TEM8 in blood vessels as we found that TEM8 expression was induced transiently between day 10 and 12 of embryonic development, when the vascular tree is undergoing final development and growth. We used the cell-binding component of anthrax toxin, Protective Antigen (PA), to engage endogenous TEM8 receptors and evaluate the effects of PA-TEM8 complexes on vascular development. PA applied at the time of highest TEM8 expression reduced vascular density and disrupted hierarchical branching as revealed by quantitative morphometric analysis of the vascular tree after 48h. PA-dependent reduced branching phenotype was partially mimicked by Wnt3a application and ameliorated by the Wnt antagonist, Dikkopf-1. These results implicate TEM8 expression in endothelial cells in regulating the canonical Wnt signaling pathway at this day of CAM development. Consistent with this model, PA increased beta catenin levels acutely in CAM blood vessels in vivo and in TEM8 transfected primary human endothelial cells in vitro. TEM8 expression in Hek293 cells, which neither express endogenous PA-binding receptors nor Wnt ligands, stabilized beta catenin levels and amplified beta catenin-dependent transcriptional activity induced by Wnt3a. This agonistic function is supported by findings in the CAM, where the increase in TEM8 expression from day 10 to day 12 and PA application correlated with Axin 2 induction, a universal reporter gene for canonical Wnt signaling. We postulate that the developmentally controlled expression of TEM8 modulates endothelial cell response to canonical Wnt signaling to regulate vessel patterning and density