EphB1-mediated cell migration requires the phosphorylation of paxillin at Tyr-31/Tyr-118.

Interactions between Eph receptors and their membrane-bound ligands (ephrins) are of critical importance for key developmental processes such as boundary formation or vascular development. Their downstream signaling pathways are intricate and heterogeneous at several levels, the combined effect being a highly complex and flexible system. Here we demonstrate that activated EphB1 induces tyrosine phosphorylation of the focal adhesion protein paxillin at Tyr-31 and Tyr-118 and is recruited to paxillin-focal adhesion kinase (FAK) complexes. Pretreatment with the specific Src inhibitor PP2, or expression of dominant-negative, kinase-dead c-Src abrogates EphB1-induced tyrosine phosphorylation of paxillin. Cells transfected with the paxillin mutant Y31F/Y118F displayed a reduced migration in response to ephrin B2 stimulation. Furthermore, expression of an LD4 deletion mutant (paxillin DeltaLD4) significantly reduces EphB1-paxillin association, paxillin tyrosine phosphorylation, as well as EphB1-dependent cell migration. Finally, mutation of the Nck-binding site of EphB1 (Y594F) interrupts the interaction between Nck, paxillin, and EphB1. These data suggest a model in which ligand-activated EphB1 forms a signaling complex with Nck, paxillin, and focal adhesion kinase and induces tyrosine phosphorylation of paxillin in a c-Src-dependent manner to promote cell migration.

Efficiency of frost-cracking processes through space and time: An example from the eastern Italian Alps

It is widely accepted that climate has a strong impact and exerts important feedbacks on erosional processes and sediment transport mechanisms. However, the extent at which climate influences erosion is still a matter of debate. In this paper we test whether frost-cracking processes and related temperature variations can influence the sediment production and surface erosion in a small catchment situated in the eastern Italian Alps. To this extent, we first present a geomorphic map of the region that we complement with published 10Be-based denudation rates. We then apply a preexisting heat-flow model in order to analyze the variations of the frost-cracking intensity (FCI) in the study area, which could have controlled the sediment production in the basin. Finally, we compare the model results with the pattern of denudation rates and Quaternary deposits in the geomorphic map. The model results, combined with field observations, mapping, and quantitative geomorphic analyses, reveal that frost-cracking processes have had a primary role in the production of sediment where the intensity of sediment supply has been dictated and limited by the combined effect of temperature variations and conditions of bedrock preservation. These results highlight the importance of a yet poorly understood process for the production of sediment in mountain areas.

PEDro or Cochrane to Assess the Quality of Clinical Trials? A Meta-Epidemiological Study.

OBJECTIVE There is debate on how the methodological quality of clinical trials should be assessed. We compared trials of physical therapy (PT) judged to be of adequate quality based on summary scores from the Physiotherapy Evidence Database (PEDro) scale with trials judged to be of adequate quality by Cochrane Risk of Bias criteria. DESIGN Meta-epidemiological study within Cochrane Database of Systematic Reviews. METHODS Meta-analyses of PT trials were identified in the Cochrane Database of Systematic Reviews. For each trial PeDro and Cochrane assessments were extracted from the PeDro and Cochrane databases. Adequate quality was defined as adequate generation of random sequence, concealment of allocation, and blinding of outcome assessors (Cochrane criteria) or as trials with a PEDro summary score ≥5 or ≥6 points. We combined trials of adequate quality using random-effects meta-analysis. RESULTS Forty-one Cochrane reviews and 353 PT trials were included. All meta-analyses included trials with PEDro scores ≥5, 37 (90.2%) included trials with PEDro scores ≥6 and only 22 (53.7%) meta-analyses included trials of adequate quality according to the Cochrane criteria. Agreement between PeDro and Cochrane was poor for PeDro scores of ≥5 points (kappa = 0.12; 95% CI 0.07 to 0.16) and slight for ≥6 points (kappa 0.24; 95% CI 0.16-0.32). When combining effect sizes of trials deemed to be of adequate quality according to PEDro or Cochrane criteria, we found that a substantial difference in the combined effect size (≥0.15) was evident in 9 (22%) out of the 41 meta-analyses for PEDro cutoff ≥5 and 10 (24%) for cutoff ≥6. CONCLUSIONS The PeDro and Cochrane approaches lead to different sets of trials of adequate quality, and different combined treatment estimates from meta-analyses of these trials. A consistent approach to assessing RoB in trials of physical therapy should be adopted.

Future water quality monitoring--adapting tools to deal with mixtures of pollutants in water resource management.

Environmental quality monitoring of water resources is challenged with providing the basis for safeguarding the environment against adverse biological effects of anthropogenic chemical contamination from diffuse and point sources. While current regulatory efforts focus on monitoring and assessing a few legacy chemicals, many more anthropogenic chemicals can be detected simultaneously in our aquatic resources. However, exposure to chemical mixtures does not necessarily translate into adverse biological effects nor clearly shows whether mitigation measures are needed. Thus, the question which mixtures are present and which have associated combined effects becomes central for defining adequate monitoring and assessment strategies. Here we describe the vision of the international, EU-funded project SOLUTIONS, where three routes are explored to link the occurrence of chemical mixtures at specific sites to the assessment of adverse biological combination effects. First of all, multi-residue target and non-target screening techniques covering a broader range of anticipated chemicals co-occurring in the environment are being developed. By improving sensitivity and detection limits for known bioactive compounds of concern, new analytical chemistry data for multiple components can be obtained and used to characterise priority mixtures. This information on chemical occurrence will be used to predict mixture toxicity and to derive combined effect estimates suitable for advancing environmental quality standards. Secondly, bioanalytical tools will be explored to provide aggregate bioactivity measures integrating all components that produce common (adverse) outcomes even for mixtures of varying compositions. The ambition is to provide comprehensive arrays of effect-based tools and trait-based field observations that link multiple chemical exposures to various environmental protection goals more directly and to provide improved in situ observations for impact assessment of mixtures. Thirdly, effect-directed analysis (EDA) will be applied to identify major drivers of mixture toxicity. Refinements of EDA include the use of statistical approaches with monitoring information for guidance of experimental EDA studies. These three approaches will be explored using case studies at the Danube and Rhine river basins as well as rivers of the Iberian Peninsula. The synthesis of findings will be organised to provide guidance for future solution-oriented environmental monitoring and explore more systematic ways to assess mixture exposures and combination effects in future water quality monitoring.

Effect on false-lumen status of a combined vascular and endovascular approach for the treatment of acute type A aortic dissection

The aim of the study is to evaluate midterm results with regard to false-lumen status of a combined vascular and endovascular approach for the treatment of acute type A aortic dissection.

Influence of reported study design characteristics on intervention effect estimates from randomised controlled trials: combined analysis of meta-epidemiological studies

The design of randomised controlled trials (RCTs) should incorporate characteristics (such as concealment of randomised allocation and blinding of participants and personnel) that avoid biases resulting from lack of comparability of the intervention and control groups. Empirical evidence suggests that the absence of such characteristics leads to biased intervention effect estimates, but the findings of different studies are not consistent.

Comparison of dual-energy subtraction and electronic bone suppression combined with computer-aided detection on chest radiographs: effect on human observers' performance in nodule detection

The objective of our study was to compare the effect of dual-energy subtraction and bone suppression software alone and in combination with computer-aided detection (CAD) on the performance of human observers in lung nodule detection.

Effect of acute hypoxia on maximal oxygen uptake and maximal performance during leg and upper-body exercise in Nordic combined skiers

We examined the effect of normobaric hypoxia (3200 m) on maximal oxygen uptake (VO2max) and maximal power output (Pmax) during leg and upper-body exercise to identify functional and structural correlates of the variability in the decrement of VO2max (DeltaVO2max) and of maximal power output (DeltaPmax). Seven well trained male Nordic combined skiers performed incremental exercise tests to exhaustion on a cycle ergometer (leg exercise) and on a custom built doublepoling ergometer for cross-country skiing (upper-body exercise). Tests were carried out in normoxia (560 m) and normobaric hypoxia (3200 m); biopsies were taken from m. deltoideus. DeltaVO2max was not significantly different between leg (-9.1+/-4.9%) and upper-body exercise (-7.9+/-5.8%). By contrast, Pmax was significantly more reduced during leg exercise (-17.3+/-3.3%) than during upper-body exercise (-9.6+/-6.4%, p<0.05). Correlation analysis did not reveal any significant relationship between leg and upper-body exercise neither for DeltaVO2max nor for DeltaPmax. Furthermore, no relationship was observed between individual DeltaVO2max and DeltaPmax. Analysis of structural data of m. deltoideus revealed a significant correlation between capillary density and DeltaPmax (R=-0.80, p=0.03), as well as between volume density of mitochondria and DeltaPmax (R=-0.75, p=0.05). In conclusion, it seems that VO2max and Pmax are differently affected by hypoxia. The ability to tolerate hypoxia is a characteristic of the individual depending in part on the exercise mode. We present evidence that athletes with a high capillarity and a high muscular oxidative capacity are more sensitive to hypoxia.

Effect of Combined Systemic and Local Morpholino Treatment on the Spinal Muscular Atrophy Δ7 Mouse Model Phenotype

BACKGROUND: Spinal muscular atrophy (SMA) is a fatal motor neuron disease of childhood that is caused by mutations in the SMN1 gene. Currently, no effective treatment is available. One possible therapeutic approach is the use of antisense oligos (ASOs) to redirect the splicing of the paralogous gene SMN2, thus increasing functional SMN protein production. Various ASOs with different chemical properties are suitable for these applications, including a morpholino oligomer (MO) variant with a particularly excellent safety and efficacy profile. OBJECTIVE: We investigated a 25-nt MO sequence targeting the negative intronic splicing silencer (ISS-N1) 10 to 34 region. METHODS: We administered a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) in the SMAΔ7 mouse model and evaluated the effect and neuropathologic phenotype. We tested different concentrations (from 2 to 24 nM) and delivery protocols (intracerebroventricular injection, systemic injection, or both). We evaluated the treatment efficacy regarding SMN levels, survival, neuromuscular phenotype, and neuropathologic features. RESULTS: We found that a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) exhibited superior efficacy in transgenic SMAΔ7 mice compared with previously described sequences. In our experiments, the combination of local and systemic administration of MO (bare or conjugated to octaguanidine) was the most effective approach for increasing full-length SMN expression, leading to robust improvement in neuropathologic features and survival. Moreover, we found that several small nuclear RNAs were deregulated in SMA mice and that their levels were restored by MO treatment. CONCLUSION: These results indicate that MO-mediated SMA therapy is efficacious and can result in phenotypic rescue, providing important insights for further development of ASO-based therapeutic strategies in SMA patients.

Combined modality treatment improves tumor control and overall survival in patients with early stage Hodgkin's lymphoma: a systematic review

Combined modality treatment (CMT) of chemotherapy followed by localized radiotherapy is standard treatment for patients with early stage Hodgkin's lymphoma. However, the role of radiotherapy has been questioned recently and some clinical study groups advocate chemotherapy only for this indication. We thus performed a systematic review with meta-analysis of randomized controlled trials comparing chemotherapy alone with CMT in patients with early stage Hodgkin's lymphoma with respect to response rate, tumor control and overall survival (OS). We searched Medline, EMBASE and the Cochrane Library as well as conference proceedings from January 1980 to February 2009 for randomized controlled trials comparing chemotherapy alone versus the same chemotherapy regimen plus radiotherapy. Progression free survival and similar outcomes were analyzed together as tumor control. Effect measures used were hazard ratios for OS and tumor control as well as relative risks for complete response (CR). Meta-analyses were performed using RevMan5. Five randomized controlled trials involving 1,245 patients were included. The hazard ratio (HR) was 0.41 (95% confidence interval (CI) 0.25 to 0.66) for tumor control and 0.40 (95% CI 0.27 to 0.59) for OS for patients receiving CMT compared to chemotherapy alone. CR rates were similar between treatment groups. In sensitivity analyses another 6 trials were included that did not fulfill the inclusion criteria of our protocol but were considered relevant to the topic. These trials underlined the results of the main analysis. In conclusion, adding radiotherapy to chemotherapy improves tumor control and OS in patients with early stage Hodgkin's lymphoma.

Effect of systemic tetracycline on the degradation of tetracycline-impregnated bilayered collagen membranes: an animal study

BACKGROUND: Premature collagen membrane degradation may compromise the outcome of osseous regenerative procedures. Tetracyclines (TTCs) inhibit the catalytic activities of human metalloproteinases. Preprocedural immersion of collagen membranes in TTC and systemic administration of TTC may be possible alternatives to reduce the biodegradation of native collagen membranes. AIM: To evaluate the in vivo degradation of collagen membranes treated by combined TTC immersion and systemic administration. MATERIALS AND METHODS: Seventy-eight bilayered porcine collagen membrane disks were divided into three groups and were immersed in 0, 50, or 100 mg/mL TTC solution. Three disks, one of each of the three groups, were implanted on the calvaria of each of 26 Wistar rats. Thirteen (study group) were administered with systemic TTC (10 mg/kg), while the remaining 13 received saline injections (control group). Calvarial tissues were retrieved after 3 weeks, and histological sections were analyzed by image analysis software. RESULTS: Percentage of remaining collagen area within nonimpregnated membranes was 52.26 ± 20.67% in the study group, and 32.74 ± 13.81% in the control group. Immersion of membranes in 100 mg/mL TTC increased the amount of residual collagen to 63.46 ± 18.19% and 42.82 ± 12.99% (study and control groups, respectively). Immersion in 50 mg/mL TTC yielded maximal residual collagen values: 80.75 ± 14.86% and 59.15 ± 8.01% (study and control groups, respectively). Differences between the TTC concentrations, and between the control and the study groups were statistically significant. CONCLUSIONS: Immersion of collagen membranes in TTC solution prior to their implantation and systemic administration of TTC significantly decreased the membranes' degradation.

A randomized trial of effects of health risk appraisal combined with group sessions or home visits on preventive behaviors in older adults

Background. To explore effects of a health risk appraisal for older people (HRA-O) program with reinforcement, we conducted a randomized controlled trial in 21 general practices in Hamburg, Germany. Methods. Overall, 2,580 older patients of 14 general practitioners trained in reinforcing recommendations related to HRA-O-identified risk factors were randomized into intervention (n = 878) and control (n = 1,702) groups. Patients (n = 746) of seven additional matched general practitioners who did not receive this training served as a comparison group. Patients allocated to the intervention group, and their general practitioners, received computer-tailored written recommendations, and patients were offered the choice between interdisciplinary group sessions (geriatrician, physiotherapist, social worker, and nutritionist) and home visits (nurse). Results. Among the intervention group, 580 (66%) persons made use of personal reinforcement (group sessions: 503 [87%], home visits: 77 [13%]). At 1-year follow-up, persons in the intervention group had higher use of preventive services (eg, influenza vaccinations, adjusted odds ratio 1.7; 95% confidence interval 1.4–2.1) and more favorable health behavior (eg, high fruit/fiber intake, odds ratio 2.0; 95% confidence interval 1.6–2.6), as compared with controls. Comparisons between intervention and comparison group data revealed similar effects, suggesting that physician training alone had no effect. Subgroup analyses indicated favorable effects for HRA-O with personal reinforcement, but not for HRA-O without reinforcement. Conclusions. HRA-O combined with physician training and personal reinforcement had favorable effects on preventive care use and health behavior.

EFFECT OF AGING ON MACULAR FEATURES OF X-LINKED RETINOSCHISIS ASSESSED WITH OPTICAL COHERENCE TOMOGRAPHY

X-linked retinoschisis (XLRS) is one of the most common causes of macular degeneration in young men. The purpose of this study was to use optical coherence tomography combined with ophthalmoscopy to study the effects of aging on the morphologic changes associated with XLRS.

Segmentation of brain tumor images based on atlas-registration combined with a Markov-Random-Field lesion growth model

We present an automatic method to segment brain tissues from volumetric MRI brain tumor images. The method is based on non-rigid registration of an average atlas in combination with a biomechanically justified tumor growth model to simulate soft-tissue deformations caused by the tumor mass-effect. The tumor growth model, which is formulated as a mesh-free Markov Random Field energy minimization problem, ensures correspondence between the atlas and the patient image, prior to the registration step. The method is non-parametric, simple and fast compared to other approaches while maintaining similar accuracy. It has been evaluated qualitatively and quantitatively with promising results on eight datasets comprising simulated images and real patient data.

First-line temozolomide combined with bevacizumab in metastatic melanoma: a multicentre phase II trial (SAKK 50/07)

Oral temozolomide has shown similar efficacy to dacarbazine in phase III trials with median progression-free survival (PFS) of 2.1 months. Bevacizumab has an inhibitory effect on the proliferation of melanoma and sprouting endothelial cells. We evaluated the addition of bevacizumab to temozolomide to improve efficacy in stage IV melanoma.