Shotgun Cloning of Transposon Insertions in the Genome of Caenorhabditis elegans

We present a strategy to identify and map large numbers of transposon insertions in the genome of Caenorhabditis elegans. Our approach makes use of the mutator strain mut-7, which has germline-transposition activity of the Tc1/mariner family of transposons, a display protocol to detect new transposon insertions, and the availability of the genomic sequence of C. elegans. From a pilot insertional mutagenesis screen, we have obtained 351 new Tc1 transposons inserted in or near 219 predicted C. elegans genes. The strategy presented provides an approach to isolate insertions of natural transposable elements in many C. elegans genes and to create a large-scale collection of C. elegans mutants

Hook plate fixation of acute displaced lateral clavicle fractures: mid-term results and a brief literature overview

<p>Abstract</p> <p>Background</p> <p>The clavicle hook plate achieves like most other operative techniques, a high percentage of union and a low percentage of complications however concerns about long term complications still exist, particularly the involvement of the acromioclavicular joint.</p> <p>Methods</p> <p>To evaluate the results and long term effects in use of this plate we performed a retrospective analysis with a mean follow up of 65 months (5.4 years) of 28 consecutive patients with acute displaced lateral clavicle fractures, treated with the clavicle hook plate.</p> <p>Results</p> <p>Short term functional results in all patients were good to excellent. All but one patient had a united fracture (96%). Nine patients (32%) developed impingement symptoms and in 7 patients (25%) subacromial osteolysis was found. These findings resolved after plate removal. Twenty-four patients were re-evaluated at a mean follow-up period of 5.4 years. The Constant-Murley score was 97 and the DASH score was 3.5. Four patients (14%) developed acromioclavicular joint arthrosis of which one was symptomatic. Three patients (11%) had extra articular ossifications of which one was symptomatic. There was no relation between the impingement symptoms, subacromial osteolysis and development of acromioclavicular joint arthrosis or extra articular ossifications.</p> <p>Conclusions</p> <p>The clavicle hook plate is a good primary treatment option for the acute displaced lateral clavicle fracture with few complications. At mid term the results are excellent and no long term complications can be addressed to the use of the plate.</p

Hyperactivation of the G12-Mediated Signaling Pathway in Caenorhabditis elegans Induces a Developmental Growth Arrest via Protein Kinase C

AbstractThe G12 type of heterotrimeric G-proteins play an important role in development and behave as potent oncogenes in cultured cells [1–5]. However, little is known about the molecular nature of the components that act in the G12-signaling pathway in an organism. We characterized a C. elegans Gα subunit gene, gpa-12, which is a homolog of mammalian G12/G13α, and found that animals defective in gpa-12 are viable. Expression of activated GPA-12 (G12QL) results in a developmental growth arrest caused by a feeding behavior defect that is due to a dramatic reduction in pharyngeal pumping. To elucidate the molecular nature of the signaling pathways in which G12 participates, we screened for suppressors of the G12QL phenotype. We isolated 50 suppressors that contain mutations in tpa-1, which encodes two protein kinase C isoforms, TPA-1A and TPA-1B, most similar to PKCθ/δ. TPA-1 mediates the action of the tumor promoter PMA [6]. Expression of G12QL and treatment of wild-type animals with PMA induce an identical growth arrest caused by inhibition of larval feeding, which is dependent on TPA-1A and TPA-1B function. These results suggest that TPA-1 is a downstream target of both G12 signaling and PMA in modulating feeding and growth in C. elegans. Taken together, our findings provide a potential molecular mechanism for the transforming capability of G12 proteins

Screening for psychological distress before radiotherapy for painful bone metastases may be useful to identify patients with high levels of distress

Background: Psychological distress (PD) has a major impact on quality of life. We studied the incidence of PD before and after radiotherapy for painful bone metastases. Furthermore, we aimed to identify factors predictive for PD.Methods: Between 1996 and 1998, the Dutch Bone Metastasis Study included 1157 patients with painful bone metastases. Patients were randomized between two fractionation schedules. The study showed a pain response of 74% in both groups. Patients filled out weekly questionnaires for 13 weeks, then monthly for two years. The questionnaires included a subscale for PD on the Rotterdam Symptom Checklist. We used generalized estimating equations and multivariable logistic regression analyses.Results: At baseline, 290 patients (27%) had a high level of PD. For the entire group, the level of PD remained constant over time. The majority of patients with a low level of PD at baseline remained at a low level during follow-up. In patients with a high level of PD at baseline, the mean level of PD decreased after treatment and stabilized around the cutoff level. Female patients, higher age, worse performance, lower pain score and worse self-reported QoL were associated with an increased chance of PD, although the model showed moderate discriminative power.Conclusions: A substantial proportion of patients had a high level of PD before and after radiotherapy for painful bone metastases. Most patients who reported high levels of PD when referred for palliative radiotherapy remained at high levels thereafter. Therefore, screening of PD prior to treatment seems appropriate, in order to select patients requiring intervention.</p

Dexamethasone for the prevention of a pain flare after palliative radiotherapy for painful bone metastases:a multicenter double-blind placebo-controlled randomized trial

Background: Radiotherapy has a good effect in palliation of painful bone metastases, with a pain response rate of more than 60%. However, shortly after treatment, in approximately 40% of patients a temporary pain flare occurs, which is defined as a two-point increase of the worst pain score on an 11-point rating scale compared to baseline, without a decrease in analgesic intake, or a 25% increase in analgesic intake without a decrease in worst pain score, compared to baseline. A pain flare has a negative impact on daily functioning and mood of patients. It is thought to be caused by periostial edema after radiotherapy. Dexamethasone might diminish this edema and thereby reduce the incidence of pain flare. Two non-randomized studies suggest that dexamethasone reduces the incidence of a pain flare by 50%. The aim of this trial is to study the effectiveness of dexamethasone to prevent a pain flare after palliative radiotherapy for painful bone metastases and to determine the optimal dose schedule. Methods and design: This study is a three-armed, double-blind, placebo-controlled multicenter trial. We aim to include 411 patients with uncomplicated painful bone metastases from any type of primary solid tumor who receive short schedule radiotherapy (all conventional treatment schedules from one to six fractions). Arm 1 consists of daily placebo for four days, arm 2 starts with 8 mg dexamethasone before the (first) radiotherapy and three days placebo thereafter. Arm 3 consists of four days 8 mg dexamethasone. The primary endpoint is the occurrence of a pain flare. Secondary endpoints are pain, quality of life and side-effects of dexamethasone versus placebo. Patients complete a questionnaire (Brief Pain Inventory with two added questions about side-effects of medication, the EORTC QLQ-C15-PAL and QLQ-BM22 for quality of life) at baseline, daily for two weeks and lastly at four weeks. Discussion: This study will show whether dexamethasone is effective in preventing a pain flare after palliative radiotherapy for painful bone metastases and, if so, to determine the optimal dose

Randomized controlled study of pain education in patients receiving radiotherapy for painful bone metastases

BACKGROUND: Although short-course radiotherapy is an effective treatment for patients with painful bone metastases, pain is not always sufficiently controlled. We therefore investigated the additional effect of a nurse-led pain education program on pain control and quality of life (QoL).PATIENTS AND METHODS: In this multicenter study, patients with solid tumor bone metastases and a worst pain intensity of ≥5 on a 0-10 numeric rating scale (NRS) were randomized between care as usual (control-group) and care as usual plus the Pain Education Program (PEP-group). PEP consisted of a structured interview and personalized education with follow-up phone calls. Patients completed the Brief Pain Inventory, EORTC QLQ-C15-PAL and BM22 at week 0, 1, 4, 8 and 12. The primary outcome was pain control, defined as the number of patients whose worst pain intensity was &lt;5 on a 0-10 NRS after 12 weeks. Secondary outcomes were time to reach control of pain (NRS &lt; 5), mean worst pain and average pain, and QoL at weeks 1, 4, 8 and 12.RESULTS: Of 308 included patients, 182 (92 PEP-group) completed 12 weeks follow-up. At 12 weeks, more patients in the PEP-group (71%) compared to the control-group (52%) reported pain control (P =.008). In the PEP-group, pain control was reached earlier than in the control-group (median 29 days versus 56 days; P =.003). Mean worst and average pain decreased in both groups but decreased more in the PEP-group. QoL did not differ between the groups.CONCLUSION: The addition of PEP to care as usual for patients treated with radiotherapy for painful bone metastases resulted in less pain and faster pain control.</p

Ultrasound-guided breast-sparing surgery to improve cosmetic outcomes and quality of life. A prospective multicentre randomised controlled clinical trial comparing ultrasound-guided surgery to traditional palpation-guided surgery (COBALT trial)

<p>Abstract</p> <p>Background</p> <p>Breast-conserving surgery for breast cancer was developed as a method to preserve healthy breast tissue, thereby improving cosmetic outcomes. Thus far, the primary aim of breast-conserving surgery has been the achievement of tumour-free resection margins and prevention of local recurrence, whereas the cosmetic outcome has been considered less important. Large studies have reported poor cosmetic outcomes in 20-40% of patients after breast-conserving surgery, with the volume of the resected breast tissue being the major determinant. There is clear evidence for the efficacy of ultrasonography in the resection of nonpalpable tumours. Surgical resection of palpable breast cancer is performed with guidance by intra-operative palpation. These palpation-guided excisions often result in an unnecessarily wide resection of adjacent healthy breast tissue, while the rate of tumour-involved resection margins is still high. It is hypothesised that the use of intra-operative ultrasonography in the excision of palpable breast cancer will improve the ability to spare healthy breast tissue while maintaining or even improving the oncological margin status. The aim of this study is to compare ultrasound-guided surgery for palpable tumours with the standard palpation-guided surgery in terms of the extent of healthy breast tissue resection, the percentage of tumour-free margins, cosmetic outcomes and quality of life.</p> <p>Methods/design</p> <p>In this prospective multicentre randomised controlled clinical trial, 120 women who have been diagnosed with palpable early-stage (T1-2N0-1) primary invasive breast cancer and deemed suitable for breast-conserving surgery will be randomised between ultrasound-guided surgery and palpation-guided surgery. With this sample size, an expected 20% reduction of resected breast tissue and an 18% difference in tumour-free margins can be detected with a power of 80%. Secondary endpoints include cosmetic outcomes and quality of life. The rationale, study design and planned analyses are described.</p> <p>Conclusion</p> <p>The COBALT trial is a prospective, multicentre, randomised controlled study to assess the efficacy of ultrasound-guided breast-conserving surgery in patients with palpable early-stage primary invasive breast cancer in terms of the sparing of breast tissue, oncological margin status, cosmetic outcomes and quality of life.</p> <p>Trial Registration Number</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2579">NTR2579</a></p

Cytokines as Therapeutic Targets in Rheumatoid Arthritis and Other Inflammatory Diseases

The human immune system involves highly complex and coordinated processes in which small proteins named cytokines play a key role. Cytokines have been implicated in the pathogenesis of a number of inflammatory and autoimmune diseases. Cytokines are therefore attractive therapeutic targets in these conditions. Anticytokine therapy for inflammatory diseases became a clinical reality with the introduction of tumor necrosis factor (TNF) inhibitors for the treatment of severe rheumatoid arthritis. Although these therapies have transformed the treatment of patients with severe inflammatory arthritis, there remain significant limiting factors: treatment failure is commonly seen in the clinic; safety concerns remain; there is uncertainty regarding the relevance of immunogenicity; the absence of biomarkers to direct therapy decisions and high drug costs limit availability in some healthcare systems. In this article, we provide an overview of the key efficacy and safety trials for currently approved treatments in rheumatoid arthritis and review the major lessons learned from a decade of use in clinical practice, focusing mainly on anti-TNF and anti–interleukin (IL)-6 agents. We also describe the clinical application of anticytokine therapies for other inflammatory diseases, particularly within the spondyloarthritis spectrum, and highlight differential responses across diseases. Finally, we report on the current state of trials for newer therapeutic targets, focusing mainly on the IL-17 and IL-23 pathways

Galaxy Zoo: the dependence of morphology and colour on environment

We analyse the relationships between galaxy morphology, colour, environment and stellar mass using data for over 100,000 objects from Galaxy Zoo, the largest sample of visually classified morphologies yet compiled. We conclusively show that colour and morphology fractions are very different functions of environment. Both are sensitive to stellar mass; however, at fixed stellar mass, while colour is also highly sensitive to environment, morphology displays much weaker environmental trends. Only a small part of both relations can be attributed to variation in the stellar mass function with environment. Galaxies with high stellar masses are mostly red, in all environments and irrespective of their morphology. Low stellar-mass galaxies are mostly blue in low-density environments, but mostly red in high-density environments, again irrespective of their morphology. The colour-density relation is primarily driven by variations in colour fractions at fixed morphology, in particular the fraction of spiral galaxies that have red colours, and especially at low stellar masses. We demonstrate that our red spirals primarily include galaxies with true spiral morphology. We clearly show there is an environmental dependence for colour beyond that for morphology. Before using the Galaxy Zoo morphologies to produce the above results, we first quantify a luminosity-, size- and redshift-dependent classification bias that affects this dataset, and probably most other studies of galaxy population morphology. A correction for this bias is derived and applied to produce a sample of galaxies with reliable morphological type likelihoods, on which we base our analysis.Comment: 25 pages, 20 figures (+ 6 pages, 11 figures in appendices); moderately revised following referee's comments; accepted by MNRA

Progress on optimizing miscanthus biomass production for the European bioeconomy:Results of the EU FP7 project OPTIMISC

This paper describes the complete findings of the EU-funded research project OPTIMISC, which investigated methods to optimize the production and use of miscanthus biomass. Miscanthus bioenergy and bioproduct chains were investigated by trialing 15 diverse germplasm types in a range of climatic and soil environments across central Europe, Ukraine, Russia, and China. The abiotic stress tolerances of a wider panel of 100 germplasm types to drought, salinity, and low temperatures were measured in the laboratory and a field trial in Belgium. A small selection of germplasm types was evaluated for performance in grasslands on marginal sites in Germany and the UK. The growth traits underlying biomass yield and quality were measured to improve regional estimates of feedstock availability. Several potential high-value bioproducts were identified. The combined results provide recommendations to policymakers, growers and industry. The major technical advances in miscanthus production achieved by OPTIMISC include: (1) demonstration that novel hybrids can out-yield the standard commercially grown genotype Miscanthus x giganteus; (2) characterization of the interactions of physiological growth responses with environmental variation within and between sites; (3) quantification of biomass-quality-relevant traits; (4) abiotic stress tolerances of miscanthus genotypes; (5) selections suitable for production on marginal land; (6) field establishment methods for seeds using plugs; (7) evaluation of harvesting methods; and (8) quantification of energy used in densification (pellet) technologies with a range of hybrids with differences in stem wall properties. End-user needs were addressed by demonstrating the potential of optimizing miscanthus biomass composition for the production of ethanol and biogas as well as for combustion. The costs and life-cycle assessment of seven miscanthusbased value chains, including small- and large-scale heat and power, ethanol, biogas, and insulation material production, revealed GHG-emission- and fossil-energy-saving potentials of up to 30.6 t CO2eqC ha(-1) y(-1) and 429 GJ ha(-1)y(-1), respectively. Transport distance was identified as an important cost factor. Negative carbon mitigation costs of-78 epsilon t(-1) CO2eq C were recorded for local biomass use. The OPTIMISC results demonstrate the potential of miscanthus as a crop for marginal sites and provide information and technologies for the commercial implementation of miscanthus-based value chains