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1.  Omics technologies provide new insights into the molecular physiopathology of equine osteochondrosis 
BMC Genomics  2014;15(1):947.
Osteochondrosis (OC(D)) is a juvenile osteo-articular disorder affecting several mammalian species. In horses, OC(D) is considered as a multifactorial disease and has been described as a focal disruption of endochondral ossification leading to the development of osteoarticular lesions. Nevertheless, OC(D) physiopathology is poorly understood. Affected horses may present joint swelling, stiffness and lameness. Thus, OC(D) is a major concern for the equine industry. Our study was designed as an integrative approach using omics technologies for the identification of constitutive defects in epiphyseal cartilage and/or subchondral bone associated with the development of primary lesions to further understand OC(D) pathology. This study compared samples from non-affected joints (hence lesion-free) from OC(D)-affected foals (n = 5, considered predisposed samples) with samples from OC-free foals (n = 5) considered as control samples. Consequently, results are not confounded by changes associated with the evolution of the lesion, but focus on altered constitutive molecular mechanisms. Comparative proteomics and micro computed tomography analyses were performed on predisposed and OC-free bone and cartilage samples. Metabolomics was also performed on synovial fluid from OC-free, OC(D)-affected and predisposed joints.
Two lesion subtypes were identified: OCD (lesion with fragment) and OC (osteochondral defects). Modulated proteins were identified using omics technologies (2-DE proteomics) in cartilage and bone from affected foals compare to OC-free foals. These were associated with cellular processes including cell cycle, energy production, cell signaling and adhesion as well as tissue-specific processes such as chondrocyte maturation, extracellular matrix and mineral metabolism. Of these, five had already been identified in synovial fluid of OC-affected foals: ACTG1 (actin, gamma 1), albumin, haptoglobin, FBG (fibrinogen beta chain) and C4BPA (complement component 4 binding protein, alpha).
This study suggests that OCD lesions may result from a cartilage defect whereas OC lesions may be triggered by both bone and cartilage defects, suggesting that different molecular mechanisms responsible for the equine osteochondrosis lesion subtypes and predisposition could be due to a defect in both bone and cartilage. This study will contribute to refining the definition of OC(D) lesions and may improve diagnosis and development of therapies for horses and other species, including humans.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-947) contains supplementary material, which is available to authorized users.
PMCID: PMC4233069  PMID: 25359417
Equine osteochondrosis; Cartilage; Subchondral bone; Proteomics; Metabolomics; μCT
2.  Midterm results of biologic fixation or mosaicplasty and drilling in osteochondritis dissecans 
Indian Journal of Orthopaedics  2011;45(5):445-449.
Osteochondritis dissecans (OCD) primarily affects subchondral bone. Multiple drilling, fixation implant or autogenous osteochondral grafts are reported as treatment options. We present the midterm results of cases in which an OCD lesion was treated by osteochondral autograft transfer and drilling.
Materials and Methods:
Between 2002 and 2006, 14 knees with International Cartilage Repair Society (ICRS-OCD) type II and III lesions were treated in our clinic using osteochondral autograft transfer and drilling by arthroscopic or open surgery. The average age of our patients was 22.14 years (range 17-29 years) and average followup was of 24.3 months (range 11-40 months). Lesion type was ICRS type II in five patients (35.7%) and ICRS type III in nine patients (64.3%). In cases with ICRS-OCD type II lesions, in situ fixation was applied following circumferential multiple drilling, while mosaicplasty was done following debridement and multiple drilling in cases with ICRS-OCD type III lesion. Mosaicplasty was performed in the lesion area by an average of 2.5 (range 1-3) cylindrical osteochondral autografts. Patients were not allowed to perform loading activities for 3 weeks in the postoperative period; movement was initiated by using CPM device in the early phase; full range of motion was achieved in third week, and full weight bearing was permitted in 6 to 8 weeks
While 6 and 8 patients were classified preoperatively as fair and poor, respectively, according to Hughston scale, excellent and good results were obtained postoperatively in 10 and 4 patients, respectively. During the followup, no problems were detected in any of the patients in the regions where osteochondral graft was harvested.
Biologic fixation or mosaicplasty and drilling as a technique to treatment of the lesion in OCD by osteochondral autograft transfer has resulted in good and excellent clinical outcomes in our patients and it is considered that providing blood flow to subchondral bone by circumferencial drilling leads to an increase in the robustness of biological internal fixation and shortens the duration of recovery.
PMCID: PMC3162682  PMID: 21886927
Osteochondritis dissecans; Hughston scale; knee; mosaicplasty
3.  Incidence of osteochondrosis (dissecans) in Dutch warmblood horses presented for pre-purchase examination 
Irish Veterinary Journal  2008;61(1):33-37.
Data are lacking in the literature regarding the incidence of osteochondrosis (dissecans) [OC(D)] in relation to lameness evaluation in Dutch Warmblood horses. The objective of this retrospective study was to assess the incidence of radiological abnormalities consistent with osteochondrosis or osteochondrosis dissecans in 1,231 sound Dutch Warmblood (DW) horses presented for pre-purchase examination. Standardised (Dutch) pre-purchase examination protocols were evaluated. The pre-purchase examination included a clinical, lameness and radiological evaluation, performed at a private equine clinic in the Netherlands. Radiographical examination included views of the distal (DIP) and proximal (PIP) interphalangeal, metacarpo- and metatarsophalangeal (MCP/MTP), tarsocrural (TC) and femoropatellar (FP) joints. Radiographical evidence of OC(D) was found in 44.3% of clinically sound DW horses. In this study, 443 horses (36%, n = 1,231) had evidence of OCD and 102 horses (8.3%, n = 1,231) had evidence of OC on pre-purchase radiographs. The results also indicated that the TC joints were significantly more likely to be affected. A considerable number of horses did not demonstrate any lameness, although radiographs revealed OC(D).
PMCID: PMC3113880  PMID: 21851701
Osteochondrosis; dissecans; lameness; pre-purchase; examination
4.  Three Osteochondritis Dissecans Lesions in One Knee: A Case Report 
Osteochondritis dissecans (OCD) has been defined as a localized process in which a focus of subchondral bone and adjacent articular cartilage separates from the surrounding bone. With the knee being the most common location for OCD development and the propensity for this lesion to be found in those who participate in sports, a repetitive microtrauma hypothesis for its cause has gained favor. However, the cause of OCD remains controversial, as does the most appropriate treatment for the varying degrees of OCD lesions.
Case Description
We present a unique case of three OCD lesions in one knee. The patient was a young, athletic boy who developed three separate OCD lesions in his right knee over the course of 4 years. Temporally, the OCD lesions developed first in the lateral femoral condyle, then in the medial femoral condyle, and finally in the trochlea.
Literature Review
Our literature review yielded a few reports of bicondylar OCD lesions. We identified no previous reports of three separate OCD lesions found in a single joint.
Purposes and Clinical Relevance
This report illustrates how a uniquely affected knee with three OCD lesions was treated in three different ways with resolution of symptoms. Each of the OCD lesions was evaluated individually and treatment for each based on the severity of the lesion from the physical examination, imaging studies, and arthroscopic findings.
PMCID: PMC3586005  PMID: 22453935
5.  Radiographic closure time of appendicular growth plates in the Icelandic horse 
The Icelandic horse is a pristine breed of horse which has a pure gene pool established more than a thousand years ago, and is approximately the same size as living and extinct wild breeds of horses. This study was performed to compare the length of the skeletal growth period of the "primitive" Icelandic horse relative to that reported for large horse breeds developed over the recent centuries. This information would provide practical guidance to owners and veterinarians as to when the skeleton is mature enough to commence training, and would be potentially interesting to those scientists investigating the pathogenesis of osteochondrosis. Interestingly, osteochondrosis has not been documented in the Icelandic horse.
The radiographic closure time of the appendicular growth plates was studied in 64 young Icelandic horses. The results were compared with previously published closure times reported for other, larger horse breeds. The radiographs were also examined for any signs of developmental orthopaedic diseases. In order to describe further the growth pattern of the Icelandic horse, the total serum alkaline phosphatase (ALP) activity was determined and the height at the withers was measured.
Most of the examined growth plates were fully closed at the age of approximately three years. The horses reached adult height at this age; however ALP activity was still mildly increased over baseline values. The growth plates in the digits were the first to close at 8.1 to 8.5 months of age, and those in the regions of the distal radius (27.4 to 32.0 months), tuber olecrani (31.5 to 32.2 months), and the stifle (27.0 to 40.1 months) were the last to close. No horse was found to have osteochondrosis type lesions in the neighbouring joints of the evaluated growth plates.
The Icelandic horse appears to have similar radiographic closure times for most of the growth plates of its limbs as reported for large new breeds of horses developed during the past few centuries. It thus appears that different breeding goals and the intensity of breeding have not altered the length of the growth period in horses. Instead, it can be assumed that the pristine and relatively small Icelandic horse has a slower rate of growth. The appendicular skeleton of Icelandic horses has completed its bone growth in length at approximately 3 years of age, and therefore may be able to enter training at this time.
PMCID: PMC1950711  PMID: 17640333
6.  Culling Rate of Icelandic Horses due to Bone Spavin 
Acta Veterinaria Scandinavica  2003;44(4):161-169.
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 11 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.
PMCID: PMC1831549  PMID: 15074629
Icelandic horses; bone spavin osteoarthroses; survival analysis; questionnaire
7.  Non-terminal animal model of post-traumatic osteoarthritis induced by acute joint injury 
Develop a non-terminal animal model of acute joint injury that demonstrates clinical and morphological evidence of early post-traumatic osteoarthritis (PTOA).
An osteochondral (OC) fragment was created arthroscopically in one metacarpophalangeal (MCP) joint of 11 horses and the contralateral joint was sham operated. Eleven additional horses served as unoperated controls. Every 2 weeks, force plate analysis, flexion response, joint circumference, and synovial effusion scores were recorded. At weeks 0 and 16, radiographs (all horses) and arthroscopic videos (OC injured and sham joints) were graded. At week 16, synovium and cartilage biopsies were taken arthroscopically from OC injured and sham joints for histologic evaluation and the OC fragment was removed.
Osteochondral fragments were successfully created and horses were free of clinical lameness after fragment removal. Forelimb gait asymmetry was observed at week 2 (P=0.0012), while joint circumference (P<0.0001) and effusion scores (P<0.0001) were increased in injured limbs compared to baseline from weeks 2 to 16. Positive flexion response of injured limbs was noted at multiple time points. Capsular enthesophytes were seen radiographically in injured limbs. Articular cartilage damage was demonstrated arthroscopically as mild wear-lines and histologically as superficial zone chondrocyte death accompanied by mild proliferation. Synovial hyperemia and fibrosis were present at the site of OC injury.
Acute OC injury to the MCP joint resulted in clinical, imaging, and histologic changes in cartilage and synovium characteristic of early PTOA. This model will be useful for defining biomarkers of early osteoarthritis and for monitoring response to therapy and surgery.
PMCID: PMC3624059  PMID: 23467035
osteoarthritis; PTOA; animal model; cartilage; trauma; equine
8.  Effects of lesion size and location on equine articular cartilage repair. 
The mechanisms and completeness of equine articular cartilage repair were studied in ten horses over a nine month period. Large (15 mm square) and small (5 mm square) full-thickness lesions were made in weight bearing and nonweight bearing areas of the radiocarpal, middle carpal and femoropatellar joints. The horses were euthanized in groups of two 1, 2.5, 4, 5 and 9 months later. Gross pathology, microradiography, and histopathology were used to evaluate qualitative aspects of articular repair. Computer assisted microdensitometry of safranin-O stained cartilage sections was used to quantitate cartilage matrix proteoglycan levels. Structural repair had occurred in most small defects at the end of nine months by a combination of matrix flow and extrinsic repair mechanisms. Elaboration of matrix proteoglycans was not complete at this time. Statistically better healing occurred in small weight bearing lesions, compared to large or nonweight bearing lesions. Synovial and perichondrial pannus interfered with healing of osteochondral defects that were adjacent to the cranial rim of the third carpal bone. Clinical and experimental experience suggests that these lesions are unlikely to heal, whereas similar lesions in the radiocarpal and femoropatellar joints had satisfactory outcomes. Observations made in this study support the use of early postoperative ambulation, passive flexion of operated joints, and recuperative periods of up to a year for large cartilage defects.
PMCID: PMC1255413  PMID: 3349393
9.  Palliative therapy of osteochondrosis dessicans in a Duroc boar 
A 2-year-old, 210-kg, Duroc boar manifested with a grade II–III left front lameness. The boar was treated systemically with isolfupredone acetate and a 5-week course of ketoprofen. The lameness resolved and the ketoprofen was discontinued; however, the lameness returned and the boar was euthanized humanely. Postmortem examination was consistent with osteochondrosis dessicans.
PMCID: PMC2147703  PMID: 18320984
10.  Development of osteochondrosis in Lusitano foals: A radiographic study 
The Canadian Veterinary Journal  2012;53(10):1079-1084.
This study aimed to detect, by radiographic examination, the evolution of osteochondral lesions in the tarsocrural and femoropatellar joints of Lusitano foals. Within 1 month of age, 76.08% of foals had radiographic signs of osteochondrosis, but only 16.20% had lesions at 18 months. The radiographic signs resolved by 5 mo of age in most foals, but some cases that involved either joint, were not resolved until 12 mo of age. It is thought that the “age of no return” is 5 mo for the tarsocrural and 8 mo for the femoropatellar joint but this study demonstrated regression of osteochondral lesions in both joints of Lusitano foals up to 12 months of age.
PMCID: PMC3447310  PMID: 23543926
11.  Pathological changes in the navicular bone and associated structures of the horse. 
Navicular bones from 74 horses were examined at necropsy. Animals ranged in age from eight months to 30 years. Eight horses had a clinical history of navicular disease. Degenerative lesions in the fibrocartilaginous surface of the navicular bone and of the surface of the deep flexor tendons were age related changes not necessarily related to lameness. These lesions were more extensive in horses with a history of navicular disease, and were often accompanied by adhesions and subchondral cavitation of the fibrocartilaginous surface of the navicular bone. Osteophytes, present in 12 of the 74 horses, appeared to be age-related and were uncommon in horses with a history of navicular disease. Nutrient foramina on the distal border of the navicular bone were highly variable in size and shape; in horses with a history of navicular disease they often had a small external opening that became larger as it penetrated the bone. Occlusive vascular disease (arteriosclerosis) was found in sound horses and in horses with a history of navicular disease. Thrombosis of arteries or ischemic necrosis of bone was not identified in any case.
PMCID: PMC1235964  PMID: 6667428
12.  Treatment principles for osteochondral lesions in foot and ankle 
International Orthopaedics  2013;37(9):1697-1706.
Osteochondral lesion of the talus (OLT) is a broad term used to describe an injury or abnormality of the talar articular cartilage and adjacent bone. A variety of terms have been used to refer to this clinical entity, including osteochondritis dissecans (OCD), osteochondral fracture and osteochondral defect. Whether OLT is a precursor to more generalised arthrosis of the ankle remains unclear, but the condition is often symptomatic enough to warrant treatment. In more than one third of cases, conservative treatment is unsuccessful, and surgery is indicated. There is a wide variety of treatment strategies for osteochondral defects of the ankle, with new techniques that have substantially increased over the last decade. The common treatment strategies of symptomatic osteochondral lesions include nonsurgical treatment, with rest, cast immobilisation and use of nonsteroidal anti-inflammatory drugs (NSAIDs). Surgical options are lesion excision, excision and curettage, excision combined with curettage and microfracturing, filling the defect with autogenous cancellous bone graft, antegrade (transmalleolar) drilling, retrograde drilling, fixation and techniques such as osteochondral transplantation [osteochondral autograft transfer system (OATS)] and autologous chondrocyte implantation (ACI). Furthermore, smaller lesions are symptomatic and when left untreated, OCDs can progress; current treatment strategies have not solved this problem. The target of these treatment strategies is to relieve symptoms and improve function. Publications on the efficacy of these treatment strategies vary. In most cases, several treatment options are viable, and the choice of treatment is based on defect type and size and preferences of the treating clinician.
PMCID: PMC3764304  PMID: 23982639
Osteochondral lesions; Osteochondritis dissecans; Talus; Foot and ankle; Cartilage damage; Subchondral bone
13.  Joint disorder; a contributory cause to reproductive failure in beef bulls? 
The lame sire, unsound for breeding, can cause substantial economic loss due to reduced pregnancies in the beef-producing herd.
To test the hypothesis that joint disorder is a possible cause of infertility in beef sires, right and left hind limb bones from 34 beef sires were examined postmortem to identify lesions in the femorotibial, femoropatellar (stifle), tarsocrural, talocalcaneus, and proximal intertarsal (tarsal) joints. The bulls were slaughtered during or after the breeding season due to poor fertility results. Aliquots of the cauda epididymal contents taken postmortem from 26 bulls were used for sperm morphology evaluation. As a control, hind limbs (but no semen samples) from 11 beef bulls with good fertility results were included.
Almost all infertile bulls (30/34) had lesions in at least one joint. Twenty-eight bulls (28/30, 93%) had lesions in the stifle joint, and 24 (24/28, 86%) of these were bilateral. Fourteen bulls (14/30, 47%) had lesions in the tarsal joint, and 10 (10/14, 71%) of these were bilateral. Four bulls (4/34, 12%) had no lesions, three bulls (3/34, 9%) had mild osteoarthritis (OA), 5 (5/34, 15%) moderate OA, 17 (17/34, 50%) severe OA and 5 (5/34, 15%) deformed OA. Almost all OA lesions (97%) were characterized as lesions secondary to osteochondrosis dissecans. All the bulls with satisfactory sperm morphology (n = 12/34) had joint lesions, with mostly severe or deformed bilateral lesions (83%). Consequently, the most likely cause of infertility in these 12 bulls was joint disease. Almost all control bulls (10/11) had OA lesions, but most of them were graded as mild (55%) or moderate (36%). None of the control bulls had severe lesions or deformed OA.
We suggest that joint lesions should be taken into consideration as a contributory cause of reproductive failure in beef sires without symptoms of lameness.
PMCID: PMC2212630  PMID: 17983470
14.  Weightbearing ovine osteochondral defects heal with inadequate subchondral bone plate restoration: implications regarding osteochondral autograft harvesting 
It is unknown what causes donor site morbidity following the osteochondral autograft transfer procedure or how donor sites heal. Contact pressure and edge loading at donor sites may play a role in the healing process. It was hypothesized that an artificially created osteochondral defect in a weightbearing area of an ovine femoral condyle will cause osseous bridging of the defect from the upper edges, resulting in incomplete and irregular repair of the subchondral bone plate.
To simulate edge loading, large osteochondral defects were created in the most unfavourable weightbearing area of 24 ovine femoral condyles. After killing at 3 and 6 months, osteochondral defects were histologically and histomorphometrically evaluated with specific attention to subchondral bone healing and subchondral bone plate restoration.
Osteochondral defect healing showed progressive osseous defect bridging by sclerotic circumferential bone apposition. Unfilled area decreased significantly from 3 to 6 months (P = 0.004), whereas bone content increased (n.s.). Complete but irregular subchondral bone plate restoration occurred in ten animals. In fourteen animals, an incomplete subchondral bone plate was found. Further common findings included cavitary lesion formation, degenerative cartilage changes and cartilage and subchondral bone collapse.
Osteochondral defect healing starts with subchondral bone plate restoration. However, after 6 months, incomplete or irregular subchondral bone plate restoration and subsequent failure of osteochondral defect closure is common. Graft harvesting in the osteochondral autograft transfer procedure must be viewed critically, as similar changes are also present in humans.
Level of evidence
Prognostic study, Level III.
PMCID: PMC3445791  PMID: 22186925
Donor site morbidity; Osteochondral autograft transfer; Subchondral bone plate
15.  Infection of Immunodeficient Horses with Sarcocystis neurona Does Not Result in Neurologic Disease 
Equine protozoal myeloencephalitis is a progressive neurologic disease of horses most commonly caused by infection with the apicomplexan parasite Sarcocystis neurona. Factors affecting neuroinvasion and neurovirulence have not been determined. We investigated the pathogenesis of infection with S. neurona in horses with severe combined immune deficiency (SCID). Two immunocompetent (IC) Arabian horses and two Arabian horses with SCID were infected orally with 5 × 105 sporocysts of S. neurona. Four IC horses and one SCID horse were infected intravenously (i.v.) with 5 × 108 merozoites of the WSU-1 isolate of S. neurona. Despite prolonged parasitemia and persistent infection of visceral tissues (skeletal muscle, cardiac muscle, lung, liver, and spleen) as demonstrated by PCR and culture, SCID horses did not develop neurologic signs after oral or i.v. infection. S. neurona was undetectable in the neuronal tissues of SCID horses by either PCR, immunohistochemistry, or culture. In contrast, although parasitemia was undetectable in orally infected IC horses and of only short duration in i.v. infected IC horses, four of six IC horses developed neurologic signs. S. neurona was detectable by PCR and/or culture of neural tissue but not visceral tissue of IC horses with neurologic disease. Infected SCID horses are unable to clear S. neurona from visceral tissues, but the infection does not result in neurologic signs; in contrast, IC horses rapidly control parasitemia and infection of visceral tissues but frequently experience neuroinvasion and exhibit clinical signs of neurologic disease.
PMCID: PMC524751  PMID: 15539518
16.  A Review of Knowledge in Osteochondritis Dissecans: 123 Years of Minimal Evolution from König to the ROCK Study Group 
Osteochondritis dissecans (OCD) was first described to provide an explanation for the nontraumatic development of loose bodies within a joint. Despite many reports on the subject, there remains no clear understanding of the etiology, natural history, or treatment.
This review was undertaken to delineate (1) the etiology of OCD; (2) the presentation and locations; (3) the most appropriate imaging modalities; and (4) the most effective treatment strategies.
We reviewed the English literature using a database compiled from a Medline search for “osteochondritis dissecans”. We identified 1716 publications, 1246 of which were in English. After exclusions, we reviewed 748 articles and of these cited 85. The observations of each study were then synthesized into this report.
There appears to be no consensus concerning the etiology of OCD lesions. The presentations and locations are variable, but the knee, ankle, and elbow are most commonly involved. Although plain film assessment is important in OCD, there appears to be a trend toward the use of MRI, but the preferred sequences are in evolution. We found no consensus on the treatment of these lesions, related in part to the lack of agreement of methods for assessing outcomes.
Despite more than a century of study, we have made little advancement in our understanding of OCD. A study group has been formed to address this issue and actively seeks to answer these unknown issues regarding OCD.
PMCID: PMC3586043  PMID: 22362466
17.  Copy Number Variation in the Horse Genome 
PLoS Genetics  2014;10(10):e1004712.
We constructed a 400K WG tiling oligoarray for the horse and applied it for the discovery of copy number variations (CNVs) in 38 normal horses of 16 diverse breeds, and the Przewalski horse. Probes on the array represented 18,763 autosomal and X-linked genes, and intergenic, sub-telomeric and chrY sequences. We identified 258 CNV regions (CNVRs) across all autosomes, chrX and chrUn, but not in chrY. CNVs comprised 1.3% of the horse genome with chr12 being most enriched. American Miniature horses had the highest and American Quarter Horses the lowest number of CNVs in relation to Thoroughbred reference. The Przewalski horse was similar to native ponies and draft breeds. The majority of CNVRs involved genes, while 20% were located in intergenic regions. Similar to previous studies in horses and other mammals, molecular functions of CNV-associated genes were predominantly in sensory perception, immunity and reproduction. The findings were integrated with previous studies to generate a composite genome-wide dataset of 1476 CNVRs. Of these, 301 CNVRs were shared between studies, while 1174 were novel and require further validation. Integrated data revealed that to date, 41 out of over 400 breeds of the domestic horse have been analyzed for CNVs, of which 11 new breeds were added in this study. Finally, the composite CNV dataset was applied in a pilot study for the discovery of CNVs in 6 horses with XY disorders of sexual development. A homozygous deletion involving AKR1C gene cluster in chr29 in two affected horses was considered possibly causative because of the known role of AKR1C genes in testicular androgen synthesis and sexual development. While the findings improve and integrate the knowledge of CNVs in horses, they also show that for effective discovery of variants of biomedical importance, more breeds and individuals need to be analyzed using comparable methodological approaches.
Author Summary
Genomes of individuals in a species vary in many ways, one of which is DNA copy number variation (CNV). This includes deletions, duplications, and complex rearrangements typically larger than 50 base-pairs. CNVs are part of normal genetic variation contributing to phenotypic diversity but can also be pathogenic and associated with diseases and disorders. In order to distinguish between the two, detailed knowledge about CNVs in the species of interest is needed. Here we studied the genomes of 38 normal horses of 16 diverse breeds, and identified 258 CNV regions. We integrated our findings with previously published horse CNVs and generated a composite dataset of ∼1400 CNVRs. Despite this large number, our analysis shows that CNV research in horses needs further improvement because the current data are based on 10% of horse breeds and that most CNVRs are study-specific and require validation. Finally, we analyzed CNVs in horses with disorders of sexual development and found in two male pseudo-hermaphrodites a large deletion disrupting a group of genes involved in sex hormone metabolism and sexual differentiation. The findings underline the possible role of CNVs in complex disorders such as development and reproduction.
PMCID: PMC4207638  PMID: 25340504
18.  Osteochondritis dissecans and Osgood Schlatter disease in a family with Stickler syndrome 
Stickler syndrome is among the most common autosomal dominant connective tissue disorders but is often unrecognised and therefore not diagnosed by clinicians. Despite much speculation, the cause of osteochondrosis in general and osteochondritis dissecans (OCD) and Osgood Schlatter syndrome (OSS) in particular remain unclear. Etiological understanding is essential. We describe a pair of family subjects presented with OCD and OSS as a symptom complex rather than a diagnosis.
Detailed clinical and radiographic examinations were undertaken with emphasis on the role of MRI imaging. Magnetic resonance imaging may allow early prediction of articular lesion healing potential in patients with Stickler syndrome.
The phenotype of Stickler syndrome can be diverse and therefore misleading. The expectation that the full clinical criteria of any given genetic disorder such as Stickler syndrome will always be present can easily lead to an underestimation of these serious inheritable disorders. We report here two family subjects, a male proband and his aunt (paternal sister), both presented with the major features of Stickler syndrome. Tall stature with marfanoid habitus, astigmatism/congenital vitreous abnormality and submucus cleft palate/cleft uvula, and enlarged painful joints with early onset osteoarthritis. Osteochondritis dissecans (OCD) and Osgood Schlatter syndrome (OSS) were the predominating joint abnormalities.
We observed that the nature of the articular and physeal abnormalities was consistent with a localised manifestation of a more generalised epiphyseal dysplasia affecting the weight-bearing joints. In these two patients, OCD and OSS appeared to be the predominant pathologic musculoskeletal consequences of an underlying Stickler's syndrome. It is empirical to consider generalised epiphyseal dysplasia as a major underlying causation that might drastically affect the weight-bearing joints.
PMCID: PMC2645398  PMID: 19193224
19.  The Hypersensitivity of Horses to Culicoides Bites in British Columbia 
The Canadian Veterinary Journal  1988;29(9):718-723.
Culicoides hypersensitivity is a chronic, recurrent, seasonal dermatitis of horses that has a worldwide distribution, but has only recently been reported in Canada. It is characterized by intense pruritus resulting in lesions associated with self-induced trauma.
A survey of veterinarians and horse-owners in British Columbia showed no differences in susceptibility due to the sex, color, breed, or height of the horses. The prevalence of the disease in the 209 horses surveyed was 26%. Horses sharing the same pasture could be unaffected. The disease was reported primarily from southwestern British Columbia; it occurred between April and October and usually affected the ventral midline, mane, and tail. Horses were generally less than nine years old when the clinical signs first appeared ([unk]=5.9 yr). Culicoides hypersensitivity was common in the lineage of several affected horses, possibly indicating a genetic susceptibility. Most cases were severe enough to require veterinary attention and some horses were euthanized.
PMCID: PMC1680856  PMID: 17423117
20.  Radiographic Risk Factors for Contralateral Rupture in Dogs with Unilateral Cranial Cruciate Ligament Rupture 
PLoS ONE  2014;9(9):e106389.
Complete cranial cruciate ligament rupture (CR) is a common cause of pelvic limb lameness in dogs. Dogs with unilateral CR often develop contralateral CR over time. Although radiographic signs of contralateral stifle joint osteoarthritis (OA) influence risk of subsequent contralateral CR, this risk has not been studied in detail.
Methodology/Principal Findings
We conducted a retrospective longitudinal cohort study of client-owned dogs with unilateral CR to determine how severity of radiographic stifle synovial effusion and osteophytosis influence risk of contralateral CR over time. Detailed survival analysis was performed for a cohort of 85 dogs after case filtering of an initial sample population of 513 dogs. This population was stratified based on radiographic severity of synovial effusion (graded on a scale of 0, 1, and 2) and severity of osteophytosis (graded on a scale of 0, 1, 2, and 3) of both index and contralateral stifle joints using a reproducible scoring method. Severity of osteophytosis in the index and contralateral stifles was significantly correlated. Rupture of the contralateral cranial cruciate ligament was significantly influenced by radiographic OA in both the index and contralateral stifles at diagnosis. Odds ratio for development of contralateral CR in dogs with severe contralateral radiographic stifle effusion was 13.4 at one year after diagnosis and 11.4 at two years. Odds ratio for development of contralateral CR in dogs with severe contralateral osteophytosis was 9.9 at one year after diagnosis. These odds ratios were associated with decreased time to contralateral CR. Breed, age, body weight, gender, and tibial plateau angle did not significantly influence time to contralateral CR.
Subsequent contralateral CR is significantly influenced by severity of radiographic stifle effusion and osteophytosis in the contralateral stifle, suggesting that synovitis and arthritic joint degeneration are significant factors in the disease mechanism underlying the arthropathy.
PMCID: PMC4177807  PMID: 25254499
21.  The importance of early arthroscopy in athletes with painful cartilage lesions of the ankle: a prospective study of 61 consecutive cases 
Ankle sprains are common in sports and can sometimes result in a persistent pain condition.
Primarily to evaluate clinical symptoms, signs, diagnostics and outcomes of surgery for symptomatic chondral injuries of the talo crural joint in athletes. Secondly, in applicable cases, to evaluate the accuracy of MRI in detecting these injuries. Type of study: Prospective consecutive series.
Over around 4 years we studied 61 consecutive athletes with symptomatic chondral lesions to the talocrural joint causing persistent exertion ankle pain.
43% were professional full time athletes and 67% were semi-professional, elite or amateur athletes, main sports being soccer (49%) and rugby (14%). The main subjective complaint was exertion ankle pain (93%). Effusion (75%) and joint line tenderness on palpation (92%) were the most common clinical findings. The duration from injury to arthroscopy for 58/61 cases was 7 months (5.7–7.9). 3/61 cases were referred within 3 weeks from injury. There were in total 75 cartilage lesions. Of these, 52 were located on the Talus dome, 17 on the medial malleolus and 6 on the Tibia plafond. Of the Talus dome injuries 18 were anteromedial, 14 anterolateral, 9 posteromedial, 3 posterolateral and 8 affecting mid talus. 50% were grade 4 lesions, 13.3% grade 3, 16.7% grade 2 and 20% grade 1. MRI had been performed pre operatively in 26/61 (39%) and 59% of these had been interpreted as normal. Detection rate of cartilage lesions was only 19%, but subchondral oedema was present in 55%. At clinical follow up average 24 months after surgery (10–48 months), 73% were playing at pre-injury level. The average return to that level of sports after surgery was 16 weeks (3–32 weeks). However 43% still suffered minor symptoms.
Arthroscopy should be considered early when an athlete presents with exertion ankle pain, effusion and joint line tenderness on palpation after a previous sprain. Conventional MRI is not reliable for detecting isolated cartilage lesions, but the presence of subchondral oedema should raise such suspicion.
PMCID: PMC1635006  PMID: 17150124
22.  Osteochondritis Dissecans Knee Histology Studies Have Variable Findings and Theories of Etiology 
Although many etiological theories have been proposed for osteochondritis dissecans (OCD), its etiology remains unclear. Histological analysis of the articular cartilage and subchondral bone tissues of OCD lesions can provide useful information about the cellular changes and progression of OCD. Previous research is predominantly comprised of retrospective clinical studies from which limited conclusions can be drawn.
The purposes of this study were threefold: (1) Is osteonecrosis a consistent finding in OCD biopsy specimens? (2) Is normal articular cartilage a consistent finding in OCD biopsy specimens? (3) Do histological studies propose an etiology for OCD based on the tissue findings?
We searched the PubMed, Embase, and CINAHL databases for studies that conducted histological analyses of OCD lesions of the knee and identified 1560 articles. Of these, 11 met our inclusion criteria: a study of OCD lesions about the knee, published in the English language, and performed a histological analysis of subchondral bone and articular cartilage. These 11 studies were assessed for an etiology proposed in the study based on the study findings.
Seven of 11 studies reported subchondral bone necrosis. Four studies reported normal articular cartilage, two studies reported degenerated or irregular articular cartilage, and five studies found a combination of normal and degenerated or irregular articular cartilage. Five studies proposed trauma or repetitive stress and two studies proposed poor blood supply as possible etiologies.
We found limited research on histological analysis of OCD lesions of the knee. Future studies with consistent methodology are necessary to draw major conclusions about the histology and progression of OCD lesions. Inconsistent histologic findings have resulted in a lack of consensus regarding the presence of osteonecrosis, whether the necrosis is primary or secondary, the association of cartilage degeneration, and the etiology of OCD. Such studies could use a standardized grading system to allow better comparison of findings.
PMCID: PMC3586021  PMID: 23054514
23.  Stifle Lameness in Cattle at Two Veterinary Teaching Hospitals: A Retrospective Study of Forty-two Cases 
The Canadian Veterinary Journal  1985;26(7):212-217.
Records of two veterinary teaching hospitals from January 1, 1976 to June 1, 1982 were searched for diagnoses of stifle lameness. Forty-two records were found and information was recorded regarding signalment, history and clinical presentation. The following abnormalities were associated with stifle lameness: subchondral bone cyst (18 cases), joint instability (15 cases), degenerative joint disease (12 cases), cranial cruciate ligament injury (9 cases), cytological or bacteriological evidence of sepsis (9 cases), collateral ligament injury (3 cases), femorotibial luxation (2 cases) and intra-articular fracture (2 cases). The duration of lameness presentation ranged from 0.3 to 24 weeks and the mean follow-up period was 20.47 ± 11.44 months (three animals were lost to follow-up). Animals (n = 15) with subchondral bone cysts as the sole association with lameness presented at an early age (range — 6 to 18 months) and apparently regardless of treatment, had a good prognosis as determined by 75% (three lost to follow-up) returning to their intended function. Cattle (n = 9) with septic arthritis were presented at an age ranging from two months to seven years and only 22.2% returned to function. Cattle (n = 15) with joint instability presented at an age varying from nine months to 13 years also did poorly as only 26.6% returned to function.
PMCID: PMC1680086  PMID: 17422551
Cattle; stifle; lameness; septic arthritis; subchondral bone cyst; degenerative joint disease
24.  Three-dimensional osteochondral microtissue to model pathogenesis of osteoarthritis 
Stem Cell Research & Therapy  2013;4(Suppl 1):S6.
Osteoarthritis (OA), the most prevalent form of arthritis, affects up to 15% of the adult population and is principally characterized by degeneration of the articular cartilage component of the joint, often with accompanying subchondral bone lesions. Understanding the mechanisms underlying the pathogenesis of OA is important for the rational development of disease-modifying OA drugs. While most studies on OA have focused on the investigation of either the cartilage or the bone component of the articular joint, the osteochondral complex represents a more physiologically relevant target because the disease ultimately is a disorder of osteochondral integrity and function. In our current investigation, we are constructing an in vitro three-dimensional microsystem that models the structure and biology of the osteochondral complex of the articular joint. Osteogenic and chondrogenic tissue components are produced using adult human mesenchymal stem cells derived from bone marrow and adipose seeded within biomaterial scaffolds photostereolithographically fabricated with defined internal architecture. A three-dimensional-printed, perfusion-ready container platform with dimensions to fit into a 96-well culture plate format is designed to house and maintain the osteochondral microsystem that has the following features: an anatomic cartilage/bone biphasic structure with a functional interface; all tissue components derived from a single adult mesenchymal stem cell source to eliminate possible age/tissue-type incompatibility; individual compartments to constitute separate microenvironment for the synovial and osseous components; accessible individual compartments that may be controlled and regulated via the introduction of bioactive agents or candidate effector cells, and tissue/medium sampling and compositional assays; and compatibility with the application of mechanical load and perturbation. The consequences of mechanical injury, exposure to inflammatory cytokines, and compromised bone quality on degenerative changes in the cartilage component are examined in the osteochondral microsystem as a first step towards its eventual application as an improved and high-throughput in vitro model for prediction of efficacy, safety, bioavailability, and toxicology outcomes for candidate disease-modifying OA drugs.
PMCID: PMC4029306  PMID: 24564995
osteoarthritis; microtissue; osteochondral tissue engineering; mesenchyme stem cells
25.  An evaluation of chemical arthrodesis of the proximal interphalangeal joint in the horse by using monoiodoacetate. 
The use of monoiodoacetate (MIA) for arthrodesis of the proximal interphalangeal joint (PIJ) and the effect of exercise on the degree of fusion were investigated. Eight horses received 3 injections (Weeks 0, 3, 6) of MIA (2 mL; 60 mg/mL) into the right or left front PIJ. Peri-operatively, the horses received phenylbutazone, butorphanol, and abaxial sesamoidean nerve blocks to relieve pain. During the study, the horses were monitored for general health, lameness, and swelling around the injection area. Radiographs were taken biweekly to evaluate bony fusion. Horses were randomly divided into non-exercised and exercised groups. Exercise consisted of 20 minutes of trotting on a treadmill (4 m/s), 3 days per week for 13 weeks. The horses were euthanized at 24 weeks. Slab sections of the PIJ were evaluated grossly and radiographically for bony fusion. Histologic examinations were performed to evaluate articular cartilage. Three horses were excluded from the study after developing soft tissue necrosis around the injection site, septic arthritis, and necrotic tendinitis. The remaining horses remained healthy, developed a grade 1 to 4 lameness with minimal to severe swelling in the PIJ region. All 5 horses showed radiographic evidence of bony fusion, however, no fusion was present when injected joints were examined on postmortem examination. Histologic examination revealed thinning of the cartilage, diffuse necrosis of chondrocytes, with the calcified zone intact. Subjectively, exercise did not influence the degree of cartilage destruction. Based on this study, chemical arthrodesis cannot be advocated in clinical cases because of the high complication rate and lack of bony fusion.
PMCID: PMC1189620  PMID: 11041498

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