Short-term hemodynamic and neuroendocrine effects of pimobendan and benazapril in dogs with myxomatous mitral valve disease and congestive heart failure.

BACKGROUND: Pimobendan and benazepril are frequently used with diuretics to treat dogs in congestive heart failure (CHF) caused by myxomatous mitral valve disease (MMVD). AIM: To compare the short-term effects of pimobendan versus benazepril on pump function, heart size, and neuroendocrine profile in dogs with CHF caused by MMVD. ANIMALS: Sixteen client-owned dogs. MATERIAL AND METHODS: Seven-day prospective single-blinded study of dogs stabilized on furosemide monotherapy, randomized to pimobendan (0.4-0.6 mg/kg/day) or benazepril (0.25-1.0 mg/kg/day). Dogs had first-pass radionuclide angiocardiography, and heart size was measured by radiography and echocardiography. Circulating neuroendocrine hormones were measured. RESULTS: Baseline variables did not differ between treatment groups. Greater decreases in the pimobendan than in the benazepril group were found for heart rate (P = .001), heart rate-normalized pulmonary transit time (P = .02), left atrial size (P = .03), and systolic and diastolic left ventricular diameters (P < .001 and P = .03, respectively) and volumes (P < .001 and P = .02, respectively), whereas ejection fraction increased more (P = .02) in the pimobendan group. Of the neuroendocrine hormones, only N-terminal proatrial natriuretic peptide (NT-ProANP) differed (P = .04) between groups. Within groups, plasma aldosterone increased (P = .01), and NT-proANP (P = .01) and NT-proB-type (P = .02) natriuretic peptide decreased in the pimobendan group, and NT-proANP (P = .02) and plasma vasopressin (P = .01) decreased in the benazepril group. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan improves short-term cardiac function more than benazepril in dogs with CHF caused by MMVD. Pimobendan treatment enables the heart to work at smaller end-systolic and diastolic dimensions while maintaining adequate forward stroke volume. Some of the treatment responses found in neuroendocrine profile might have therapeutic relevance.

Radiographic heart size and its rate of increase as tests for onset of congestive heart failure in Cavalier King Charles Spaniels with mitral valve regurgitation.

BACKGROUND: In canine mitral regurgitation (MR) the rate of heart enlargement increases in the last year before congestive heart failure (CHF). Measurement of heart size and its rate of increase may be useful tests for CHF in MR. OBJECTIVES: To determine the value of vertebral heart scale (VHS) and its rate of increase (∆VHS units/month) for diagnosing the presence and predicting the onset of CHF. ANIMALS: Longitudinal study of 94 Cavalier King Charles Spaniels (CKCS). METHODS: VHS was measured at intervals before CHF. ∆VHS/month was calculated from sequential pairs of VHS measurements and the interval between them. Diagnostic accuracy and utility were determined by the areas under receiver operating characteristic plots (AUROC), and likelihood ratios (LR). RESULTS: AUROC for VHS at the onset of CHF was 0.93 (95% CI, 0.96-0.90), to predict CHF 1-12 months before CHF was 0.74 (95% CI, 0.81-0.66), and for ∆VHS/month at CHF was 0.98 (95% CI, 0.99-0.96). Interval LRs and their cutoff values for CHF were for VHS: 13 (95% CI, 20-7.3) at ≥12.7; 1.2 (95% CI, 2.0-0.68) between 12.7 and 12.0; 0.04 (95% CI, 0.18-0.01) at ≤12.0, and for ∆VHS/month: 15 (95% CI, 30-7.7) at ≥0.08; 0.72 (95% CI, 2.0-0.25) between 0.08 and 0.06; and 0.05 (95% CI, 0.13-0.02) at ≤0.06. CONCLUSIONS AND CLINICAL IMPORTANCE: Under the conditions of this study, VHS and particularly ∆VHS/month are useful measurements for detecting onset of CHF in CKCS with MR.

Minimum Information about a Cardiac Electrophysiology Experiment (MICEE): standardised reporting for model reproducibility, interoperability, and data sharing.

Cardiac experimental electrophysiology is in need of a well-defined Minimum Information Standard for recording, annotating, and reporting experimental data. As a step towards establishing this, we present a draft standard, called Minimum Information about a Cardiac Electrophysiology Experiment (MICEE). The ultimate goal is to develop a useful tool for cardiac electrophysiologists which facilitates and improves dissemination of the minimum information necessary for reproduction of cardiac electrophysiology research, allowing for easier comparison and utilisation of findings by others. It is hoped that this will enhance the integration of individual results into experimental, computational, and conceptual models. In its present form, this draft is intended for assessment and development by the research community. We invite the reader to join this effort, and, if deemed productive, implement the Minimum Information about a Cardiac Electrophysiology Experiment standard in their own work.

Pulmonary blood volume in mitral regurgitation in Cavalier King Charles spaniels.

BACKGROUND: Pulmonary edema and venous congestion are well-recognized signs of congestive heart failure (CHF) in advanced canine chronic mitral regurgitation (MR). However, little is known about pulmonary blood volume (PBV), blood pulmonary transit time (PTT), and the regulation of these. OBJECTIVES: To measure and evaluate the relationships of PBV, forward stroke volume (FSV), and heart rate normalized blood pulmonary transit time (nPTT) in healthy dogs and dogs with MR. ANIMALS: Thirty-three Cavalier King Charles Spaniels; 11 healthy, 4 in modified New York Heart Association (NYHA) class I, 11 in class II, and 7 in CHF. METHODS: Heart rate normalized PTTs were measured by radionuclide angiocardiography. Left ventricular end diastolic and systolic diameter, left atrial/aortic root ratio, and FSV were measured by echocardiography. PBV and pulmonary blood volume index (PBVI) were calculated by established formulas. RESULTS: PBVI was 308±56 (mean±SD) mL/m2 for healthy dogs, 287±51 mL/m2 in NYHA class I, 360±66 mL/m2 in Class II, and 623±232 mL/m2 in CHF (P=.0008). Heart rate normalized PTT, not FSV, was a predictor of PBV (r=0.92 and 0.02, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Increased PBV, not decreased FSV, is the main cause of increased nPTT in MR. Increased nPTT can be used as an indicator of abnormal cardiopulmonary function in dogs with MR.

Rate of change of heart size before congestive heart failure in dogs with mitral regurgitation.

OBJECTIVES: The objective of the study was to examine the changes in vertebral heart scale, and left atrial and ventricular dimensions before and at onset of congestive heart failure in cavalier King Charles spaniels with mitral regurgitation. METHODS: Records and radiographs from 24 cavalier King Charles spaniels with mitral regurgitation were used. Vertebral heart scale (24 dogs), and left atrial dimension and left ventricular end diastolic and end systolic diameters (18 dogs) and their rate of increase were measured at intervals over years to the onset of congestive heart failure. They were plotted against time to onset of congestive heart failure. RESULTS: Dimensions and rates of change of all parameters were highest at onset of congestive heart failure, the difference between observed and chance outcome being highly significant using a two-tailed chi-square test (P<0.001). CLINICAL SIGNIFICANCE: The left heart chambers increase in size rapidly only in the last year before the onset of congestive heart failure. Increasing left ventricular end systolic dimension is suggestive of myocardial failure before the onset of congestive heart failure. Rate of increase of heart dimensions may be a useful indicator of impending congestive heart failure.

Reader performance in radiographic diagnosis of signs of mitral regurgitation in cavalier King Charles spaniels.

OBJECTIVES: To measure accuracy and variability of diagnosis by radiography of heart enlargement (HE) and heart failure (HF) in mitral regurgitation (MR). METHODS: Sixteen readers representing four levels of experience evaluated 50 sets of radiographs with varying severity of MR for presence or absence of HE, left atrial enlargement (LAE) and HF. The performance of the readers was compared with a reference standard, using area under the curve (AUC) of receiver operating characteristic (ROC) curves. The interreader agreement value kappa (K) was calculated. A subset of difficult cases of HF was analysed before and after removing an outlying reader from each group. RESULTS: AUC for HE was 0.89, for LAE it was 0.93 and for HF it was 0.92. Experience increased certainty of diagnosis but not accuracy. K ranges were HE, 0.53 to 0.67; LAE, 0.61 to 0.69 and HF, 0.49 to 0.58. When only difficult cases of HF were read, accuracy decreased and experienced readers performed better than inexperienced. When outlying readers were excluded, the differences between experienced and inexperienced readers increased. CLINICAL SIGNIFICANCE: LAE, not HE, should be used to evaluate the heart size and indirectly the severity of MR on radiographs. For HF, agreement among individual readers was only moderate. Studies of reader accuracy should consider the effects of interreader variability.

Size and shape of right heart chambers in mitral valve regurgitation in small-breed dogs.

BACKGROUND: The contribution of right heart (RH) chamber enlargement to general heart enlargement seen on thoracic radiographs in mitral regurgitation (MR) is not known. OBJECTIVES: To determine the size and shape of the RH chambers in normal dogs and dogs with varying degrees of MR. ANIMALS: Fifty-four privately owned dogs: 13 normal, 41 with varying degrees of MR including 25 with congestive heart failure (CHF). METHODS: Archived first pass radionuclide angiocardiograms were used to produce static images of the RH and left heart (LH) chambers. Indexes of size and shape of the RH and LH chambers were related to severity of MR determined by heart rate-normalized pulmonary transit time (nPTT), vertebral heart scale (VHS), and clinical status. RH shape was measured by a circularity index of RH short axis/long axis. RESULTS: A 2nd degree polynomial fit best described the ratios; RH/LH dimension to nPTT (R(2)= 0.62) and to VHS (R(2)= 0.43), RH/LH area to nPTT (R(2)= 0.64) and to VHS (R(2)= 0.58), all P < .001. RH circularity was decreased in CHF, P < .001. In CHF, the RH chambers of 16 dogs were both flattened and enlarged, whereas 9 had convex septal borders. CONCLUSIONS: RH chambers are not significantly dilated in dogs with mild to moderate MR without CHF. In CHF, RH chambers enlarge and also may be compressed by the LH chambers. Pulmonary hypertension probably is present in some dogs with CHF. Increased sternal contact is not a useful sign of right-sided heart dilatation in MR.

The (my)Grid ontology: bioinformatics service discovery.

(my)Grid supports in silico experiments in the life sciences, enabling the design and enactment of workflows as well as providing components to assist service discovery, data and metadata management. The (my)Grid ontology is one component in a larger semantic discovery framework for the identification of the highly distributed and heterogeneous bioinformatics services in the public domain. From an initial model of formal OWL-DL semantics throughout, we now adopt a spectrum of expressivity and reasoning for different tasks in service annotation and discovery. Here, we discuss the development and use of the (my)Grid ontology and our experiences in semantic service discovery.

Protein classification using ontology classification.

MOTIVATION: The classification of proteins expressed by an organism is an important step in understanding the molecular biology of that organism. Traditionally, this classification has been performed by human experts. Human knowledge can recognise the functional properties that are sufficient to place an individual gene product into a particular protein family group. Automation of this task usually fails to meet the 'gold standard' of the human annotator because of the difficult recognition stage. The growing number of genomes, the rapid changes in knowledge and the central role of classification in the annotation process, however, motivates the need to automate this process. RESULTS: We capture human understanding of how to recognise members of the protein phosphatases family by domain architecture as an ontology. By describing protein instances in terms of the domains they contain, it is possible to use description logic reasoners and our ontology to assign those proteins to a protein family class. We have tested our system on classifying the protein phosphatases of the human and Aspergillus fumigatus genomes and found that our knowledge-based, automatic classification matches, and sometimes surpasses, that of the human annotators. We have made the classification process fast and reproducible and, where appropriate knowledge is available, the method can potentially be generalised for use with any protein family. AVAILABILITY: All components described in this paper are freely available. OWL ontology http://www.bioinf.man.ac.uk/phosphabase myGrid http://www.mygrid.org.uk Instance Store http://instancestore.man.ac.uk.

Ontology driven dynamic linking of biology resources.

Biologists were early adopters of the Web and continue to use it as the primary means of delivering data, tools and knowledge to their community. The Web is made by the links between pages, yet these links have many limitations: they are static and maintained by hand; they can only link one lexical item to another single resource; ownership is necessary for the placement of link anchors and the link mechanism is essentially inflexible. Dynamic linking services, supported by ontologies, offer a mechanism to overcome such restrictions. The Conceptual Open Hypermedia Service (COHSE) system enhances web resources through the dynamic addition of hypertext links. These links are derived through the use of an ontology and associated lexicon along with a mapping from concepts to possible link targets. We describe an application of COHSE to Bioinformatics, using the Gene Ontology (GO) as an ontology and associated keyword mappings and GO associations as link targets. The resulting demonstrator (referred to here as GOHSE) provides both glossary functionality and the possibility of building knowledge based hypertext structures linking bioinformatics resources.

Relationship between scintigraphic and radiographic evaluations of spinous processes in the thoracolumbar spine in riding horses without clinical signs of back problems.

REASONS FOR PERFORMING STUDY: Radiography and scintigraphy are used to aid diagnosis of the cause of back pain, but a large variation in appearance and radiopharmaceutical uptake in fully functioning horses make diagnosis difficult. OBJECTIVES: To describe the range of and compare scintigraphic and radiographic findings in the spinous processes of horses without clinical signs of back problems. METHODS: Thirty-three apparently normal riding horses underwent scintigraphic and radiographic examinations of the spinous processes in the thoracolumbar spine. Scintigraphic images were evaluated in a continuous blue, green and red colour scale, and the level of radiopharmaceutical uptake in the spinous processes from T10-L2 was graded into none, mild, moderate or severe increased radiopharmaceutical uptake. Structural changes along the borders of the spinous processes and the width of the interspinous spaces from T10-L2 were recorded. RESULTS: Only 7 horses had no scintigraphic or radiographic findings. Nine horses had no increased radiopharmaceutical uptake, 17 had no sclerosis, 21 had no radiolucencies and 11 had normal spacing of the spinous processes (>4 mm wide). The majority of findings in 26 horses were located from T13-18 and were mild. CONCLUSIONS: The findings of a wide spectrum of scintigraphic and radiographic changes leads to the conclusion that changes within this range found in affected horses cannot be interpreted as clinically significant. POTENTIAL RELEVANCE: To determine whether scintigraphy and/or radiography can be used to separate horses with back pain from horses without clinical signs, the results from this study should be compared to the scintigraphic and radiographic findings in horses with clinical signs.

Exploring Williams-Beuren syndrome using myGrid.

MOTIVATION: In silico experiments necessitate the virtual organization of people, data, tools and machines. The scientific process also necessitates an awareness of the experience base, both of personal data as well as the wider context of work. The management of all these data and the co-ordination of resources to manage such virtual organizations and the data surrounding them needs significant computational infra-structure support. RESULTS: In this paper, we show that (my)Grid, middleware for the Semantic Grid, enables biologists to perform and manage in silico experiments, then explore and exploit the results of their experiments. We demonstrate (my)Grid in the context of a series of bioinformatics experiments focused on a 1.5 Mb region on chromosome 7 which is deleted in Williams-Beuren syndrome (WBS). Due to the highly repetitive nature of sequence flanking/in the WBS critical region (WBSCR), sequencing of the region is incomplete leaving documented gaps in the released sequence. (my)Grid was used in a series of experiments to find newly sequenced human genomic DNA clones that extended into these 'gap' regions in order to produce a complete and accurate map of the WBSCR. Once placed in this region, these DNA sequences were analysed with a battery of prediction tools in order to locate putative genes and regulatory elements possibly implicated in the disorder. Finally, any genes discovered were submitted to a range of standard bioinformatics tools for their characterization. We report how (my)Grid has been used to create workflows for these in silico experiments, run those workflows regularly and notify the biologist when new DNA and genes are discovered. The (my)Grid services collect and co-ordinate data inputs and outputs for the experiment, as well as much provenance information about the performance of experiments on WBS. AVAILABILITY: The (my)Grid software is available via http://www.mygrid.org.uk

High detail radiography and histology of the centrodistal tarsal joint of Icelandic horses age 6 months to 6 years.

REASONS FOR PERFORMING STUDY: Osteoarthrosis (OA) in the distal tarsal joints, bone spavin, is a well known condition which is common in Icelandic horses age 6-12 years. OBJECTIVES: To determine the nature, location and age of appearance of early radiographic and histological changes in the centrodistal tarsal joint (CD) of young Icelandic horses. METHODS: Slab sections from the CD of young Icelandic horses were examined by high detail radiography (age 6 months to 6 years, n = 111) and histology (age 6 months to 4 years, n = 82) to detect and describe the early changes indicative of OA. Horses younger than 5 years were unridden. RESULTS: Chondronecrotic lesions histologically similar to those described in the early pathogenesis of OA were seen in 33% of the joints, located both medially and laterally. Radiographic sclerosis of the subchondral bone was recorded in 60% of the specimens, most often medially. Medial location was not associated with chondronecrosis, but was strongly related to age. Sclerosis was an infrequent finding on the lateral side, and was probably secondary to chondronecrosis in the corresponding part of the joint. Small defects in the subchondral bone were considered to be the most specific radiographic sign of OA as they were strongly associated with chondronecrosis. CONCLUSIONS: The high prevalence of chondronecrosis in the young horses indicates an early onset and slow progression of the disease. The early appearance also shows that the initiation of the disease is unrelated to the use of horses for riding. As clinical manifestation of OA in the distal tarsal joints is most often described in mature or old horses, the first stages of the disease are not likely to result in clinical signs. Subchondral bone sclerosis did not appear to be a primary factor in the development of OA in the CD but was considered to reflect an uneven distribution of biomechanical forces within the joint. POTENTIAL RELEVANCE: The development of OA in the CD of young Icelandic horses seems to be due to poor conformation or joint architecture rather than trauma or overloading. These aetiological factors are likely to be of importance for OA in the distal tarsal joints in other breeds as well. The influence of hindlimb conformation and the architecture of the distal tarsal joints on the biomechanics of joints need to be investigated, preferably by locomotion analysis in young horses.

Investigating semantic similarity measures across the Gene Ontology: the relationship between sequence and annotation.

MOTIVATION: Many bioinformatics data resources not only hold data in the form of sequences, but also as annotation. In the majority of cases, annotation is written as scientific natural language: this is suitable for humans, but not particularly useful for machine processing. Ontologies offer a mechanism by which knowledge can be represented in a form capable of such processing. In this paper we investigate the use of ontological annotation to measure the similarities in knowledge content or 'semantic similarity' between entries in a data resource. These allow a bioinformatician to perform a similarity measure over annotation in an analogous manner to those performed over sequences. A measure of semantic similarity for the knowledge component of bioinformatics resources should afford a biologist a new tool in their repertoire of analyses. RESULTS: We present the results from experiments that investigate the validity of using semantic similarity by comparison with sequence similarity. We show a simple extension that enables a semantic search of the knowledge held within sequence databases. AVAILABILITY: Software available from http://www.russet.org.uk.

Scintigraphic evaluation of the thoracic spine in the asymptomatic riding horse.

Scintigraphic evaluation of the spinous processes of the equine spine has been done by subjective evaluation of radiotracer uptake in clinically abnormal horses. To determine the range of variation in asymptomatic riding horses, 33 normal horses were examined. Two 60 degrees oblique views of the thoracic and lumbar spine were evaluated subjectively, and a semi quantitative method based on standardized regions of interest in each spinous process in T10-L3 was also applied. A ratio between each spinous process and a reference area (Rib 15 or 16) was calculated. The effects of two different color displays and a smoothing filter were assessed. The results of the subjective evaluation was compared to the calculated ratios, and the associations between age, gender, weight, height, use and increased radiotracer uptake, and ratios were analyzed. No significant association was found between age, gender, weight, height, use and increased radiotracer uptake, or ratio. One or more areas of increased radiotracer uptake between T13 and T18 were common in the asymptomatic riding horse, which may have implications for the interpretation of clinical patients. The blue, green and red color display had a higher sensitivity for detecting increased radiotracer uptake compared to the continuous grayscale. The smoothing filter used in this study had no effect on the detection of areas with increased radiotracer uptake. The association between the results of the subjective evaluation and the semi quantitative method was apparent when analyzed in T13-17. To evaluate if the semi quantitative method can replace the subjective evaluation, studies on clinically affected horses are necessary.

Pulmonary oedema in Swedish hunting dogs.

A syndrome of acute dyspnoea after hunting in 16 Swedish hunting dogs is characterised. Radiographic pulmonary infiltrates interpreted as pulmonary oedema were found in the acute stage. In 12 dogs, the infiltrates regressed after five to 14 days. Subendocardial necrosis and pulmonary oedema were found at postmortem examination in four other dogs with acute and recurrent dyspnoea after hunting, and myocardial fibrosis in a further three dogs with a history of recurrent dyspnoea after hunting; none of these pathological changes was seen in dogs which had no previous history of dyspnoea after hunting. A pathogenetic mechanism is proposed whereby high catecholamine levels, present during hunting due to the stress of excitement and exercise, cause acute cardiac and pulmonary lesions in some susceptible dogs, similar to neurogenic or postictal pulmonary oedema.

Day-to-day variability in glomerular filtration rate in normal dogs by scintigraphic technique.

The sources of variability in variability of scintigraphic measurements of glomerular filtration rate (GFR) have not been determined. The day to day variability of GFR was studied in 18 healthy beagle dogs. The renal uptake of 99mTc-diethylenetriaminepentaacetic acid (DTPA) of each dog was measured using a scintigraphic technique three times at intervals of 5-26 days. GFR was calculated from a regression equation relating uptake to plasma clearance, derived in our laboratory. The mean GFR was 3.97 +/- 0.72 (SD) ml/min/kg with values from 2.66 to 5.67 ml/min/kg. Analysis of variance (ANOVA) using a linear mixed model showed that most variability is a result of the dogs, less because of day to day variability and very little to the measurement variability. The repeatability coefficients for the day to day variability and measurement variability were 1.06 and 0.21 ml/min/kg respectively. The day to day variability can be caused by physiological homeostatic adjustments by the kidneys needed because of fluctuations in food and fluid intake, each dog's individual capacity to adjust, and to intrinsic errors in the measurement method. These results should be considered when using the scintigraphic method for clinical evaluation and research.

Semantic similarity measures as tools for exploring the gene ontology.

Many bioinformatics resources hold data in the form of sequences. Often this sequence data is associated with a large amount of annotation. In many cases this data has been hard to model, and has been represented as scientific natural language, which is not readily computationally amenable. The development of the Gene Ontology provides us with a more accessible representation of some of this data. However it is not clear how this data can best be searched, or queried. Recently we have adapted information content based measures for use with the Gene Ontology (GO). In this paper we present detailed investigation of the properties of these measures, and examine various properties of GO, which may have implications for its future design.

Culling rate of Icelandic horses due to bone spavin.

A survival analysis was used to compare the culling rate of Icelandic horses due to the presence of radiographic and clinical signs of bone spavin. A follow-up study of 508 horses from a survey five years earlier was performed. In the original survey 46% of the horses had radiographic signs of bone spavin (RS) and/or lameness after flexion test of the tarsus. The horse owners were interviewed by telephone. The owners were asked if the horses were still used for riding and if not, they were regarded as culled. The owners were then asked when and why the horses were culled. During the 5 years, 98 horses had been culled, 151 had been withdrawn (sold or selected for breeding) and 259 were still used for riding. Hind limb lameness (HLL) was the most common reason for culling (n = 42). The rate of culling was low up to the age of II years, when it rose to 0.05 for horses with RS. The risk ratio for culling was twice as high for horses with RS compared with horses without RS and 5.5 times higher for culling because of HLL. The risk of culling (prognostic value) was highest for the combination of RS with lameness after flexion test, next highest for RS and lowest for lameness after flexion test as the only finding. It was concluded that bone spavin affects the duration of use of Icelandic horses and is the most common cause of culling due to disease of riding horses in the age range of 7-17 years.

CINEMA-MX: a modular multiple alignment editor.

UNLABELLED: Analyzing and visualizing multiple sequence alignments is a common task in many areas of molecular biology and bioinformatics. Many tools exist for this purpose, but are not easily customizable for specific in-house uses. Here we report the development of an editor, CINEMA-MX, that addresses these issues. CINEMA-MX is highly modular and configurable, and we present examples to illustrate its extensibility. AVAILABILITY: The program and full source code, which are available from http://www.bioinf.man.ac.uk/dbbrowser/cinema-mx, are being released under a combination of the LGPL and GPL, for Unix or Windows platforms.