SNP-based heritability and genetic architecture of cranial cruciate ligament rupture in Labrador Retrievers.

Cranial cruciate ligament rupture (CCLR) is one of the leading causes of pelvic limb lameness in dogs. About 6% of Labrador Retrievers suffer from this orthopedic problem. The aim of this study was to determine the heritability of CCLR in this breed using SNP array genotyping data. DNA samples were collected from CCLR-affected dogs (n = 190) and unaffected dogs over the age of 8 years (n = 143). All 333 dogs were genotyped directly or imputed up to approximately 710k SNPs on the Affymetrix Axiom CanineHD SNP array. Heritability of CCLR was calculated using multiple methodologies, including linear mixed models, Bayesian models and a model that incorporates LD. The covariates of sex and sterilization status were added to each analysis to assess their impact. Across the algorithms of these models, heritability ranged from 0.550 to 0.886, depending on covariate inclusion. The relatively high heritability for this disease indicates that a substantial genetic component contributes to CCLR in the Labrador Retriever.

Measurement of chronic pain in companion animals: Priorities for future research and development based on discussions from the Pain in Animals Workshop (PAW) 2017.

The estimation of long-standing pain in companion animals through the measurement of different dimensions impacted by pain is a fundamental requirement if pain management, and pain therapeutic development, are to advance. Although pain management in veterinary medicine has advanced considerably in the last 20 years, there is much critical work to do in the area of measurement of chronic pain. To date, most work has centered on musculoskeletal pain, and has been focused around the measurement of limb use and the development of owner-completed questionnaires, or clinical metrology instruments (CMI). Recent areas of research have extended to developing measures of activity, sensory function (quantitative sensory testing; nociceptive withdrawal reflexes), and quality of life (QoL). Across all these areas, more data on validity are needed, and studies should be extended to other painful disease states. By necessity, assessing measurement tools requires testing in field studies, which incur considerable time and expense. Facilitating these studies could be optimized with a collaborative (industry, academia and private practice) approach, and the utility of the information produced from all field studies would be enhanced by full and transparent reporting and data sharing, including data already generated by industry in the form of studies submitted to the regulatory authorities.

Measurement of chronic pain in companion animals: Discussions from the Pain in Animals Workshop (PAW) 2017.

In the face of increasing recognition and interest in treating chronic pain in companion animals, we struggle with a lack of therapeutic options. A significant barrier to the development of new therapeutics, or the critical evaluation of current therapies, is our inability to accurately measure chronic pain and its impact on companion animals. Over the last 20 years, much progress has been made in developing methods to measure chronic pain via subjective and objective methods - particularly in owner assessment tools and measurements of limb use and activity. Most work has been focused on chronic joint pain conditions, but there has been relatively little work in other areas of chronic pain, such as neuropathic and cancer pain. Although progress has been made, there is a considerable interest in improving our assessment of chronic pain, as evidenced by the multiple disciplines across industry, academia, and clinical practice from the veterinary and human medical fields that participated in the Pain in Animals Workshop held at the National Institutes of Health in 2017. This review is one product of that meeting and summarizes the current state of knowledge surrounding the measurement of chronic pain (musculoskeletal, cancer, neuropathic), and its impact, in cats and dogs.

Evaluation of the effect of signalment and owner-reported impairment level on accelerometer-measured changes in activity in osteoarthritic dogs receiving a non-steroidal anti-inflammatory.

In veterinary medicine, evaluation of osteoarthritis (OA) treatment efficacy remains challenging. Measurement of activity, utilizing accelerometers, provides a surrogate measure of pain through measuring effects on activity, and the objective data collected can be used to assess the efficacy of treatments. However, little is known about how dog characteristics impact the accelerometry-measured response to treatment. The objectives of this study were to evaluate the effect of signalment and initial impairment level on accelerometer-measured changes in activity in osteoarthritic dogs after receiving a non-steroidal anti-inflammatory (NSAID). Fifty-seven client-owned dogs with OA-associated pain and mobility impairment were administered meloxicam for 2 weeks, following a 2-week baseline, and spontaneous activity was measured using an Actical accelerometer unit. Signalment factors and disease variables were recorded (age, sex, weight, impairment level, forelimb or hindlimb pain). Initial degree of impairment had a significant effect on changes in weekly (P=0.009), weekday (P=0.044) activity following NSAID treatment. Greater initial impairment was associated with larger positive changes in activity. Degree of impairment should be taken into consideration during the development of a clinical trial. Appropriate selection of candidates based on initial degree of impairment may permit a greater treatment effect, therefore increasing the power of the study.

Quality assurance and best research practices for non-regulated veterinary clinical studies.

Veterinary clinical trials generate data that advance the transfer of knowledge from clinical research to clinical practice in human and veterinary settings. The translational success of non-regulated and regulated veterinary clinical studies is dependent upon the reliability and reproducibility of the data generated. Clinician-scientists that conduct veterinary clinical studies would benefit from a commitment to research quality assurance and best practices throughout all non-regulated and regulated research environments. Good Clinical Practice (GCP) guidance documents from the FDA provides principles and procedures designed to safeguard data integrity, reliability and reproducibility. While these documents maybe excessive for clinical studies not intended for regulatory oversight it is important to remember that research builds on research. Thus, the quality and accuracy of all data and inference generated throughout the research enterprise remains vulnerable to the impact of potentially unreliable data generated by the lowest performing contributors. The purpose of this first of a series of statement papers is to outline and reference specific quality control and quality assurance procedures that should, at least in part, be incorporated into all veterinary clinical studies.

Gene expression profiling demonstrates differential expression of osteopontin in follicular thyroid carcinomas compared to normal thyroid tissue in dogs.

Follicular thyroid carcinoma (FTC) is an aggressive tumour in dogs with little known about its molecular pathogenesis. The overall goal of this study was to examine FTC and normal thyroid tissue gene expression. Microarray analysis was performed on a pilot group of five FTC-affected dogs and four healthy dogs, and then osteopontin validated with quantitative polymerase chain reaction (PCR) and immunohistochemistry (IHC) of thyroid tissue from non-invasive FTC, invasive FTC and healthy dogs. On microarray analysis, 489 transcripts were differentially expressed between FTC and normal thyroid: 242 transcripts were down-regulated and 247 were up-regulated. Osteopontin expression was markedly increased in tumour tissue compared to normal thyroid tissue. Quantitative PCR and IHC confirmed differential expression of osteopontin in both tumour types (invasive and non-invasive) compared to normal thyroid tissue. There is justification for further investigation of osteopontin as a potential molecular marker for screening and monitoring of canine FTC.

Prevalence of incomplete ossification of the humeral condyle in the limb opposite humeral condylar fracture: 14 dogs.

OBJECTIVE: The objectives of this study were to determine the frequency of incomplete ossification of the contralateral humeral condyle (IOHC) in mature dogs with unilateral, atraumatic humeral condylar fracture (HCF), and to determine the sensitivity of radiographs as a diagnostic tool for IOHC. METHODS: Computed tomography and radiographs were obtained for both elbows of 14 dogs with unilateral HCF. The images were evaluated by two boarded radiologists and the prevalence of IOHC in the limb contralateral to the HCF was identified. Sensitivity and specificity of the radiographic diagnosis of IOHC were determined. RESULTS: Incomplete ossification of the humeral condyle was present in six of 14 dogs, however IOHC was incomplete in three of the six affected dogs. Plain radiographs had a sensitivity of 0.83 (CI 95%: 0.36 to 0.99) and specificity of 1 (CI 95%: 0.60 to1). The Kappa coefficient between radiologists for radiographic examination was 0.714. Of the Spaniel breeds, four out of eight had IOHC in the limb contralateral to the HCF. CLINICAL SIGNIFICANCE: Computed tomography evaluation is more sensitive than radiographs for diagnosis of IOHC, particularly when assessing partial or incomplete IOHC. However, sensitivity of radiographic diagnosis is good and should be adequate in most cases. Clinical suspicion of IOHC in the contralateral limb to the unilateral HCF should be present; however overall frequency may not be as high as previously reported.

Comparison of three methods for the management of fragmented medial coronoid process in the dog. A systematic review and meta-analysis.

The objective of this review and analysis was to compare arthroscopy, medial arthrotomy and medical management for treating fragmented coronoid process in the dog. The data come from manuscripts published in peer-reviewed veterinary journals, and the study design is a systematic review followed by meta-analysis. The meta-analysis combines data from a set of studies so that surgical techniques and medial management can be compared in a single analysis. Several literature databases and veterinary texts were thoroughly searched to provide a list of over 400 candidate manuscripts. Inclusion criteria were used to filter the candidate manuscripts to a final set of four manuscripts that directly pertained to the clinical question. They were scored for their evidentiary value using a semi-objective measure. The results were that arthroscopy was superior to medial arthrotomy and medical management, but medial arthrotomy was not superior to medical management. Only one manuscript was a randomized controlled trial, hence the results must be tempered by the evidentiary value of the data.

The evaluation of extracorporeal shockwave therapy in naturally occurring osteoarthritis of the stifle joint in dogs.

Extracorporeal shockwave therapy (ESWT) has expanded from the original uses of human urinary calculi treatment to veterinary orthopaedic applications. This paper investigates the feasibility and efficacy of treating dogs with osteoarthritis of the stifle joint with ESWT. In this study, dogs with persistent stifle lameness despite previous surgical or medical treatment were either treated with ESWT or served as untreated controls. The more lame rear limb of each dog was determined by force platform analysis. The range of motion (ROM) of the stifle joints was assessed by goniometry. Force platform gait analysis and goniometry were performed on both groups for four visits at three-week intervals and a final examination four weeks later. Shock wave therapy was performed three times on the treated dogs, once at each of the first three examinations. A placebo treatment consisting of clipping and wetting the hair was performed on the control dogs. The vertical forces were evaluated for objective analysis of treatment response. For peak vertical force (PVF), four of seven treated dogs improved, while only one of five of control dogs improved. The PVF for the within group analysis did not show any significant change for the treated group, however, the control group has a significant decrease (p = 0.05) in PVF consistent with an increase in lameness. The range of motion (ROM) of the stifle joint improved in five of seven treated dogs and three of five controls. Dogs in the treated group had a trend toward increased ROM (p = 0.07) and a 'positive slope' when compared to dogs in the control group which did not have a significant change (p = 0.78) and had a negative slope indicating the dogs were developing a decrease in ROM. The subjective data provided by client questionnaire did not show significant difference between groups.

Evaluation of a canine total-elbow arthroplasty system: a preliminary study in normal dogs.

OBJECTIVE: Short-term, in vivo evaluation of a total-elbow arthroplasty (TEA) system in normal dogs. STUDY DESIGN: Prospective evaluation comparing pre- and postoperative findings. ANIMALS: Six normal, skeletally mature, large-breed dogs. METHODS: Physical, radiographic, and force-plate gait examinations were performed on all dogs before surgery. TEA was performed in the dogs using a canine TEA system. Examinations were repeated every 8 weeks for 24 weeks, with an additional examination at 52 weeks. Pre- and postoperative findings were compared. RESULTS: The TEA led to an excellent outcome in 3 of 6 dogs. Force-plate gait examination found that the dogs continued to improve over time and had a peak vertical force (PVF) in the surgical limb that was 99.6% of normal (range, 95.8% to 106.4%) 52 weeks after surgery. Major problems encountered during the postoperative time period were non-weight-bearing lameness (1 dog), osteomyelitis (1 dog), and fracture of the ulna (1 dog). CONCLUSIONS: TEA can be successfully performed in dogs. CLINICAL RELEVANCE: Based on 1-year data, TEA can be successfully performed in dogs and could be considered as a treatment alternative for adult dogs with severe osteoarthritis and lameness of the elbow joint.

Effects of treatment with growth hormone and somatostatin on efficacy of diammine [1,1-cyclobutane dicarboxylato (2-)-0,0']-(SP-4-2) in athymic rats with osteosarcoma.

OBJECTIVE: To determine the effect of exogenous growth hormone or somatostatin on chemotherapeutic efficacy in athymic (nude) rats with osteosarcoma. ANIMALS: 66 female athymic rats. PROCEDURE: Osteosarcoma was induced at an intratibial site. Rats were randomly allotted to 6 treatment groups. Rats were treated with saline (0.9% NaCl) solution alone, platinum, diammine [1,1-cyclobutane dicaboxylato (2-)-0,0']-(SP-4-2) (CBDCA; ie, carboplatin) plus saline solution, somatostatin alone, somatostatin plus CBDCA, growth hormone alone, or growth hormone plus CBDCA. Variables measured included estimated WBC count and percentage of neutrophils, plasma concentration of insulin-like growth factor I (IGF-I), body weight, tumor volume, weight of primary tumor, survival time, and distant metastasis at time of death. RESULTS: Tumors formed at the injection sites in all rats. Treatment with growth hormone increased, and treatment with somatostatin decreased, plasma IGF-I concentration. Treatment with growth hormone or somatostatin altered CBDCA efficacy, as determined by evaluation of mean and median survival times. Metastatic pulmonary disease developed in 63 of 64 rats. CONCLUSIONS AND CLINICAL RELEVANCE: The technique used here reliably induced local osteosarcomas and metastatic pulmonary disease. Treatment with growth hormone and CBDCA or somatostatin may improve chemotherapeutic efficacy without increasing toxic effects. IMPLICATIONS FOR HUMAN MEDICINE: Results reported here may be useful in the study of osteosarcoma in humans.

Effect of public symphysiodesis on pelvic development in the skeletally immature greyhound.

OBJECTIVE: To evaluate the effect of pubic symphysiodesis (PS) on pelvic development in skeletally immature dogs. STUDY DESIGN: Prospective randomized clinical trial. ANIMALS: Eight 4 month-old, sexually intact female Greyhounds. METHODS: Initial PS was performed at 4 months of age using a powered stapling device. Because of failure of the initial surgery, a second PS was performed 1 month later by resecting the pubic symphysis with a rongeur followed by placement of handmade bone staples in four dogs. Sham PS was performed in four control dogs at 4 months of age. Pubic growth rate and pelvic development were evaluated using standard plane radiography and computed tomography. Specific measurements included acetabular ventroversion, Norberg angle, lateral center-edge angle, and pelvic inlet dimensions. Hip distraction indices were determined as well. RESULTS: PS at 4 months of age using a stapling device failed. Pubic symphysiodesis using hand made staples was successful at 5 months of age and did not result in any clinically significant intraoperative or postoperative complications. Pubic symphysiodesis markedly decreased pubic symphysis growth in the treatment group. Hip distraction indices and pelvic inlet circumference, area, and width significantly decreased in treated dogs compared to those in the control group. Acetabular ventroversion was significantly increased in treated dogs compared to those in the control group. CONCLUSIONS: PS decreases pelvic canal size, increases acetabular ventroversion, and does not appear to have any clinically significant complications. CLINICAL RELEVANCE: PS performed in skeletally immature dogs with hip dysplasia may provide an effect similar to a triple pelvic osteotomy and warrants further investigation.

Fracture fixation with screws and bone plates.

The treatment goal of fracture fixation is to restore the patient to normal function as quickly as possible. Fracture fixation can be accomplished by various means; fixation with screws and bone plates is not only a popular but a successful technique. In this article, the authors provide concepts that a surgeon must understand for successful screw and bone plate use. In addition, case examples demonstrating the application of many of the concepts are included.

Relationships between results of the Ortolani method of hip joint palpation and distraction index, Norberg angle, and hip score in dogs.

OBJECTIVE: To determine whether results of the Ortolani method of hip joint palpation in dogs were related to distraction index (DI), Norberg angle, or radiographic hip score. DESIGN: Cross-sectional study. ANIMALS: 459 clinically normal dogs. PROCEDURE: Dogs were sedated for radiography and palpation of the hip joints. Results of hip joint palpation were classified as negative, mild positive, moderate positive, or severe positive. Distraction indices were measured for all dogs. Norberg angles were measured for 380 dogs for which ventrodorsal hip-extended radiographic projections were available. Hip scores assigned by the Orthopedic Foundation for Animals (OFA) were available for 95 dogs. RESULTS: Age, weight, and sex were not significantly associated with results of hip joint palpation. There was moderate correlation between results of hip joint palpation and DI (r = 0.636), low-moderate correlation between results of hip joint palpation and OFA hip scores (rs = 0.437), and weak negative correlation (r = -0.236) between results of hip joint palpation and Norberg angle. For joints without degenerative joint disease (DJD), there was a significant linear relationship between results of hip palpation and DI; however, for joint with DJD, there was not. Results of hip joint palpation were 5.3-fold as likely to be negative for dogs with DJD as for dogs without. CLINICAL IMPLICATIONS: Results of hip joint palpation were at best moderately correlated with radiographic measures of hip joint laxity. Therefore, hip joint palpation should be combined with hip-extended and stress radiography when assessing hip joint quality.

Correlation between longitudinal bone growth, growth hormone, and insulin-like growth factor-I in prepubertal dogs.

OBJECTIVE: To determine the association between longitudinal bone growth and concentrations of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in serum from prepubertal dogs. Animals-6 male 14-week-old German Shepherd Dogs. PROCEDURE: Blood was obtained every 30 minutes for 14 consecutive days. Concentrations of GH and IGF-I in serum were determined, using a canine-specific radioimmunoassay and conventional radioimmunoassay after acid-ethanol extraction, respectively. Simultaneous biplanar radiography was performed daily to measure bone growth. Spectral analysis was used to estimate specific features of GH secretion during an extended period. Multiple linear regression with different lag times between independent and dependent variables was used to determine the strongest predictors of bone growth. RESULTS: The power spectra of GH concentrations in serum had a primary peak at a frequency of 0.02 cycles/h or a periodicity of 50 h/cycle. A significant determinant of longitudinal bone growth was a lag time of 1 day in concentration of GH in serum. The relationship between IGF-I concentration in serum and bone growth was not significant. CONCLUSIONS: The primary frequency of GH secretion is outside the time frame of a single day and the concentration of GH in serum is a primary determinant of bone growth. CLINICAL RELEVANCE: A better understanding of the components of bone growth provide discernment to improved diagnosis and treatment of abnormal bone growth.

Correlation between subjective and objective measures used to determine severity of postoperative pain in dogs.

OBJECTIVE: To determine the association between subjective and objective variables commonly used to evaluate severity of postoperative pain in dogs. DESIGN: Prospective double-blind study. ANIMALS: 36 dogs with unilateral rupture of the cranial cruciate ligament that underwent surgery to stabilize the stifle. PROCEDURE: Each dog was assessed to determine severity of pain before and after surgery, using various subjective and objective criteria. RESULTS: Subjective measures of pain (scores for visual analogue and numerical rating scales) correlated poorly or were not correlated with heart rate, respiratory rate, blood pressure, and results of a pain threshold test. Scores for visual analogue and numerical rating scales correlated with each other and with the amount of vocalization at most time periods. CLINICAL IMPLICATIONS: We detected a weak association between commonly employed subjective and objective measures of pain. This indicated that some of these measurement techniques do not predictably reflect severity of postoperative pain in dogs. Therefore, clinicians should not rely too heavily on these variables when assessing severity of postoperative pain in dogs.

Epidemiologic evaluation of postoperative wound infections in dogs and cats.

OBJECTIVE: To determine postoperative wound infection rates in dogs and cats for various wound contamination categories and to identify factors that influence postoperative wound infection rates. DESIGN: Epidemiologic study. SAMPLE POPULATION: 1,574 wounds in 1,255 dogs and cats. PROCEDURE: Information recorded included signalment, nutritional status, surgery duration, surgical procedures, wound contamination classification, interval from clipping until surgery, blood pressure values, active infection at a distant site, endocrinopathy, and administration of immunosuppressive medications or antibiotics. Relative risk, 95% confidence intervals, and multiple regression analyses were performed. RESULTS: Postoperative infection was evident in 86 of 1,574 (5.5%) wounds, including 54 of 1,146(4.7%) and 13 of 259 (5.0%) animals with clean and clean-contaminated wounds respectively, and 12 of 100 (12.0%) and 7 of 69 (10.1%) animals with contaminated and dirty wounds, respectively. Animals with clean wounds that received antibiotics other than as prescribed in our perioperative protocol had a higher infection rate than animals that did not receive antibiotics. Surgical sites clipped before anesthetic induction were 3 times more likely to become infected than sites clipped after induction. Risk of wound infection increased with increasing duration of surgery. CLINICAL IMPLICATIONS: Wound contamination categories had too much variation to make them useful for predicting animals that would develop wound infections. Surgical sites should be clipped immediately prior to surgery, and intraoperative time should be kept to a minimum. Unless indicated for other current active infection, prolonged use of antibiotics after surgery should be avoided in animals with clean wounds.

Omentum-enhanced reconstruction of chronic nonhealing wounds in cats: techniques and clinical use.

The greater omentum was used to aid in the reconstruction of nonhealing wounds in five cats. In each cat the cause of the nonhealing wound could not be determined. A vascular omental pedicle was created at laparotomy by dividing the dorsal leaf of the omentum at it pancreatic attachments (four cats) or by dividing the ventral leaf at its gastric attachments (one cat). The pedicle was then passed through either the ventral or lateral body wall into the nonhealing wound via a subcutaneous tunnel. The wounds were closed over the omentum after local tissue mobilization. All the wounds healed uneventfully and have remained healed with a mean follow-up period of 2.5 years. Complications included intestinal herniation through a ventral midline exit hole (one cat), presumed abdominal fat herniation through a ventral abdominal exit hole (one cat) and seroma formation (one cat). All of the complications were treated successfully. The omentum should be considered a useful adjunct in the treatment of nonhealing wounds in cats.

Postoperative analgesia for stifle surgery: a comparison of intra-articular bupivacaine, morphine, or saline.

A prospective study was undertaken to compare the analgesic effect of intra-articular bupivacaine, morphine, or saline in the 24-hour period following cranial cruciate ligament repair in dogs. Thirty-six clinical patients with ruptured cranial cruciate ligaments were randomly assigned to one of three groups. After surgical stabilization, and before skin closure, an intra-articular injection was given; group one (n = 12) received 0.5% bupivacaine HCl at 0.5 mL/kg, group two (n = 12) received morphine at 0.1 mg/kg diluted with saline to a volume of 0.5 mL/kg, and group three (n = 12) received saline at 0.5 mL/kg. Heart rate, respiratory rate, mean arterial blood pressure, cumulative pain score, visual analog pain score, and pain threshold test on both stifles were recorded preoperatively and at 0 to 6 and 24 hours postoperatively. Surgeons and pain scoring investigators were unaware of the intra-articular medication given. Supplemental analgesia, if needed, was provided in the postoperative period according to subjective assessment of patient discomfort. Postoperative pain scores were lowest in the bupivacaine group and highest in the saline group. Pain threshold, measured by applying calibrated loads to the knee, was higher postoperatively in the bupivacaine group than in the saline group. Dogs in the morphine and bupivacaine groups required less supplemental analgesia than dogs in the saline group. The local provision of analgesia reduces the need for systemic drugs with potential side effects. Both intra-articular morphine and intra-articular bupivacaine provided better postoperative analgesia than intra-articular saline, with intra-articular bupivacaine showing the greatest effect.