Are mice good models for human neuromuscular disease? Comparing muscle excursions in walking between mice and humans

The mouse is one of the most widely used animal models to study neuromuscular diseases and test new therapeutic strategies. However, findings from successful pre-clinical studies using mouse models frequently fail to translate to humans due to various factors. Differences in muscle function between the two species could be crucial but often have been overlooked. The purpose of this study was to evaluate and compare muscle excursions in walking between mice and humans

Protocol for a multicentre randomised feasibility trial evaluating early Surgery Alone In LOw Rectal cancer (SAILOR)

Introduction There are 11,500 rectal cancers diagnosed annually in the UK. Although surgery remains the primary treatment there is evidence that preoperative radiotherapy (RT) improves local recurrence rates. High quality surgery in rectal cancer is equally important in minimising local recurrence. Advances in magnetic resonance imaging (MRI)-guided prediction of resection margin status and improvements in abdominoperineal excision of the rectum (APER) technique supports a reassessment of the contribution of preoperative RT. A more selective approach to RT may be appropriate given the associated toxicity. Methods and analysis This trial will explore the feasibility of a definitive trial evaluating the omission of RT in resectable low rectal cancer requiring APER. It will test the feasibility of randomising patients to i) standard care (neoadjuvant long course radiotherapy +/- chemotherapy and APER, or ii) APER surgery alone for cT2/T3ab N0/1 low rectal cancer with clear predicted resection margins on MRI. Radiotherapy schedule will be 45Gy over 5 weeks as current standard, with restaging and surgery after 8-12 weeks. Recruitment will be for 24 months with a minimum 12 month follow up. Objectives include testing the ability to recruit, consent and retain patients, to quantify the number of patients eligible for a definitive trial and to test feasibility of outcomes measures. These include locoregional recurrence rates, distance to circumferential resection margin, toxicity and surgical complications including perineal wound healing, quality of life and economic analysis. The quality of MRI staging, radiotherapy delivery and surgical specimen quality will be closely monitored. Ethics and dissemination The trial is approved by the regional ethics committee and Health Research Authority (HRA) or equivalent. Written informed consent will be obtained. Serious adverse events will be reported to Swansea Trials Unit (STU), the ethics committee and trial sites. Trial results will be submitted for peer review publication and to trial participants. Strengths and limitations of this study • A unique interventional study specific to low rectal cancer • Will explore the contribution of the modern abdominoperineal excision operation to cancer outcomes • Strict quality assurance processes for imaging, radiotherapy, surgery and pathology • Will establish if a future trial minimising radiotherapy use in low rectal cancer is feasible • Study is limited by short follow up perio

Breath biomarkers in idiopathic pulmonary fibrosis:A systematic review 11 Medical and Health Sciences

Background: Exhaled biomarkers may be related to disease processes in idiopathic pulmonary fibrosis (IPF) however their clinical role remains unclear. We performed a systematic review to investigate whether breath biomarkers discriminate between patients with IPF and healthy controls. We also assessed correlation with lung function, ability to distinguish diagnostic subgroups and change in response to treatment. Methods: MEDLINE, EMBASE and Web of Science databases were searched. Study selection was limited to adults with a diagnosis of IPF as per international guidelines. Results: Of 1014 studies screened, fourteen fulfilled selection criteria and included 257 IPF patients. Twenty individual biomarkers discriminated between IPF and controls and four showed correlation with lung function. Meta-analysis of three studies indicated mean (± SD) alveolar nitric oxide (CalvNO) levels were significantly higher in IPF (8.5 ± 5.5 ppb) than controls (4.4 ± 2.2 ppb). Markers of oxidative stress in exhaled breath condensate, such as hydrogen peroxide and 8-isoprostane, were also discriminatory. Two breathomic studies have isolated discriminative compounds using mass spectrometry. There was a lack of studies assessing relevant treatment and none assessed differences in diagnostic subgroups. Conclusions: Evidence suggests CalvNO is higher in IPF, although studies were limited by small sample size. Further breathomic work may identify biomarkers with diagnostic and prognostic potential

Baseline and follow-up assessment of regional left ventricular volume using 3-dimensional echocardiography: comparison with cardiac magnetic resonance

The assessment of regional volumes is an option for analysis of the response of LV segments to interventions such as revascularization or cell therapy. We sought to compare regional volumes from 3D-echocardiography (3DE) with cardiac magnetic resonance (CMR) over follow-up

Comparison of contrast enhanced three dimensional echocardiography with MIBI gated SPECT for the evaluation of left ventricular function

Background. In clinical practice and in clinical trials, echocardiography and scintigraphy are used the most for the evaluation of global left ejection fraction (LVEF) and left ventricular (LV) volumes. Actually, poor quality imaging and geometrical assumptions are the main limitations of LVEF measured by echocardiography. Contrast agents and 3D echocardiography are new methods that may alleviate these potential limitations. Methods. Therefore we sought to examine the accuracy of contrast 3D echocardiography for the evaluation of LV volumes and LVEF relative to MIBI gated SPECT as an independent reference. In 43 patients addressed for chest pain, contrast 3D echocardiography (RT3DE) and MIBI gated SPECT were prospectively performed on the same day. The accuracy and the variability of LV volumes and LVEF measurements were evaluated. Results. Due to good endocardial delineation, LV volumes and LVEF measurements by contrast RT3DE were feasible in 99% of the patients. The mean LV end-diastolic volume (LVEDV) of the group by scintigraphy was 143 65 mL and was underestimated by triplane contrast RT3DE (128 60 mL; p < 0.001) and less by full-volume contrast RT3DE (132 62 mL; p < 0.001). Limits of agreement with scintigraphy were similar for triplane andfull-volume, modalities with the best results for full-volume. Results were similar for calculation of LV end-systolic volume (LVESV). The mean LVEF was 44 16% with scintigraphy and was not significantly different with both triplane contrast RT3DE (45 15%) and full-volume contrast RT3DE (45 15%). There was an excellent correlation between two different observers for LVEDV, LVESV and LVEF measurements and inter observer agreement was also good for both contrast RT3DE techniques. Conclusion. Contrast RT3DE allows an accurate assessment of LVEF compared to the LVEF measured by SPECT, and shows low variability between observers. Although RT3DE triplane provides accurate evaluation of left ventricular function, RT3DE full-volume is superior to triplane modality in patients with suspected coronary artery disease. © 2009 Cosyns et al; licensee BioMed Central Ltd.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

The Location and Nature of General Anesthetic Binding Sites on the Active Conformation of Firefly Luciferase; A Time Resolved Photolabeling Study

Firefly luciferase is one of the few soluble proteins that is acted upon by a wide variety of general anesthetics and alcohols; they inhibit the ATP–driven production of light. We have used time–resolved photolabeling to locate the binding sites of alcohols during the initial light output, some 200 ms after adding ATP. The photolabel 3-azioctanol inhibited the initial light output with an IC50 of 200 µM, close to its general anesthetic potency. Photoincorporation of [3H]3-azioctanol into luciferase was saturable but weak. It was enhanced 200 ms after adding ATP but was negligible minutes later. Sequencing of tryptic digests by HPLC–MSMS revealed a similar conformation–dependence for photoincorporation of 3-azioctanol into Glu-313, a residue that lines the bottom of a deep cleft (vestibule) whose outer end binds luciferin. An aromatic diazirine analog of benzyl alcohol with broader side chain reactivity reported two sites. First, it photolabeled two residues in the vestibule, Ser-286 and Ile-288, both of which are implicated with Glu-313 in the conformation change accompanying activation. Second, it photolabeled two residues that contact luciferin, Ser-316 and Ser-349. Thus, time resolved photolabeling supports two mechanisms of action. First, an allosteric one, in which anesthetics bind in the vestibule displacing water molecules that are thought to be involved in light output. Second, a competitive one, in which anesthetics bind isosterically with luciferin. This work provides structural evidence that supports the competitive and allosteric actions previously characterized by kinetic studies

Three-dimensional echocardiography for left ventricular quantification: fundamental validation and clinical applications

One of the earliest applications of clinical echocardiography is evaluation of left ventricular (LV) function and size. Accurate, reproducible and quantitative evaluation of LV function and size is vital for diagnosis, treatment and prediction of prognosis of heart disease. Early three-dimensional (3D) echocardiographic techniques showed better reproducibility than two-dimensional (2D) echocardiography and narrower limits of agreement for assessment of LV function and size in comparison to reference methods, mostly cardiac magnetic resonance (CMR) imaging, but acquisition methods were cumbersome and a lack of user-friendly analysis software initially precluded widespread use. Through the advent of matrix transducers enabling real-time three-dimensional echocardiography (3DE) and improvements in analysis software featuring semi-automated volumetric analysis, 3D echocardiography evolved into a simple and fast imaging modality for everyday clinical use. 3DE provides the possibility to evaluate the entire LV in three spatial dimensions during the complete cardiac cycle, offering a more accurate and complete quantitative evaluation the LV. Improved efficiency in acquisition and analysis may provide clinicians with important diagnostic information within minutes. The current article reviews the methodology and application of 3DE for quantitative evaluation of the LV, provides the scientific evidence for its current clinical use, and discusses its current limitations and potential future directions

Three-dimensional echocardiography using single-heartbeat modality decreases variability in measuring left ventricular volumes and function in comparison to four-beat technique in atrial fibrillation

BACKGROUND: Three dimensional echocardiography (3DE) approaches the accuracy of cardiac magnetic resonance in measuring left ventricular (LV) volumes and ejection fraction (EF). The multibeat modality in comparison to single-beat (SB) requires breath-hold technique and regular heart rhythm which could limit the use of this technique in patients with atrial fibrillation (AF) due to stitching artifact. The study aimed to investigate whether SB full volume 3DE acquisition reduces inter- and intraobserver variability in assessment of LV volumes and EF in comparison to four-beat (4B) ECG-gated full volume 3DE recording in patients with AF. METHODS: A total of 78 patients were included in this study. Fifty-five with sinus rhythm (group A) and 23 having AF (group B). 4B and SB 3DE was performed in all patients. LV volumes and EF was determined by these two modalities and inter- and intraobserver variability was analyzed. RESULTS: SB modality showed significantly lower inter- and intraobserver variability in group B in comparison to 4B when measuring LV volumes and EF, except for end-systolic volume (ESV) in intraobserver analysis. There were significant differences when calculating the LV volumes (p<0.001) and EF (p<0.05) with SB in comparison to 4B in group B. CONCLUSION: Single-beat three-dimensional full volume acquisition seems to be superior to four-beat ECG-gated acquisition in measuring left ventricular volumes and ejection fraction in patients having atrial fibrillation. The variability is significantly lower both for ejection fraction and left ventricular volumes

Laboratory Studies of Feeding and Oviposition Preference, Developmental Performance, and Survival of the Predatory Beetle, Sasajiscymnus tsugae on Diets of the Woolly Adelgids, Adelges tsugae and Adelges piceae

The suitability of the balsam woolly adelgid, Adelges piceae Ratzeburg (Hemiptera: Adelgidae) as an alternate mass rearing host for the adelgid predator, Sasajiscymnus tsugae Sasaji and McClure (Coleoptera: Coccinellidae) was studied in the laboratory. This predator is native to Japan and has been introduced to eastern hemlock, Tsuga canadensis (L.) Carrière (Pinales: Pinaceae), forests throughout the eastern United States for biological control of the hemlock woolly adelgid, Adelges tsugae Annand (Hemiptera: Adelgidae), also of Japanese origin. Feeding, oviposition, immature development, and adult long-term survival of S. tsugae were tested in a series of no choice (single-prey) and paired-choice experiments between the primary host prey, A. tsugae, and the alternate host prey, A. piceae. In paired-choice feeding tests, the predator did not discriminate between eggs of the two adelgid species, but in the no choice tests the predator did eat significantly more eggs of A. piceae than those of A. tsugae. S. tsugae accepted both test prey for oviposition and preferred to lay eggs on adelgid infested versus noninfested host plants. Overall oviposition rates were very low (< 1 egg per predator female) in the oviposition preference tests. Predator immature development rates did not differ between the two test prey, but only 60% of S. tsugae survived egg to adult development when fed A. piceae compared to 86% when fed A. tsugae. S. tsugae adult long-term survival was significantly influenced (positively and negatively) by prey type and the availability of a supplemental food source (diluted honey) when offered aestivating A. tsugae sistens nymphs or ovipositing aestivosistens A. piceae adults, but not when offered ovipositing A. tsugae sistens adults. These results suggest that the development of S. tsugae laboratory colonies reared on a diet consisting only of A. piceae may be possible, and that the biological control potential of the predator might be expanded to include management of A. piceae in Christmas tree plantations