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Osteoarthritis (OA) is a global disease that, despite extensive research, has limited treatment options. Pet dogs share both an environment and lifestyle attributes with their owners, and a growing awareness is developing in the public and among researchers that One Medicine, the mutual co-study of animals and humans, could be beneficial for both humans and dogs. To that end, this Review highlights research opportunities afforded by studying dogs with spontaneous OA, with a view to sharing this active area of veterinary research with new audiences. Similarities and differences between dog and human OA are examined, and the proposition is made that suitably aligned studies of spontaneous OA in dogs and humans, in particular hip and knee OA, could highlight new avenues of discovery. Developing cross-species collaborations will provide a wealth of research material and knowledge that is relevant to human OA and that cannot currently be obtained from rodent models or experimentally induced dog models of OA. Ultimately, this Review aims to raise awareness of spontaneous dog OA and to stimulate discussion regarding its exploration under the One Medicine initiative to improve the health and well-being of both species., Osteoarthritis occurs spontaneously in pet dogs, which often share environmental and lifestyle risk-factors with their owners. This Review aims to stimulate cooperation between medical and veterinary research under the One Medicine initiative to improve the welfare of dogs and humans., Key points Dogs have many analogous spontaneous diseases that result in end-stage osteoarthritis (OA).Inbreeding and the predisposition of certain dog breeds for OA enable easier identification of candidate genetic associations than in outbred humans.Dog OA subtypes offer a potential stratification rationale for aetiological differences and alignment to analogous human OA phenotypes.The relatively compressed time course of spontaneous dog OA offers longitudinal research opportunities.Collaboration with veterinary researchers can provide tissue samples from early-stage OA and opportunities to evaluate new therapeutics in a spontaneous disease model.Awareness of the limitations and benefits of using clinical veterinary patients in research is important.

Canine hip dysplasia and developmental dysplasia of the human hip share demographic, phenotypic, and clinical features including the predisposition to develop osteoarthritis in affected joints. To support the results of genetic mapping studies for CHD and its concomitant osteoarthritis with functional information, we performed RNA-seq on hip capsule and teres ligament of affected and unaffected dogs. RNA seq showed that expressed genes segregated according age, capsule or ligament, and hip phenotype. Expression of HHIP, DACT2, and WIF1 was significantly higher in capsule from control hips than dysplastic hips indicating a disruption of the hedgehog signaling pathway. Expression of SPON 1, a key component of the WNT pathway, was increased significantly in both dysplastic capsule and ligament while FBN2 and EMILIN3 were significantly increased in dysplastic capsule. Of genes associated with human hip osteoarthritis, expression of ACAN, IGF1, CILP2, COL11A1, COL8A1, and HAPLN was increased significantly in dysplastic capsule. The significant increase in expression of PLA2F, TNFRSF, TMEM, and IGFBP in dysplastic capsule indicated an injury response. Gene set enrichment analysis revealed that genes involved in extracellular matrix structure, epithelial to mesenchymal transition, myogenesis, growth factor signaling, cancer and immune pathways were enriched in dysplastic capsule. For teres ligament from dysplastic joints, genes in retinoic signaling pathways and those encoding extracellular matrix molecules, but not proteoglycans, were enriched. Hip tissues respond to abnormal mechanics early in dysplastic hip development and these pathways present targets for intervention in the early synovitis and capsulitis secondary to canine and human hip dysplasia. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:313-324, 2019.

Lubricin is an important boundary lubricant and chondroprotective glycoprotein in synovial fluid. Both increased and decreased synovial fluid lubricin concentrations have been reported in experimental post-traumatic osteoarthritis (PTOA) animal models and in naturally occurring joint injuries in humans and animals, with no consensus about how lubricin is altered in different species or injury types. Increased synovial fluid lubricin has been observed following intra-articular fracture in humans and horses and in human late-stage osteoarthritis; however, it is unknown how synovial lubricin is affected by knee-destabilizing injuries in large animals. Spontaneous rupture of cranial cruciate ligament (RCCL), the anterior cruciate ligament equivalent in quadrupeds, is a common injury in dogs often accompanied by OA. Here, clinical records, radiographs, and synovial fluid samples from 30 dogs that sustained RCCL and 9 clinically healthy dogs were analyzed. Synovial fluid lubricin concentrations were nearly 16-fold greater in RCCL joints as compared to control joints, while IL-2, IL-6, IL-8, and TNF-α concentrations did not differ between groups. Synovial fluid lubricin concentrations were correlated with the presence of radiographic OA and were elevated in three animals sustaining RCCL injury prior to the radiographic manifestation of OA, indicating that lubricin may be a potential biomarker for early joint injury.

Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity is driven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exome sequencing, we identified heterozygous KIF3B variants in two unrelated families with hallmark ciliopathy phenotypes. In the first family, the proband presents with hepatic fibrosis, retinitis pigmentosa, and postaxial polydactyly; he harbors a de novo c.748G>C (p.Glu250Gln) variant affecting the kinesin motor domain encoded by KIF3B. The second family is a six-generation pedigree affected predominantly by retinitis pigmentosa. Affected individuals carry a heterozygous c.1568T>C (p.Leu523Pro) KIF3B variant segregating in an autosomal-dominant pattern. We observed a significant increase in primary cilia length in vitro in the context of either of the two mutations while variant KIF3B proteins retained stability indistinguishable from wild type. Furthermore, we tested the effects of KIF3B mutant mRNA expression in the developing zebrafish retina. In the presence of either missense variant, rhodopsin was sequestered to the photoreceptor rod inner segment layer with a concomitant increase in photoreceptor cilia length. Notably, impaired rhodopsin trafficking is also characteristic of recessive KIF3B models as exemplified by an early-onset, autosomal-recessive, progressive retinal degeneration in Bengal cats; we identified a c.1000G>A (p.Ala334Thr) KIF3B variant by genome-wide association study and whole-genome sequencing. Together, our genetic, cell-based, and in vivo modeling data delineate an autosomal-dominant syndromic retinal ciliopathy in humans and suggest that multiple KIF3B pathomechanisms can impair kinesin-driven ciliary transport in the photoreceptor.

Developmental dysplasia of the hip (DDH) in humans is a common condition that is associated with hip pain, functional limitations, and secondary osteoarthritis (OA). Surgical treatment of DDH has improved in the last decade, allowing excellent outcomes at short- and mid-term follow-up. Still, the etiology, mechanobiology, and pathology underlying this disease are not well understood. A pre-clinical animal model of DDH could help advance the field with a deeper understanding of specific pathways that initiate hip joint degeneration secondary to abnormal biomechanics. An animal model would also facilitate different interventional treatments that could be tested in a rigorous and controlled environment. The dog model exhibits several important characteristics that make it valuable as a pre-clinical animal model for human DDH. Dogs are naturally prone to develop canine hip dysplasia (CHD), which is treated in a similar manner as in humans. Comparable to human DDH, CHD is considered a pre-OA disease; if left untreated it will progress to OA. However, progression to OA is significantly faster in dogs than humans, with progression to OA within 1-2 years of age, associated with their shorter life span compared to humans. Animal studies could potentially reveal the underlying biochemical pathway(s), which can inform refined treatment modalities and provide opportunities for new treatment and prevention targets. Herein, we review the similarities and differences between the two species and outline the argument supporting CHD as an appropriate pre-clinical model of human DDH. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1807-1817, 2018.

OBJECTIVE: To determine perioperative inadvertent hypothermia (PIH) incidence, risk factors, prevention methods, and effect of PIH prevention on anesthesia recovery times. STUDY DESIGN: Nonrandomized controlled before‐and‐after trial. ANIMALS: Dogs (n = 277) and cats (n = 20) undergoing open surgery. METHODS: Incidence and risk factors for PIH (core temperature

Postmortem evaluation of racehorses has focused primarily on musculoskeletal injuries; however, horses also die suddenly on the track (sudden death [SD]). Although cardiac conditions are frequently suspected as a cause of death, SD racehorses are often autopsy negative; however, previous studies have been limited due to inconsistent or insufficient cardiac sampling and lack of controls. SD in New York (NY) and Maryland (MD) racehorses was evaluated in an observational case vs control study comparing clinical information, postmortem evaluation including cardiac dissection, and cardiac conduction system histopathology. In the study period, there were 40 cases of SD. In NY, SD occurred in 12% (37/316) of submissions, and 36 (11%) cases of SD were exercise associated (EASD); 3 EASD cases occurred in MD. In NY/MD EASD cases with histologic examination of the heart, 11 of 36 (31%) had significant lesions, including mesenteric artery rupture (1), axial trauma (2), systemic inflammation (2), pulmonary hemorrhage (1), and cardiac disease (5). Mild myocardial fibrosis, mild inflammation, coronary arteriosclerosis, and variation in cardiac nodal connective tissue were present in both SD cases and controls and thus were not considered to be causes of SD. While not excluding a genetic basis for SD, analysis of the genotypes (GGP Equine 70 K Array) of cases and controls did not reveal significant differences in allele frequencies at any locus. Most SD racehorses were autopsy negative; further research using standardized protocols and controls is needed to understand the underlying causes of SD, which is crucial to protecting the viability of racing.

Background Noninvasive methods of quantitating exercise tolerance in dogs with neuromuscular disease are needed both for clinical and research use. The 6-minute walk test (6MWT) has been validated as a reliable test of exercise tolerance in dogs with pulmonary and cardiac disease, but not in dogs with neuromuscular disease. Hypothesis/Objectives Distance walked and number of steps taken during 6MWT will differ between Labrador retriever dogs with centronuclear myopathy (CNM) and control (ie, healthy) littermates. Animals Eight purebred Labrador retrievers were drawn from a purpose-bred research colony (status: 3 clear, 2 carrier, and 3 homozygous mutants for the protein tyrosine phosphatase-like A (PTPLA) gene mutation associated with CNM). Methods Pilot, prospective, Case–controlled study. Researchers were blinded to disease status. Each dog was leash-trained and acclimatized to the testing area (length, 12.8 m). At the start of testing, each animal was fitted with a pedometer, a timer was started, and dogs were allowed to walk at their own pace for 6 minutes. Distance walked and pedometer readings were recorded. Results Degree of paresis varied among affected dogs, and was reflected by significant differences in distance walked between CNM-affected dogs and those with clear and carrier genotypes (P = .048). Pedometer readings did not vary according to genotype (P = .86). Conclusions The 6MWT appears to differentiate between the ambulatory capacity of normal and CNM-affected dogs. Additional studies are needed to confirm this relationship in a larger number of dogs, and to evaluate the ability of the 6MWT to differentiate between dogs with variable severity of neuromuscular disease-associated exercise intolerance.

OBJECTIVE To identify risk factors associated with surgical site infection (SSI) in dogs following tibial plateau leveling osteotomy (TPLO). DESIGN Retrospective cohort study. ANIMALS 320 dogs that underwent unilateral or bilateral TPLO (n = 405 procedures) between 2007 and 2015 and were reexamined by a veterinarian at least once ≥ 8 weeks after the procedure. PROCEDURES Data were extracted from medical records regarding signalment, TPLO procedure details, medical history of dermatitis, and SSI status. Logistic regression was performed to identify factors associated with SSI development. RESULTS An SSI developed following 34 (8.4%; 95% confidence interval [CI], 6.1% to 11.5%) procedures. Prophylactic antimicrobial administration was provided following 36.8% (n = 149) of procedures. For 71 (17.5%) procedures, the dog had dermatitis at the time of surgery; 12 of these procedures involved dermatitis at the surgical site. The incidence of SSI following the 12 procedures for dogs with dermatitis at the surgical site was 16.7% (2/12 [95% CI, 3.3% to 54.3%]) and was 10.2% (6/59 [95% CI, 4.5% to 21.3%]) for dogs with dermatitis elsewhere; however, these differences in incidence were not significant. On multivariable analysis, German Shepherd Dogs (vs other breeds), meniscectomy (vs no meniscectomy), and attending surgeon having performed ≤ 20 (vs > 20) procedures during the study period were associated with increased odds of SSI. CONCLUSIONS AND CLINICAL RELEVANCE SSI following TPLO was associated with the German Shepherd breed, meniscectomy, and surgeon. Prospective studies are needed to investigate the mechanisms underlying these associations.

Canine hip dysplasia and developmental dysplasia of the human hip share demographic, phenotypic, and clinical features including the predisposition to develop osteoarthritis in affected joints. To support the results of genetic mapping studies for CHD and its concomitant osteoarthritis with functional information, we performed RNA-seq on hip capsule and teres ligament of affected and unaffected dogs. RNA seq showed that expressed genes segregated according age, capsule or ligament, and hip phenotype. Expression of HHIP, DACT2, and WIF1 was significantly higher in capsule from control hips than dysplastic hips indicating a disruption of the hedgehog signaling pathway. Expression of SPON 1, a key component of the WNT pathway, was increased significantly in both dysplastic capsule and ligament while FBN2 and EMILIN3 were significantly increased in dysplastic capsule. Of genes associated with human hip osteoarthritis, expression of ACAN, IGF1, CILP2, COL11A1, COL8A1, and HAPLN was increased significantly in dysplastic capsule. The significant increase in expression of PLA2F, TNFRSF, TMEM, and IGFBP in dysplastic capsule indicated an injury response. Gene set enrichment analysis revealed that genes involved in extracellular matrix structure, epithelial to mesenchymal transition, myogenesis, growth factor signaling, cancer and immune pathways were enriched in dysplastic capsule. For teres ligament from dysplastic joints, genes in retinoic signaling pathways and those encoding extracellular matrix molecules, but not proteoglycans, were enriched. Hip tissues respond to abnormal mechanics early in dysplastic hip development and these pathways present targets for intervention in the early synovitis and capsulitis secondary to canine and human hip dysplasia. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:313-324, 2019.

Dogs were the first domesticated species, originating at least 15, 000 y ago from Eurasian gray wolves. Dogs today consist primarily of two specialized groups—a diverse set of nearly 400 pure breeds and a far more populous group of free-ranging animals adapted to a human commensal lifestyle (village dogs). Village dogs are more genetically diverse and geographically widespread than purebred dogs making them vital for unraveling dog population history. Using a semicustom 185, 805- marker genotyping array, we conducted a large-scale survey of autosomal, mitochondrial, and Y chromosome diversity in 4, 676 purebred dogs from 161 breeds and 549 village dogs from 38 countries. Geographic structure shows both isolation and gene flow have shaped genetic diversity in village dog populations. Some populations (notably those in the Neotropics and the South Pacific) are almost completely derived from European stock, whereas others are clearly admixed between indigenous and European dogs. Importantly, many populations—including those of Vietnam, India, and Egypt—show minimal evidence of European admixture. These populations exhibit a clear gradient of short-range linkage disequilibrium consistent with a Central Asian domestication origin.

Developmental dysplasia of the hip (DDH) in humans is a common condition that is associated with hip pain, functional limitations, and secondary osteoarthritis (OA). Surgical treatment of DDH has improved in the last decade, allowing excellent outcomes at short- and mid-term follow-up. Still, the etiology, mechanobiology, and pathology underlying this disease are not well understood. A pre-clinical animal model of DDH could help advance the field with a deeper understanding of specific pathways that initiate hip joint degeneration secondary to abnormal biomechanics. An animal model would also facilitate different interventional treatments that could be tested in a rigorous and controlled environment. The dog model exhibits several important characteristics that make it valuable as a pre-clinical animal model for human DDH. Dogs are naturally prone to develop canine hip dysplasia (CHD), which is treated in a similar manner as in humans. Comparable to human DDH, CHD is considered a pre-OA disease; if left untreated it will progress to OA. However, progression to OA is significantly faster in dogs than humans, with progression to OA within 1-2 years of age, associated with their shorter life span compared to humans. Animal studies could potentially reveal the underlying biochemical pathway(s), which can inform refined treatment modalities and provide opportunities for new treatment and prevention targets. Herein, we review the similarities and differences between the two species and outline the argument supporting CHD as an appropriate pre-clinical model of human DDH. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1807-1817, 2018.

African black-footed cats (Felis nigripes) are endangered wild felids. One male and full-sibling female African black-footed cat developed vision deficits and mydriasis as early as 3 months of age. The diagnosis of early-onset progressive retinal atrophy (PRA) was supported by reduced direct and consensual pupillary light reflexes, phenotypic presence of retinal degeneration, and a non-recordable electroretinogram with negligible amplitudes in both eyes. Whole genome sequencing, conducted on two unaffected parents and one affected offspring was compared to a variant database from 51 domestic cats and a Pallas cat, revealed 50 candidate variants that segregated concordantly with the PRA phenotype. Testing in additional affected cats confirmed that cats homozygous for a 2 base pair (bp) deletion within IQ calmodulin-binding motif-containing protein-1 (IQCB1), the gene that encodes for nephrocystin-5 (NPHP5), had vision loss. The variant segregated concordantly in other related individuals within the pedigree supporting the identification of a recessively inherited early-onset feline PRA. Analysis of the black-footed cat studbook suggests additional captive cats are at risk. Genetic testing for IQCB1 and avoidance of matings between carriers should be added to the species survival plan for captive management.

Canine hip dysplasia (CHD) is a common problem in veterinary medicine. We report the demographics of CHD using the entire hip dysplasia registry from the Orthopedic Foundation for Animals, analyzing differences by breed, sex, laterality, seasonal variation in birth, and latitude. There were 921,046 unique records. Each dog was classified using the American Kennel Club (AKC) and Fédération Cynologique Internationale (FCI) systems. Statistical analysis was performed with bivariate and logistic regression procedures. The overall CHD prevalence was 15.56%. The OR for CHD was higher in females (1.05), those born in spring (1.14) and winter (1.13), and those in more southern latitudes (OR 2.12). Within AKC groups, working dogs had the highest risk of CHD (OR 1.882) with hounds being the reference group. Within FCI groups, the pinscher/molossoid group had the highest risk of CHD (OR 4.168) with sighthounds being the reference group. The similarities between CHD and DDH are striking. Within DDH there are two different types, the typical infantile DDH and the late onset adolescent/adult acetabular dysplasia, with different demographics; the demographics of CHD are more similar to the later onset DDH group. Comparative studies of both disorders should lead to a better understanding of both CHD and DDH.

Hip dysplasia (HD), elbow dysplasia (ED), and rupture of the cranial (anterior) cruciate ligament (RCCL) are the most common complex orthopedic traits of dogs and all result in debilitating osteoarthritis. We reanalyzed previously reported data: the Norberg angle (a quantitative measure of HD) in 921 dogs, ED in 113 cases and 633 controls, and RCCL in 271 cases and 399 controls and their genotypes at ~185,000 single nucleotide polymorphisms. A novel fixed and random model with a circulating probability unification (FarmCPU) function, with marker-based principal components and a kinship matrix to correct for population stratification, was used. A Bonferroni correction at p

Objective To determine if currently used ground reaction force (GRF) normalization methods are accurate and precise enough to be used on a single-limb basis. Study Design Prospective clinical trial. Animals Clinically normal (n = 69) dogs and 40 dogs with unilateral ruptured cranial cruciate ligaments (CCL). Methods Pelvic limb GRFs of orthopedically normal dogs and those with unilateral ruptured CCL were collected. Normalization methods included none, body weight (BW), withers height (WH), WH and relative velocity (WH*F) and principal component 1 (PC1). Normalization methods were evaluated both by individual GRFs and additively. Binary logistic regression was performed for all normalization methods; sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) calculated. Stepwise backward logistic regression was used; significant values were retained in the final model. P 80%.

Objective To determine (1) the effect of elbow incongruity on contact mechanics and (2) the effect of treatment of this incongruity with 1 of 2 ulnar ostectomies in the canine elbow. Study Design Ex vivo biomechanical study. Sample Population Unpaired cadaveric canine forelimbs (n = 17). Methods In a servohydraulic testing frame, thin-film pressure sensors were placed into the lateral and medial compartments of the elbow. Specimens were tested in 135° of elbow joint flexion at 200 N of cyclic axial force, followed by a 20 seconds hold. Intra-articular contact area (CA), mean contact pressure (mCP) and peak contact pressure (pCP) were measured in each compartment. After radial shortening, testing was repeated and limbs randomized into proximal ulnar ostectomy with IM pin (PUO) or sequential distal ulnar ostectomy (DUO), interosseous ligament release (DUO-L), and ulnar attachment of the abductor pollicis longus muscle and interosseous membrane release (DUO-ML). Paired t-tests were used to compare each treatment to baseline values. Differences between treatment groups were evaluated with a mixed model with random effect to adjust for the clustering of limbs within dog. P

Objective To evaluate subchondral joint space width measurements (SJSW) and CT-osteoabsorptiometry (CTOAM) measurements in the elbow of dogs with naturally occurring fragmented medial coronoid process (FMCP) preoperatively and 6 months postoperatively, and to compare these to normal dogs. Study Design Prospective randomized clinical trial. Animals Large breed dogs

Background Concentrated breeding effort to produce various body structures and behaviors of dogs to suit human demand has inadvertently produced unwanted traits and diseases that accompany the morphological and behavioral phenotypes. We explored the relationship between pelvic conformation and canine hip dysplasia (HD) because purebred dogs which are predisposed, or not, to HD share common morphologic features, respectively. Thirteen unique bilateral anatomical features of the pelvis were measured on 392 dogs of 51 breeds and 95 mixed breed dogs. Principal components (PCs) were derived to describe pelvic morphology. Dogs were genotyped at ~183,000 single nucleotide polymorphisms and their hip conformation was measured by the Norberg angle and angle of inclination between the femoral neck and diaphysis. Results No associations reached genome wide significance for the Norberg angle when averaged over both hips. PC1 was negatively correlated with the Norberg angle (r = -0.31; P 0.05). PC1, 2, 4, and 5 differed significantly between male and female dogs confirming pelvic sexual dimorphism. With sex as a covariate, the eigenvector contribution to PC1 reflected the overall size of the pelvis and was significantly associated with the IGF-1 locus, a known contributor to canine body size. PC3, which represented a tradeoff between ilial length and ischial length in which a longer ischium is associated with a shorter ilium, was significantly associated with a marker on canine chromosome 16:5181388 bp. The closest candidate gene is TPK1, a thiamine-dependent enzyme and part of the PKA complex. Associations with the remaining PCs did not reach genome wide significance. Conclusion IGF-1 was associated with the overall size of the pelvis and sex is related to pelvic size. Ilial/ischial proportion is genetically controlled and the closest candidate gene is thiamine-dependent and affects birth weight and development of the nervous system. Dogs with larger pelves tend to have smaller NAs consistent with increased tendency toward HD in large breed dogs. Based on the current study, pelvic shape alone was not strongly associated with canine hip dysplasia. Electronic supplementary material The online version of this article (doi:10.1186/s40575-017-0043-7) contains supplementary material, which is available to authorized users.

Genomic resources for the domestic dog have improved with the widespread adoption of a 173k SNP array platform and updated reference genome. SNP arrays of this density are sufficient for detecting genetic associations within breeds but are underpowered for finding associations across multiple breeds or in mixed-breed dogs, where linkage disequilibrium rapidly decays between markers, even though such studies would hold particular promise for mapping complex diseases and traits. Here we introduce an imputation reference panel, consisting of 365 diverse, whole-genome sequenced dogs and wolves, which increases the number of markers that can be queried in genome-wide association studies approximately 130-fold. Using previously genotyped dogs, we show the utility of this reference panel in identifying potentially novel associations, including a locus on CFA20 significantly associated with cranial cruciate ligament disease, and fine-mapping for canine body size and blood phenotypes, even when causal loci are not in strong linkage disequilibrium with any single array marker. This reference panel resource will improve future genome-wide association studies for canine complex diseases and other phenotypes., Author summary Complex traits are controlled by more than one gene and as such are difficult to map. For complex trait mapping in the domestic dog, researchers use the current array of 173,000 variants, with only minimal success. Here, we use a method called imputation to increase the number of variants–from 173,000 to 24 million–that can be queried in canine association studies. We use sequence data from the whole genomes of 365 dogs and wolves to accurately predict variants, in a separate cohort of dogs, that are not present on the array. Using dog body size, blood phenotypes, and a common orthopedic disease that involves rupture of the cranial cruciate ligament, we show that the increase in variants results in an increase in mapping power, through the identification of new associations and the narrowing of regions of interest. This imputation panel is particularly important because of its usefulness in improving complex trait mapping in the dog, which has significant implications for discovery of variants in humans with similar diseases.

The aims of this study were to undertake principal component analysis (PCA) of hip dysplasia (HD) and to examine the power of the principal components (PCs) in genome-wide association studies. A cohort of 278 dogs for PCA and that of 369 dogs for genotyping were used. The distraction index (DI), the dorsolateral subluxation (DLS) score, the Norberg angle (NA), and the extended-hip radiographic (EHR) score were used for the PCA. One thousand single-nucleotide polymorphisms (SNPs) (of 23,500) were used to simulate genetic locus sharing between the HD phenotypes and 1000 SNPs were used to calculate the genetic mapping power of the PCs. The DI and the DLS score (first group) reflected hip laxity and the NA and the EHR score (second group) reflected the congruency between the femoral head and acetabulum. The average hip measurements of the two groups reflected in the first PC captured 55% of total radiographic variation. The first four PCs captured 90% of the total variation. The PCs had higher statistical map...

Canine hip dysplasia (CHD) is a common complex trait characterized by abnormal hip joint development. Hip joint laxity, an early characteristic of CHD, results in degeneration of the joint due to mechanical trauma, which is a clinical problem mostly in medium to large breed dogs. Clinical signs include pain, decreased activity and lameness. A retrospective, multi-center, cross sectional study of 437 dogs was performed to determine if a Norberg angle (NA) ≥105° accurately predicts a non-dysplastic hip based on a distraction index (DI) cut-off of ≤0.3 or a dorsolateral subluxation (DLS) score cut-off of ≥55%. The predictive capacity of the NA against a DI ≤0.3 or a DLS score ≥55% was assessed using area under the receiver operator characteristic (ROC) curve analysis. The ROC curve of NA for the prediction of a DI ≤0.3 was 0.59 (95% CI=0.50-0.69) and for the prediction of DLS score ≥55% was 0.69 (95% CI=0.63-0.75). Optimizing the specificity of the NA to ≥80% for prediction of a DI ≤0.3 and a DLS score ≥55% gave a cut-point for the NA of ≥112° and 108.7°, respectively. In conclusion, at the cut-point of 105°, the NA is not an accurate measurement to score normal or abnormal hips, based on the DI or DLS score. Application of screening methods for CHD based on hip laxity, such as the DI or the DLS score, would help to remove additional dysplastic dogs from the breeding pool or the NA criterion should be higher when selecting unaffected dogs for breeding.

We welcome the additional data and analyses of Wang et al. (1), but believe there are some misunderstandings regarding the methods and findings of Shannon et al. (2). First, although we merged Nepal and Mongolia when plotting linkage disequilibrium (LD) decay in figure 5B of ref. 2 for legibility, we did not assume Nepal and Mongolia represented a single, interbreeding population, and indeed computed separate LD scores for each population (figure 5A of ref. 2), matching Wang et al.’s (1) observation of slightly lower LD in Nepal than Mongolia. Although Nepal (along with India) is commonly considered part of South Asia, Nepal borders Central Asia. Dog populations in two Central Asian countries, Mongolia and Afghanistan, both have lower LD than India. Nepal does not border Southeast Asia. Because we cannot, given the resolution of current sampling … [↵][1]1To whom correspondence should be addressed. Email: arb359{at}cornell.edu. [1]: #xref-corresp-1-1

To determine a long term function of tibial tuberosity advancement (TTA) for treatment of ruptured cranial cruciate ligament (CCL) in dogs, and to compare this to the long term function of previously reported tibial plateau leveling osteotomy (TPLO), extracapsular reconstruction (ECR), and a population of normal dogs.Prospective clinical trial.Dogs with unilateral ruptured CCL treated with TTA (n = 14), TPLO (n = 15), and ECR (n = 23), and normal adult dogs (control, n = 80).Force plate gait analysis was performed at 1 time point for the normal control group and preoperatively, and at 2 and 8 weeks and 6 and 12 months postoperatively for the treatment groups. Using serial force plates, symmetry indices (SI) were calculated between the operated and unoperated pelvic limbs for peak vertical force (PVF), contact time (CT), and vertical impulse (VI). Ground reaction forces (GRF) of the treatment and control group were compared using a general linear model.Walk SI for dogs with TTA were not significantly different from the control group at 12 months postoperatively. At the trot, neither TTA nor ECR achieved normal GRF. SI of the TPLO group were not different from the normal control group by 6-12 months postoperatively.At the walk, TTA achieves normal function by 12 months; however, at the trot TTA is indistinguishable from ECR. TPLO resulted in operated limb function that was similar to the control population by 6-12 months postoperatively at the walk and the trot.

Objective To compare the long-term outcome of tibial plateau leveling osteotomy (TPLO) and extracapsular repair (ECR) for treatment of a ruptured cranial cruciate ligament (RCCL). Study Design Prospective clinical trial. Animals Normal adult dogs (control, n = 79); dogs with unilateral CCL disease (n = 38). Methods Dogs had TPLO (n = 15) or ECR (n = 23) for treatment of RCCL. Force plate gait analysis was performed for the control group at one time point and for treatment groups at serial points: preoperatively, 2 weeks, 8 weeks, 6 and 12 months postoperatively. Symmetry indices (SIs) were calculated between operated and unoperated pelvic limb for ground reaction forces (GRFs), including peak vertical force (PVF), contact time (CT), and vertical impulse (VI). GRFs of the treatment groups and control group were compared using a general linear model and Kaplan–Meier survival analysis. Results At 8 weeks, for PVF and VI, the TPLO group had more symmetric limb loading than the ECR group at the walk and trot. SIs of the TPLO group were not different from the control group by 6 months to 1 year postoperatively. SIs for the ECR group were less symmetrical than the control group at all time periods. Using survival analysis, median time to normal function was no different at the walk between groups, but was shorter for the TPLO group for VI and PVF. Conclusions Dogs achieved normal limb loading faster after TPLO than ECR. TPLO resulted in operated limb function that was indistinguishable from the control population by 1 year postoperatively.

Body weight squared, TTA, and age affect MPL grade, suggestingthatatorsionaldeformitymaycontributetothedevelopmentofMPLinYorkshireterriers along with weight and age.The patella, a sesamoid bone, resides within the tendon ofinsertion of the quadriceps musculature and moves pas-sively with the tendon, changing the direction of pull ofthe quadriceps tendon.

Canine hip dysplasia (CHD) is characterized by hip laxity and subluxation that can lead to hip osteoarthritis. Studies have shown the involvement of multiple genetic regions in the expression of CHD. Although we have associated some variants in the region of fibrillin 2 with CHD in a subset of dogs, no major disease-associated gene has been identified. The focus of this study is to identify quantitative trait loci (QTL) associated with CHD. Two sequential multipoint linkage analyses based on a reversible jump Markov chain Monte Carlo approach were applied on a cross-breed pedigree of 366 dogs. Hip radiographic trait (Norberg Angle, NA) on both hips of each dog was tested for linkage to 21,455 single nucleotide polymorphisms across 39 chromosomes. Putative QTL for the NA was found on 11 chromosomes (1, 2, 3, 4, 7, 14, 19, 21, 32, 36, and 39). Identification of genes in the QTL region(s) can assist in identification of the aberrant genes and biochemical pathways involving hip dysplasia in both dogs and humans.

Objective To propose a direct measure of subluxation of the femoral head (S) in the assessment of hip joint laxity and evaluate it for clinical use. Study Design Method comparison study. Animals Dogs (n = 51). Methods Dogs were sedated or anesthetized for a dorsolateral subluxation (DLS) examination. Two sets of radiographs were acquired, 1 each by a different technologist. A calibrated measuring bar was included on the image at the height of the hip to assess magnification. The DLS was calculated for each hip and different persons unaware of these details measured the “S”-value. One person measured the S-value 3 times over 3 days. Box plots were used to determine a cut-off for the empiric (8 mm) and corrected (4 mm) S-value. Results Of 51 dogs, 33 were dysplastic based on a DLS score

Developmental dysplasia of the hip (DDH) is a common cause of elevated contact stress and early onset osteoarthritis (OA). We hypothesized that adaptation to focal loading during postnatal development would result in signature changes to the shape of the femoral head secondary center of ossification (SCO). SCO shape was evaluated in a canine model of DDH at ages 14 and 32 weeks. The evolving 3D morphology of the SCO was captured using serial quantitative computed tomography. A discrete medial representation shape model was fit to each SCO and served as the basis for quantitative thickness and bending measurements. Shape measurements were tested for associations with hip subluxation and degeneration. At 32 weeks, the SCO was thinner (flatter) in the perifoveal region, the site of focal loading; a greater bend to the SCO was present lateral to the site of thinning; SCO thinning and bending were associated with less femoral head coverage and with a higher probability of degeneration. Shape changes were not detected at 14 weeks. Measurement and visualization of SCO shape changes due to altered loading may provide a basis for identifying hips at risk of early onset OA and a tool for surgical planning of hip restructuring.

Objective—To determine whether a mutation in the fibrillin 2 gene (FBN2) is associated with canine hip dysplasia (CHD) and osteoarthritis in dogs. Animals—-1,551 dogs. Procedures—Hip conformation was measured radiographically. The FBN2 was sequenced from genomic DNA of 21 Labrador Retrievers and 2 Greyhounds, and a haplotype in intron 30 of FBN2 was sequenced in 90 additional Labrador Retrievers and 143 dogs of 6 other breeds. Steady-state values of FBN2 mRNA and control genes were measured in hip joint tissues of fourteen 8-month-old Labrador Retriever–Greyhound crossbreeds. Results—The Labrador Retrievers homozygous for a 10-bp deletion haplotype in intron 30 of FBN2 had significantly worse CHD as measured via higher distraction index and extended-hip joint radiograph score and a lower Norberg angle and dorsolateral subluxation score. Among 143 dogs of 6 other breeds, those homozygous for the same deletion haplotype also had significantly worse radiographic CHD. Among the 14 crossbred dogs, as the dorsolateral subluxation score decreased, the capsular FBN2 mRNA increased significantly. Those dogs with incipient hip joint osteoarthritis had significantly increased capsular FBN2 mRNA, compared with those dogs without osteoarthritis. Dogs homozygous for the FBN2 deletion haplotype had significantly less FBN2 mRNA in their femoral head articular cartilage. Conclusions and Clinical Relevance—The FBN2 deletion haplotype was associated with CHD. Capsular gene expression of FBN2 was confounded by incipient secondary osteoarthritis in dysplastic hip joints. Genes influencing complex traits in dogs can be identified by genome-wide screening, fine mapping, and candidate gene screening.

Summary Objective To establish a predictive method using whole genome genotyping for early intervention in canine hip dysplasia (CHD) risk management, for the prevention of the progression of secondary osteoarthritis (OA), and for selective breeding. Design Two sets of dogs (six breeds) were genotyped with dense SNPs covering the entire canine genome. The first set contained 359 dogs upon which a predictive formula for genomic breeding value (GBV) was derived by using their estimated breeding value (EBV) of the Norberg angle (a measure of CHD) and their genotypes. To investigate how well the formula would work for an individual dog with genotype only (without using EBV), a cross validation was performed by masking the EBV of one dog at a time. The genomic data and the EBV of the remaining dogs were used to predict the GBV for the single dog that was left out. The second set of dogs included 38 new Labrador retriever dogs, which had no pedigree relationship to the dogs in the first set. Results The cross validation showed a strong correlation ( R >0.7) between the EBV and the GBV. The independent validation showed a moderate correlation ( R =0.5) between GBV for the Norberg angle and the observed Norberg angle (no EBV was available for the new 38 dogs). Sensitivity, specificity, positive and negative predictive values of the genomic data were all above 70%. Conclusions Prediction of CHD from genomic data is feasible, and can be applied for risk management of CHD and early selection for genetic improvement to reduce the prevalence of CHD in breeding programs. The prediction can be implemented before maturity, at which age current radiographic screening programs are traditionally applied, and as soon as DNA is available.

Objective—To identify the quantitative trait loci (QTL) that contribute to hip dysplasia in dogs. Animals—192 Labrador Retrievers. Procedures—Hip dysplasia was measured by use of the Norberg angle (NA), dorsolateral subluxation (DLS) score, and distraction index (DI). Genome-wide screening was conducted by use of 276 unique microsatellites. Linkage analysis was performed with a variance-based linear model. Logarithm of the odds (LOD) scores were reported when values were > 2.0. Results—Canis familiaris autosomes (CFAs) 01, 02, 10, 20, 22, and 32 harbored significant QTL at LOD scores > 2.0. Among the 6 QTL, the QTL on CFA02 had not been reported to harbor QTL for hip dysplasia. The highest LOD score of 3.32 on CFA20 contributed to the second principal component of the DLS score and NA of the right hip joint. The QTL that was mapped on CFA01 (LOD score of 3.13 at 55 centimorgans) was located on the same chromosome reported to harbor a QTL for hip dysplasia in Portuguese Water Dogs and German Shepherd Dogs. In this study, CFAs 10, 20, 22, and 32 harbored QTL for hip dysplasia that have been identified in a Labrador Retriever–Greyhound pedigree and in German Shepherd Dogs. Conclusions and Clinical Relevance—Multiple QTL were clearly involved with hip dysplasia. Identification of these QTL will enable fine-resolution mapping and subsequent assessment of candidate genes within the refined intervals to enable researchers to develop genetic screening tests and preventative and novel therapeutic regimens.

High genetic diversity of East Asian village dogs has recently been used to argue for an East Asian origin of the domestic dog. However, global village dog genetic diversity and the extent to which semiferal village dogs represent distinct, indigenous populations instead of admixtures of various dog breeds has not been quantified. Understanding these issues is critical to properly reconstructing the timing, number, and locations of dog domestication. To address these questions, we sampled 318 village dogs from 7 regions in Egypt, Uganda, and Namibia, measuring genetic diversity >680 bp of the mitochondrial D-loop, 300 SNPs, and 89 microsatellite markers. We also analyzed breed dogs, including putatively African breeds (Afghan hounds, Basenjis, Pharaoh hounds, Rhodesian ridgebacks, and Salukis), Puerto Rican street dogs, and mixed breed dogs from the United States. Village dogs from most African regions appear genetically distinct from non-native breed and mixed-breed dogs, although some individuals cluster genetically with Puerto Rican dogs or United States breed mixes instead of with neighboring village dogs. Thus, African village dogs are a mosaic of indigenous dogs descended from early migrants to Africa, and non-native, breed-admixed individuals. Among putatively African breeds, Pharaoh hounds, and Rhodesian ridgebacks clustered with non-native rather than indigenous African dogs, suggesting they have predominantly non-African origins. Surprisingly, we find similar mtDNA haplotype diversity in African and East Asian village dogs, potentially calling into question the hypothesis of an East Asian origin for dog domestication.

The sequencing of the human genome and genomes of several model organisms has revolutionized the ability of researchers and clinicians to study the genetic basis of disease, relationships between genes and phenotypes, and the molecular basis of normal development and physiology. This information has led to better diagnosis of traits and diseases, improved treatment for patients, an ability to conduct genetic testing for many inherited diseases, and novel drug development. The benefits of the genomics revolution have been extended to companion animals. Most unique is the enormous variation among breeds, which is typified in dogs as the result of human-driven selective breeding. In addition to the selected positive traits, breeds often are susceptible to certain diseases, in part, as a result of inbreeding. Considerable progress has been made in identifying mutations that cause simple Mendelian traits and diseases in domestic animals, but dissecting the molecular basis of complex or polygenic traits and diseases is a challenge to those involved in genetic mapping of animals. A draft 7.6X sequence of the genome of Boxers was developed through funding provided by the National Institutes of Health; this project was completed in 2005 at the Broad Institute of the Massachusetts Institute of Technology and Harvard University. A map of 500,000 SNPs was developed as part of the National Institutes of Health–funded project by comparing sequences between the 1.5X sequence for a single Poodle that had been placed in the public domain and 100,000 random sequences of 12 other dog breeds. Because the dog genome is approximately 2.4 gigabases, this yielded an SNP every 10 kb across the genome for LD-based map

Hip laxity is one characteristic of canine hip dysplasia (CHD), an inheritable disease that leads to hip osteoarthritis. Using a genome-wide screen with 250 microsatellites in a crossbreed pedigree of 159 dysplastic Labrador retrievers and unaffected greyhounds, we previously identified putative (P < 0.01) QTL on canine chromosomes 11 and 29 (CFA11 and CFA29). To refine these QTL locations, we have genotyped 257 dogs including 105 Labrador retrievers, seven greyhounds, four generations of their crossbreed offspring and three German shepherds for 111 and 171 SNPs on CFA11 and CFA29 respectively. The distraction index (DI, a measure of maximum hip laxity) was used as an intermediate phenotype that predicts whether a hip joint will or will not develop osteoarthritis. Using a multipoint linkage analysis, significant evidence (95% posterior probability) was found for QTL contributing to hip laxity in the 16.2-21 cM region on CFA11 that explained 15-18% of the total variance in DI. Evidence for an independent QTL on CFA29 was weaker than that on CFA11. Identification of the causative mutation(s) will lead to better understanding of biochemical pathways in both dogs and humans with hip laxity and dysplasia.

Genetic imprinting may have played a more notable role in shaping embryonic development of plants, animals, and humans than previously appreciated. Quantitative trait loci that are imprinted (iQTL) exert monoallelic effects, depending on the parent of origin, which is an exception to the laws of Mendelian genetics. In this article, we present a modified random effect-based mapping model to use in a genome-wide scan for the distribution of iQTL that contribute to genetic variance for a complex trait in a structured pedigree. This model, implemented with the maximum likelihood method, capitalizes on a network of relatedness for maternally and paternally derived alleles through identical-by-descent sharing, thus allowing for the discrimination of the genetic variances due to alleles derived from maternal and paternal parents. The model was employed to map iQTL responsible for canine hip dysplasia in a multihierarchical canine pedigree, founded with seven greyhounds and six Labrador retrievers. Of eight significant QTL detected, three, located on CFA1, CFA8, and CF28, were found to trigger significant parent-of-origin effects on the age of femoral capital ossification measured at the left and right hips of a canine. The detected iQTL provide important candidate regions for fine-mapping of imprinted genes and for studying their structure and function in the control of complex traits.

Mutations of pigment type switching have provided basic insight into melanocortin physiology and evolutionary adaptation. In all vertebrates that have been studied to date, two key genes, Agouti and Melanocortin 1 receptor (Mc1r), encode a ligand-receptor system that controls the switch between synthesis of red–yellow pheomelanin vs. black–brown eumelanin. However, in domestic dogs, historical studies based on pedigree and segregation analysis have suggested that the pigment type-switching system is more complicated and fundamentally different from other mammals. Using a genomewide linkage scan on a Labrador × greyhound cross segregating for black, yellow, and brindle coat colors, we demonstrate that pigment type switching is controlled by an additional gene, the K locus. Our results reveal three alleles with a dominance order of black (KB) > brindle (kbr) > yellow (ky), whose genetic map position on dog chromosome 16 is distinct from the predicted location of other pigmentation genes. Interaction studies reveal that Mc1r is epistatic to variation at Agouti or K and that the epistatic relationship between Agouti and K depends on the alleles being tested. These findings suggest a molecular model for a new component of the melanocortin signaling pathway and reveal how coat-color patterns and pigmentary diversity have been shaped by recent selection.

The widespread use of the set of multiple-trait derivative-free REML programs for prediction of breeding values and estimation of variance components has led to significant improvement in traits of economic importance. The initial version of this software package, however, was generally limited to pedigree-based relationships. With continued advances in genomic research and the increased availability of genotyping, relationships based on molecular markers are obtainable and desirable. The addition of a new program to the set of multiple-trait derivative-free REML programs is described that allows users the flexibility to calculate relationships using standard pedigree files or an arbitrary relationship matrix based on genetic marker information. The strategy behind this modification and its design is described. An application is illustrated in a QTL association study for canine hip dysplasia.

Objective—To determine the effect of nonthermal plasma on Staphylococcus aureus, fibroblasts in monolayer culture, and clean and contaminated skin explants. Sample Population—Normal skin from euthanized horses. Procedures—S aureus organisms were plated and treated with nonthermal plasma followed by bacterial culture to assess viability. Fibroblasts in monolayer culture and the epidermal and dermal surfaces of clean and S aureus–contaminated skin explants were treated. The effects of distance and duration on the response to treatment were compared. Results—Compared with controls, treatment with nonthermal plasma resulted in significantly decreased bacterial growth and significantly inhibited survival of fibroblasts in monolayer culture. When epidermal and dermal surfaces of skin explants were treated, there was no effect on production of normal fibroblasts during explant culture, except when extended exposure times of ≥ 2 minutes were used. Treatment with nonthermal plasma resulted in significantly lower bacterial counts after 24 hours of culture of S aureus–contaminated epidermis but not of dermis. Conclusions and Clinical Relevance—Nonthermal plasma resulted in bacterial decontamination of agar and epithelium; negative effects on fibroblasts in monolayer; and no negative effects on skin explants, except at long exposure times. Use of nonthermal plasma appears safe for treatment of epithelialized surfaces, may be safe for granulating wounds, and results in decontamination of S aureus. Investigations on the effects that nonthermal plasma may have on patient tissues are indicated with a clinically applicable delivery device.

Recent advances in genomics resources and tools are facilitating quantitative trait locus mapping. We developed a crossbreed pedigree for mapping quantitative trait loci for hip dysplasia in dogs by crossing dysplastic Labrador Retrievers and normal Greyhounds. We show that one advantage to using a crossbreed pedigree is the increased marker informativeness in the backcross/F2 population relative to the founder populations. We also discuss three factors that affect the detection power in the context of this crossbreed pedigree: being able to detect and correct genotyping errors, increasing marker density for chromosomes with a sparse coverage, and adding individuals to the mapping population as soon as they become available.

SummaryThe locking compression plate (LCP) supports biological osteosynthesis by functioning as an internal fixator, rather than as a full or limited contact bone plate which must be adequately contoured and affixed directly to the bone for stable internal fixation of the fracture. In order to help justify the use of the LCP in our veterinary patients, in vitro biomechanical testing was performed comparing the LCP to the conventional limited contact dynamic compression plate (LC-DCP) in canine femurs. We hypothesized that the LCP construct would be at least as stiff under bending and torsional loads as the LC-DCP. The LCP and LC-DCP were applied over a 20-mm osteotomy gap to contralateral bones within each pair of 14 femora. Non-destructive four-point bending and torsion, and cyclical testing in torsion were performed. The constructs were then loaded to failure in torsion. In medial-lateral and lateral-medial structural bending, significant differences were not found between the LCP and LC-DCP, however, at the gap, the LCP construct was stiffer than the LC-DCP in lateral-medial bending. Significant differences in behaviour over time were not noted between the plate designs during cyclical testing. When loading the constructs to failure in internal rotation, the LC-DCP failed at a significantly lower twist angle (P = .0024) than the LCP. Based on the similar performance with loading, the locking compression plate is a good alternative implant for unstable diaphyseal femoral fracture repair in dogs.