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1.  Quantitative Trait Loci (QTL) Study Identifies Novel Genomic Regions Associated to Chiari-Like Malformation in Griffon Bruxellois Dogs 
PLoS ONE  2014;9(4):e89816.
Chiari-like malformation (CM) is a developmental abnormality of the craniocervical junction that is common in the Griffon Bruxellois (GB) breed with an estimated prevalence of 65%. This disease is characterized by overcrowding of the neural parenchyma at the craniocervical junction and disturbance of cerebrospinal fluid (CSF) flow. The most common clinical sign is pain either as a direct consequence of CM or neuropathic pain as a consequence of secondary syringomyelia. The etiology of CM remains unknown but genetic factors play an important role. To investigate the genetic complexity of the disease, a quantitative trait locus (QTL) approach was adopted. A total of 14 quantitative skull and atlas measurements were taken and were tested for association to CM. Six traits were found to be associated to CM and were subjected to a whole-genome association study using the Illumina canine high density bead chip in 74 GB dogs (50 affected and 24 controls). Linear and mixed regression analyses identified associated single nucleotide polymorphisms (SNPs) on 5 Canis Familiaris Autosomes (CFAs): CFA2, CFA9, CFA12, CFA14 and CFA24. A reconstructed haplotype of 0.53 Mb on CFA2 strongly associated to the height of the cranial fossa (diameter F) and an haplotype of 2.5 Mb on CFA14 associated to both the height of the rostral part of the caudal cranial fossa (AE) and the height of the brain (FG) were significantly associated to CM after 10 000 permutations strengthening their candidacy for this disease (P = 0.0421, P = 0.0094 respectively). The CFA2 QTL harbours the Sall-1 gene which is an excellent candidate since its orthologue in humans is mutated in Townes-Brocks syndrome which has previously been associated to Chiari malformation I. Our study demonstrates the implication of multiple traits in the etiology of CM and has successfully identified two new QTL associated to CM and a potential candidate gene.
doi:10.1371/journal.pone.0089816
PMCID: PMC3989173  PMID: 24740420
2.  How much are radiological parameters related to clinical symptoms and function in osteoarthritis of the shoulder? 
International Orthopaedics  2009;34(5):677-681.
Loss of joint space, formation of osteophytes and deformation are common features of osteoarthritis. Little information exists about the radiological features of arthrosis in relation to clinical findings and the radiological appearance in degenerative shoulder joint disease especially with regard to decision making about the timing of joint replacement. We retrospectively examined 120 standardised X-rays of patients with advanced osteoarthritis of the shoulder. Exclusion criteria included rotator cuff tear, severe glenoid erosion or protrusion. Measurements of joint space width at three levels in each plane (anteroposterior and axillary view), humeral head diameter and size of humeral osteophytes were made by two independent examiners. Osteoarthritis was graded according to Samilson and Prieto. Seventy-five of these patients had a complete record from the clinical investigation (pain record on VAS scale, active and passive range of motion) and the constant score (CS). Mean joint space width in the central anteroposterior level was 1.46 mm ± 1.08 and in the central axillary 0.98 mm ± 1.02. Increasing age was positively correlated with joint space narrowing at all measured levels. The joint space width was not correlated with the Samilson grade or the size of osteophytes. The joint space width was neither correlated with pain nor active or passive ROM. Pain was correlated with active and passive flexion and abduction but not for internal or external rotation. The size of the osteophytes was negatively correlated (active and passive) with flexion, abduction and external and internal rotation. The study illustrates that joint space narrowing and development of osteophytes are reliable but independent parameters of primary shoulder arthrosis and should be recorded separately. The size of the caudal humeral osteophyte is a predictive factor for function and should be taken into account for clinical decision making. The primary clinical feature, pain, as the main indication for surgery is not related to radiological parameters.
doi:10.1007/s00264-009-0846-6
PMCID: PMC2903182  PMID: 19652970
3.  Genetic Mapping of Fixed Phenotypes: Disease Frequency as a Breed Characteristic 
Journal of Heredity  2009;100(Suppl 1):S37-S41.
Traits that have been stringently selected to conform to specific criteria in a closed population are phenotypic stereotypes. In dogs, Canis familiaris, such stereotypes have been produced by breeding for conformation, performance (behaviors), etc. We measured phenotypes on a representative sample to establish breed stereotypes. DNA samples from 147 dog breeds were used to characterize single nucleotide polymorphism allele frequencies for association mapping of breed stereotypes. We identified significant size loci (quantitative trait loci [QTLs]), implicating candidate genes appropriate to regulation of size (e.g., IGF1, IGF2BP2 SMAD2, etc.). Analysis of other morphological stereotypes, also under extreme selection, identified many additional significant loci. Behavioral loci for herding, pointing, and boldness implicated candidate genes appropriate to behavior (e.g., MC2R, DRD1, and PCDH9). Significant loci for longevity, a breed characteristic inversely correlated with breed size, were identified. The power of this approach to identify loci regulating the incidence of specific polygenic diseases is demonstrated by the association of a specific IGF1 haplotype with hip dysplasia, patella luxation, and pacreatitis.
doi:10.1093/jhered/esp011
PMCID: PMC3139361  PMID: 19321632
association; canine; disease; longevity; morphology; QTL
4.  Double acetabular wall—a misleading point for hip arthroplasty: an anatomical, radiological, clinical study 
International Orthopaedics  2013;37(6):1007-1011.
Purpose
Despite the great attention focused on cup positioning in primary total hip arthroplasty (PTHA), it is surprising to find so few studies that have dealt with cup placement. A common thwarting problem for correct cup placement during PTHA is the existence of osteophytes, which obscure the anatomical landmarks. In this study we aimed to evaluate the morphology of acetabular osteophyte formation in patients with osteoarthritis.
Method
We evaluated 276 patients with hip complaints, using plain X-rays and CT scans.
Results
Of these patients, 57 underwent surgery. We developed a staging system for central osteophytes in hip osteoarthritis based on the radiographic and anatomical findings of our patients.
Conclusion
We recommend routine use of CT scans for patients scheduled for PTHA in order to assess the stage of osteophyte before surgery and, thus, reduce the risk of failure resulting from the interrupted acetabular landmarks.
doi:10.1007/s00264-013-1780-1
PMCID: PMC3664162  PMID: 23436163
5.  A Posteriori Comparison of Natural and Surgical Destabilization Models of Canine Osteoarthritis 
BioMed Research International  2013;2013:180453.
For many years Canis familiaris, the domestic dog, has drawn particular interest as a model of osteoarthritis (OA). Here, we optimized the dog model of experimental OA induced by cranial cruciate ligament sectioning. The usefulness of noninvasive complementary outcome measures, such as gait analysis for the limb function and magnetic resonance imaging for structural changes, was demonstrated in this model. Relationships were established between the functional impairment and the severity of structural changes including the measurement of cartilage thinning. In the dog model of naturally occurring OA, excellent test-retest reliability was denoted for the measurement of the limb function. A criterion to identify clinically meaningful responders to therapy was determined for privately owned dogs undergoing clinical trials. In addition, the recording of accelerometer-based duration of locomotor activity showed strong and complementary agreement with the biomechanical limb function. The translation potential of these models to the human OA condition is underlined. A preclinical testing protocol which combines the dog model of experimental OA induced by cranial cruciate ligament transection and the Dog model of naturally occurring OA offers the opportunity to further investigate the structural and functional benefits of disease-modifying strategies. Ultimately, a better prediction of outcomes for human clinical trials would be brought.
doi:10.1155/2013/180453
PMCID: PMC3833019  PMID: 24288664
6.  Influence of radiographic phenotype on risk of hip osteoarthritis within families 
Annals of the Rheumatic Diseases  2004;63(3):259-263.
Objective: To determine whether the magnitude of the genetic influence on the development of hip osteoarthritis (OA) varies according to the radiographic phenotype within families.
Participants and methods: 331 families in which at least one sibling (index participant) had undergone total hip replacement for OA and whose preoperative x ray findings were available; 505 siblings of these index participants, who have high exposure to genetic risk of hip OA; and 1718 participants who had previously undergone intravenous urography, representative of the average general population exposure to genetic risk. Prevalence of hip OA was determined by individual radiographic features and minimum hip joint space. OA phenotype was partitioned according to pattern of femoral head migration and osteophyte bone response. Age adjusted odds ratios for hip OA in siblings, stratified according to phenotypic pattern in their index sibling, were assessed by unconditional logistic regression.
Results: The superior pattern of femoral head migration was more common in men, and the axial pattern more common in women. A poor bone response (absent osteophytosis) was associated with an indeterminate pattern of migration. The age adjusted odds ratios for definite hip OA were twofold higher in siblings of index participants who had no osteophyte response than in siblings whose index case had any degree of osteophyte (OR 2.05, 95% CI 1.12 to 3.76). The risk of the siblings from these families having undergone hip replacement themselves was threefold higher. Patterns of migration and bone response were not concordant within families, even among same sex siblings.
Conclusion: Careful phenotypic characterisation is essential for genetic studies of hip OA. The results of these studies are likely to be influenced by the phenotypic pattern of hip disease, particularly osteophyte bone response.
doi:10.1136/ard.2002.003780
PMCID: PMC1754908  PMID: 14962959
7.  Expression of transforming growth factor‐β (TGFβ) and the TGFβ signalling molecule SMAD‐2P in spontaneous and instability‐induced osteoarthritis: role in cartilage degradation, chondrogenesis and osteophyte formation 
Annals of the Rheumatic Diseases  2006;65(11):1414-1421.
Background
The primary feature of osteoarthritis is cartilage loss. In addition, osteophytes can frequently be observed. Transforming growth factor‐β (TGFβ) has been suggested to be associated with protection against cartilage damage and new cartilage formation as seen in osteophytes.
Objective
To study TGFβ and TGFβ signalling in experimental osteoarthritis to gain insight into the role of TGFβ in cartilage degradation and osteophyte formation during osteoarthritis progression.
Methods
Histological sections of murine knee joints were stained immunohistochemically for TGFβ3 and phosphorylated SMAD‐2 (SMAD‐2P). Expression patterns were studied in two murine osteoarthritis models, representing spontaneous (STR/ort model) and instability‐associated osteoarthritis (collagenase‐induced instability model).
Results
TGFβ3 and SMAD‐2P staining was increasingly reduced in cartilage during osteoarthritis progression in both models. Severely damaged cartilage was negative for TGFβ3. In contrast, bone morphogenetic protein‐2 (BMP‐2) expression was increased. In chondrocyte clusters, preceding osteophyte formation, TGFβ3 and SMAD‐2P were strongly expressed. In early osteophytes, TGFβ3 was found in the outer fibrous layer, in the peripheral chondroblasts and in the core. Late osteophytes expressed TGFβ3 only in the fibrous layer. SMAD‐2P was found throughout the osteophyte at all stages. In the late‐stage osteophytes, BMP‐2 was strongly expressed.
Conclusion
Data show that lack of TGFβ3 is associated with cartilage damage, suggesting loss of the protective effect of TGFβ3 during osteoarthritis progression. Additionally, our results indicate that TGFβ3 is involved in early osteophyte development, whereas BMP might be involved in late osteophyte development.
doi:10.1136/ard.2005.045971
PMCID: PMC1798346  PMID: 16439443
8.  Cranial acetabular retroversion is common in developmental dysplasia of the hip as assessed by the weight bearing position 
Acta Orthopaedica  2010;81(4):436-441.
Background and purpose
The appearance of acetabular version differs between the supine and weight bearing positions in developmental dysplasia of the hip. Weight bearing radiographic evaluation has been recommended to ensure the best coherence between symptoms, functional appearance, and hip deformities. Previous prevalence estimates of acetabular retroversion in dysplastic hips have been established in radiographs recorded with the patient supine and with inclusion only if pelvic tilt met standardized criteria. We assessed the prevalence and the extent of acetabular retroversion in dysplastic hip joints in weight bearing pelvic radiographs.
Patients and methods
We assessed 95 dysplastic hip joints (54 patients) in weight bearing anteroposterior pelvic radiographs, measuring the acetabular height and the distance from the acetabular roof to the point of crossing of the acetabular rims, if present.
Results
Acetabular retroversion was found in 31 of 95 dysplastic hip joints. In 28 of 31 hip joints with retroversion, crossover of the acetabular rims was positioned within the cranial 30% sector. The degree of pelvic tilt differed between retroverted and non-retroverted dysplastic hip joints, though only reaching a statistically significant level in male dysplastic hip joints.
Interpretation
We identified cranial acetabular retroversion in one-third of dysplastic hip joints when assessed on weight bearing pelvic radiographs. If assessed on pelvic radiographs obtained with the patient supine, and with inclusion only if the degree of pelvic tilt meets standardized criteria, the prevalence of acetabular retroversion may be underestimated.
doi:10.3109/17453674.2010.501745
PMCID: PMC2917565  PMID: 20809742
9.  Radiographic Hip Joint Phenotype of the Pembroke Welsh Corgi 
Veterinary surgery : VS  2012;41(1):10.1111/j.1532-950X.2011.00938.x.
Objective
To investigate the radiographic hip joint phenotype of the Pembroke Welsh Corgi.
Study Design
Prospective and retrospective cross-sectional study.
Animals
Pembroke Welsh Corgis (n = 399).
Methods
Ventrodorsal, hip-extended radiographs were evaluated for subluxation, osteoarthritis (OA), caudolateral curvilinear osteophytes (CCO), and circumferential femoral head osteophytes (CFHO) of PennHIP evaluated Corgis. Joint laxity was measured by distraction index (DI).
Results
All Corgis had DI > 0.30 (mean, 0.66), 6.8% had OA, 18% had subluxation, 22.3% had CCO, and 74.4% had CFHO. Higher DI increased the odds for subluxation and canine hip dysplasia (CHD) but not for OA, CCO, or CFHO. The presence of CCO increased the odds for OA by 4.6 times (P = .002) and 2.2 times (P = .01) for hip dysplasia. All dogs with OA had CFHO. The presence of CFHO increased the odds for subluxation by 8.7 times (p < .001) and 8.9 times (P < .001) for hip dysplasia. Subluxation increased the odds for OA by 15.4 times (P < .001).
Conclusion
Corgis had a low frequency of conventional OA despite having hip laxity that has been shown to correlate with hip OA and hip dysplasia in large-breed dogs. The relationship between CCO and OA was similar to published findings in nonchondrodystrophic large-breed dogs and the CFHO was significantly associated with subluxation. Both CCO and CFHO are associated with hip dysplasia in this small chondrodystrophic breed.
doi:10.1111/j.1532-950X.2011.00938.x
PMCID: PMC3842694  PMID: 23253037
10.  Characterisation of size and direction of osteophyte in knee osteoarthritis: a radiographic study 
Annals of the Rheumatic Diseases  2002;61(4):319-324.
Objectives: To examine the size and direction of osteophyte in knee osteoarthritis (OA) and to determine associations between osteophyte size and other radiographic features.
Methods: Knee radiographs (standing extended anteroposterior and 30 degrees flexion skyline views) were examined from 204 patients referred to hospital with symptomatic knee OA (155 women, 49 men; mean age 70, range 34–91 years). A single observer assessed films for osteophyte size and direction at eight sites; narrowing in each compartment; varus/valgus angulation; patellofemoral subluxation; attrition; and chondrocalcinosis using a standard atlas, direct measurement, or visual assessment. For analysis, one OA knee was selected at random from each subject.
Results: Osteophyte direction at the eight sites was divisible into five categories. At all sites, except for the lateral tibial plateau and the medial patella, osteophyte direction varied according to (a) the size of osteophyte and (b) the degree of local narrowing. At the medial femur, medial tibia, and lateral femur osteophyte direction changed from being predominantly horizontal to predominantly vertical with increasing size. The size of osteophyte correlated positively with the severity of local narrowing, except for the medial patellofemoral compartment where osteophyte size correlated positively with the severity of narrowing in the medial tibiofemoral compartment. Logistic regression analysis showed that osteophyte size was associated not only with local narrowing but also with local malalignment and bone attrition, and that chondrocalcinosis was positively associated with osteophyte size at multiple sites.
Conclusion: In patients referred to hospital with knee OA different patterns of osteophyte direction are discernible. Osteophyte size is associated with local compartmental narrowing but also local alignment and attrition. Chondrocalcinosis is associated with osteophytosis throughout the joint. These data suggest that both local biomechanical and constitutional factors influence the size and direction of osteophyte formation in knee OA.
doi:10.1136/ard.61.4.319
PMCID: PMC1754047  PMID: 11874834
11.  Bilaterally Asymmetric Effects of Quantitative Trait Loci (QTLs): QTLs That Affect Laxity in the Right Versus Left Coxofemoral (Hip) Joints of the Dog (Canis familiaris) 
In dogs hip joint laxity that can lead to degenerative joint disease (DJD) is frequent and heritable, providing a genetic model for some aspects of the human disease. We have used Portuguese water dogs (PWDs) to identify Quantitative trait loci (QTLs) that regulate laxity in the hip joint.A population of 286 PWDs, each characterized by ca. 500 molecular genetic markers, was analyzed for subluxation of the hip joint as measured by the Norberg angle, a quantitative radiographic measure of laxity. A significant directed asymmetry was observed, such that greater laxity was observed in the left than the right hip. This asymmetry was not heritable. However, the average Norberg angle was highly heritable as were the Norberg angles of either the right or left hips. After correction for pedigree effects, two QTLs were identified using the metrics of the left and right hips as separate data sets. Both are on canine chromosome 1 (CFA1), separated by about 95 Mb. One QTL, associated with the SSR marker FH2524 was significant for the left, but not the right hip. The other, associated with FH2598, was significant for the right but not the left hip. For both QTLs, some extreme phenotypes were best explained by specific interactions between haplotypes.
doi:10.1002/ajmg.a.20363
PMCID: PMC2778498  PMID: 14708095
quantitative trait loci (QTLs); dog; hip laxity; bilateral asymmetry; Norberg angle; Canine genetics; hip dysplasia
12.  Diagnostic accuracy of a short-duration 3 Tesla magnetic resonance protocol for diagnosing stifle joint lesions in dogs with non-traumatic cranial cruciate ligament rupture 
Background
Magnetic resonance (MR) imaging is the preferred diagnostic tool to evaluate internal disorders of many joints in humans; however, the usefulness of MR imaging in the context of osteoarthritis, and joint disease in general, has yet to be characterized in veterinary medicine. The objective of this study was to assess the diagnostic accuracy of short-duration 3 Tesla MR imaging for the evaluation of cranial and caudal cruciate ligament, meniscal and cartilage damage, as well as the degree of osteoarthritis, in dogs affected by non-traumatic, naturally-occurring cranial cruciate ligament rupture (CCLR). Diagnoses made from MR images were compared to those made during surgical exploration. Twenty-one client-owned dogs were included in this study, and one experienced evaluator assessed all images.
Results
All cranial cruciate ligaments were correctly identified as ruptured. With one exception, all caudal cruciate ligaments were correctly identified as intact. High sensitivities and specificities were obtained when diagnosing meniscal rupture. MR images revealed additional subclinical lesions in both the cranial and caudal cruciate ligaments and in the menisci. There was a “clear” statistical (kappa) agreement between the MR and the surgical findings for both cartilage damage and degree of osteoarthritis. However, the large 95% confidence intervals indicated that evaluation of cartilage damage and of degree of osteoarthritis is not clinically satisfactory.
Conclusions
The presence of cruciate ligament damage and meniscal tears could be accurately assessed using the MR images obtained with our protocol. However, in the case of meniscal evaluation, occasional misdiagnosis did occur. The presence of cartilage damage and the degree of osteoarthritis could not be properly evaluated.
doi:10.1186/1746-6148-9-40
PMCID: PMC3599255  PMID: 23448526
Dog; Stifle; Cranial cruciate ligament; High-field MRI; Radiography
13.  Distinct developmental growth patterns account for the disproportionate expansion of the rostral and caudal isocortex in evolution 
In adulthood, the isocortex of several species is characterized by a gradient in neurons per unit of cortical surface area with fewer neurons per unit of cortical surface area in the rostral pole relative to the caudal pole. A gradient in neurogenesis timing predicts differences in neurons across the isocortex: neurons per unit of cortical surface area are fewer rostrally, where neurogenesis duration is short, and higher caudally where neurogenesis duration is longer. How species differences in neurogenesis duration impact cortical progenitor cells across its axis is not known. I estimated progenitor cells per unit of ventricular area across the rostro-caudal axis of the isocortex in cats (Felis catus) and in dogs (Canis familiaris) mostly before layers VI-II neurons are generated. I also estimated the ventricular length across the rostro-caudal axis at various stages of development in both species. These two species were chosen because neurogenesis duration in dogs is extended compared with cats. Caudally, cortical progenitors expand more tangentially and in numbers in dogs compared with cats. Rostrally, the cortical proliferative zone expands more tangentially in dogs compared with cats. However, the tangential expansion in the rostral cortical proliferative zone occurs without a concomitant increase in progenitor cell numbers. The tangential expansion of the ventricular surface in the rostral cortex is mediated by a reduction in cell density. These different developmental growth patterns account for the disproportionate expansion of the rostral (i.e., frontal cortex) and caudal cortex (e.g., primary visual cortex) when neurogenesis duration lengthens in evolution.
doi:10.3389/fnhum.2014.00190
PMCID: PMC3986531  PMID: 24782736
cortex; gradient; neurogenesis; development; evolution
14.  Increased levels of the 14-3-3 η and γ proteins in the synovial fluid of dogs with unilateral cranial cruciate ligament rupture 
The present study investigated whether the 14-3-3 η and γ proteins, which are potent matrix metalloprotease (MMP) stimulators, are detectable in the synovial fluid of dogs with cranial cruciate ligament rupture (CCLR). Synovial fluid samples from 7 dogs with unilateral CCLR and control samples from 4 dogs without a history of any joint inflammation or any other abnormalities underwent Western blot analysis for the 14-3-3 η, γ, and σ proteins as well as MMP-1 and MMP-3. Craniocaudal and lateral radiographic projections of the stifle joint were evaluated for the presence and severity of 13 specific radiographic markers of osteoarthritis and graded numerically. The Spearman method was used to detect any correlation between the 14-3-3-η level in the synovial fluid and the radiograph-based grade. The η isoform was present only in the samples from the dogs with CCLR. The levels of 14-3-3-γ, MMP-1, and MMP-3 were significantly higher in the samples from the dogs with CCLR than in the control samples (P < 0.05). However, there was no significant difference between the CCLR and control samples in the level of the σ isoform. The Spearman method showed a significant correlation between the 14-3-3-η level in the synovial fluid and the presence of either patellar osteophytes or lateral or medial (or both) condylar periarticular osteophytes (P < 0.05). The MMP stimulatory effect of the 14-3-3 η and γ isoforms may be the reason for the high levels of MMP-1 and MMP-3 observed. Thus, 14-3-3 proteins, especially the η isoform, may be important markers of osteoarthritis caused by CCLR.
PMCID: PMC3187633  PMID: 22468024
15.  Population prevalence of ultrasound features of osteoarthritis in the hand, knee and hip at age 63 years: the Newcastle thousand families birth cohort 
Background
Musculoskeletal ultrasound has been found to be more sensitive than radiographs in detecting osteophytes. Our objective was to measure the prevalence of features of osteoarthritis (OA), in the dominant hand, knees and hips using ultrasound, within the Newcastle Thousand Families birth cohort.
Methods
Participants were aged 61–63 (mean 63) years. Knee images were scored for presence of osteophytes and effusion. Hip images were scored for the presence of osteophytes and femoral head abnormality. The first carpometacarpal joint, metacarpophalangeal, proximal interphalangeal and distal interphalangeal joints of the index finger (dominant hand) were imaged for osteophytes.
Results
Among 311 participants, prevalence of osteophytes at the distal interphalangeal joint was 70% while it was 23%, 10% and 41% for index proximal interphalangeal and metacarpophalangeal and thumb base carpometacarpal joints respectively. Prevalence of knee osteophytes was 30%, hip OA was 41%. Prevalence of knee effusions was 24% (right) and 20% (left). Ultrasound evidence of generalised OA (48%) and isolated hand OA (31%) was common, compared to isolated hip or knee OA (5%) and both hip and knee OA (3%).
Conclusion
This is the first study to assess prevalence of ultrasound features of OA in a population-based sample. The higher prevalence of hand/hip OA, when compared to previous radiographic studies, supports the hypothesis that ultrasound is more sensitive than radiography in detecting OA, particularly for osteophytes.
doi:10.1186/1471-2474-15-162
PMCID: PMC4031490  PMID: 24884977
Osteoarthritis; Ultrasonography; Prevalence; Epidemiology
16.  Genetic regulation of canine skeletal traits: trade-offs between the hind limbs and forelimbs in the fox and dog 
Synopsis
Genetic variation in functionally integrated skeletal traits can be maintained over 10 million years despite bottlenecks and stringent selection. Here, we describe an analysis of the genetic architecture of the canid axial skeleton using populations of the Portuguese Water Dog Canis familiaris) and silver fox (Vulpes vulpes). Twenty-one skeletal metrics taken from radiographs of the forelimbs and hind limbs of the fox and dog were used to construct separate anatomical principal component (PC) matrices of the two species. In both species, 15 of the 21 PCs exhibited significant heritability, ranging from 25% to 70%. The second PC, in both species, represents a trade-off in which limb-bone width is inversely correlated with limb-bone length. PC2 accounts for approximately 15% of the observed skeletal variation, ~30% of the variation in shape. Many of the other significant PCs affect very small amounts of variation (e.g., 0.2–2%) along trade-off axes that partition function between the forelimbs and hind limbs. These PCs represent shape axes in which an increase in size of an element of the forelimb is associated with a decrease in size of an element of the hind limb and vice versa. In most cases, these trade-offs are heritable in both species and genetic loci have been identified in the Portuguese Water Dog for many of these. These PCs, present in both the dog and the fox, include ones that affect lengths of the forelimb versus the hind limb, length of the forefoot versus that of the hind foot, muscle moment (i.e., lever) arms of the forelimb versus hind limb, and cortical thickness of the bones of the forelimb versus hind limb. These inverse relationships suggest that genetic regulation of the axial skeleton results, in part, from the action of genes that influence suites of functionally integrated traits. Their presence in both dogs and foxes suggests that the genes controlling the regulation of these PCs of the forelimb versus hind limb may be found in other tetrapod taxa.
doi:10.1093/icb/icm023
PMCID: PMC2367254  PMID: 18458753
17.  Defining Incident Radiographic Hip Osteoarthritis for Epidemiologic Studies in Women 
Arthritis and rheumatism  2009;60(4):1052-1059.
Objectives
To evaluate definitions of radiographic hip osteoarthritis (RHOA) for use in longitudinal epidemiologic studies of disease incidence in women.
Methods
We studied 5,839 women from the Study of Osteoporotic Fractures who had had serial pelvic radiographs obtained (mean of 8.3 years apart) and who were followed up (mean followup 7.1 years from the time of the second radiograph) for evaluation of clinical outcomes. Definitions of RHOA were assessed for construct validity (association with symptoms and signs at the time of the second radiograph) and predictive validity (association with total hip replacement [THR] and signs and symptoms a mean of 7.1 years later). Odds ratios (ORs) and 95% confidence intervals were calculated to assess the strength of association using logistic regression.
Results
The cumulative incidence of RHOA ranged from 2.2% to 11.7%. All definitions displayed significant construct validity; the most consistent was found for composite definitions that required the concurrent presence of 2 or more individual radiographic features and definitions based on stringent criteria for joint space narrowing. All definitions except minimum joint space ≤2.5 mm displayed consistent predictive validity. Composite definitions had the strongest associations with THR (OR 10.5–18.5) and hip pain (OR 2.6–2.9). The hips identified as having OA by each definition varied, with especially small overlap between findings using definitions based on osteophytes and those using definitions based on joint space narrowing alone.
Conclusions
Most definitions of incident RHOA display good construct and predictive validity. Composite definitions have the best overall performance, and definitions requiring the presence of both osteophytes (in particular, femoral osteophytes) and joint space narrowing would be recommended for most epidemiologic and genetic studies.
doi:10.1002/art.24382
PMCID: PMC3777428  PMID: 19333950
18.  Synovial perlecan is required for osteophyte formation in knee osteoarthritis 
The osteophyte associated with osteoarthritis (OA) is a bony outgrowth formed at the margins of the affected joint through endochondral ossification-like processes. However, the mechanism of osteophyte formation and its pathogenesis are unclear. Perlecan (Hspg2), a heparan sulfate proteoglycan, is expressed in many extracellular tissues and plays critical roles in skeletal development and diseases. The aim of the present study is to identify the role of synovial perlecan in osteophyte formation using perinatal lethality rescued perlecan-knockout mice (Hspg2−/−-Tg) wherein perlecan expression is lacking in the synovial and other tissues, except for cartilage. We analyzed the development of osteophytes in joints of Hspg2−/−-Tg mice in two different animal models: the surgical OA model, in which the medial collateral ligament was transected and the medial meniscus was resected, and the TGF-β-induced osteophyte formation model. In the surgical OA model, the osteophyte size and maturation were significantly reduced in the OA joints of Hspg2−/−-Tg mice compared with control mice, while OA developed on the medial side of the knee joints with no differences in the cartilage degradation score or synovitis score between control and Hspg2−/−-Tgmice. The reduced osteophyte formation in Hspg2−/−-Tg mice was associated with reduced cell proliferation and chondrogenesis. In the TGF-β model, the osteophyte size and maturation were also significantly reduced in Hspg2−/−-Tg mice compared with control mice. Our findings suggest that synovial perlecan plays an important role in osteophyte development in OA, and they provide insights that may facilitate the development of OA therapy.
doi:10.1016/j.matbio.2013.01.004
PMCID: PMC3843243  PMID: 23339896
Synovial perlecan; Osteophyte; Osteoarthritis; TGF-β Synovium
19.  Periarticular Osteophytes as an Appendicular Joint Stress Marker (JSM): Analysis in a Contemporary Japanese Skeletal Collection 
PLoS ONE  2013;8(2):e57049.
Objective
The aim of this study was to investigate the possibility that periarticular osteophytes plays a role as a appendicular joint stress marker (JSM) which reflects the biomechanical stresses on individuals and populations.
Methods
A total of 366 contemporary Japanese skeletons (231 males, 135 females) were examined closely to evaluate the periarticular osteophytes of six major joints, the shoulder, elbow, wrist, hip, knee, and ankle and osteophyte scores (OS) were determined using an original grading system. These scores were aggregated and analyzed statistically from some viewpoints.
Results
All of the OS for the respective joints were correlated logarithmically with the age-at-death of the individuals. For 70 individuals, in whom both sides of all six joints were evaluated without missing values, the age-standardized OS were calculated. A right side dominancy was recognized in the joints of the upper extremities, shoulder and wrist joints, and the bilateral correlations were large in the three joints on the lower extremity. For the shoulder joint and the hip joint, it was inferred by some distinctions that systemic factors were relatively large. All of these six joints could be assorted by the extent of systemic and local factors on osteophytes formation. Moreover, when the age-standardized OS of all the joints was summed up, some individuals had significantly high total scores, and others had significantly low total scores; namely, all of the individuals varied greatly in their systemic predisposition for osteophytes formation.
Conclusions
This study demonstrated the significance of periarticular osteophytes; the evaluating system for OS could be used to detect differences among joints and individuals. Periarticular osteophytes could be applied as an appendicular joint stress marker (JSM); by applying OS evaluating system for skeletal populations, intra-skeletal and inter-skeletal variations in biomechanical stresses throughout the lives could be clarified.
doi:10.1371/journal.pone.0057049
PMCID: PMC3577756  PMID: 23437307
20.  Individuals with high bone mass have an increased prevalence of radiographic knee osteoarthritis 
Bone  2015;71:171-179.
We previously reported an association between high bone mass (HBM) and a bone-forming phenotype of radiographic hip osteoarthritis (OA). As knee and hip OA have distinct risk factors, in this study we aimed to determine (i) whether HBM is also associated with knee OA, and (ii) whether the HBM knee OA phenotype demonstrates a similar pattern of radiographic features to that observed at the hip.
HBM cases (defined by DXA BMD Z-scores) from the UK-based HBM study were compared with unaffected family controls and general population controls from the Chingford and Hertfordshire cohort studies. A single blinded observer graded AP weight-bearing knee radiographs for features of OA (Kellgren–Lawrence score, osteophytes, joint space narrowing (JSN), sclerosis) using an atlas. Analyses used logistic regression, adjusting a priori for age and gender, and additionally for BMI as a potential mediator of the HBM–OA association, using Stata v12.
609 HBM knees in 311 cases (mean age 60.8 years, 74% female) and 1937 control knees in 991 controls (63.4 years, 81% female) were analysed. The prevalence of radiographic knee OA, defined as Kellgren–Lawrence grade ≥ 2, was increased in cases (31.5% vs. 20.9%), with age and gender adjusted OR [95% CI] 2.38 [1.81, 3.14], p < 0.001. The association between HBM and osteophytosis was stronger than that for JSN, both before and after adjustment for BMI which attenuated the ORs for knee OA and osteophytes in cases vs. controls by approximately 50%.
Our findings support a positive association between HBM and knee OA. This association was strongest for osteophytes, suggesting HBM confers a general predisposition to a subtype of OA characterised by increased bone formation.
Highlights
•We examined associations between high bone mass and radiographic knee osteoarthritis (OA).•High bone mass cases had an increased prevalence of knee OA compared with controls.•The OA phenotype in high bone mass is characterised by osteophytosis.•Body mass index is a partial mediator of the high bone mass–OA association.
doi:10.1016/j.bone.2014.10.015
PMCID: PMC4289915  PMID: 25445455
Osteoarthritis; DXA; Bone mineral density; High bone mass
21.  Evolutionary History of Rabies in Ghana 
Rabies virus (RABV) is enzootic throughout Africa, with the domestic dog (Canis familiaris) being the principal vector. Dog rabies is estimated to cause 24,000 human deaths per year in Africa, however, this estimate is still considered to be conservative. Two sub-Saharan African RABV lineages have been detected in West Africa. Lineage 2 is present throughout West Africa, whereas Africa 1a dominates in northern and eastern Africa, but has been detected in Nigeria and Gabon, and Africa 1b was previously absent from West Africa. We confirmed the presence of RABV in a cohort of 76 brain samples obtained from rabid animals in Ghana collected over an eighteen-month period (2007–2009). Phylogenetic analysis of the sequences obtained confirmed all viruses to be RABV, belonging to lineages previously detected in sub-Saharan Africa. However, unlike earlier reported studies that suggested a single lineage (Africa 2) circulates in West Africa, we identified viruses belonging to the Africa 2 lineage and both Africa 1 (a and b) sub-lineages. Phylogeographic Bayesian Markov chain Monte Carlo analysis of a 405 bp fragment of the RABV nucleoprotein gene from the 76 new sequences derived from Ghanaian animals suggest that within the Africa 2 lineage three clades co-circulate with their origins in other West African countries. Africa 1a is probably a western extension of a clade circulating in central Africa and the Africa 1b virus a probable recent introduction from eastern Africa. We also developed and tested a novel reverse-transcription loop-mediated isothermal amplification (RT-LAMP) assay for the detection of RABV in African laboratories. This RT-LAMP was shown to detect both Africa 1 and 2 viruses, including its adaptation to a lateral flow device format for product visualization. These data suggest that RABV epidemiology is more complex than previously thought in West Africa and that there have been repeated introductions of RABV into Ghana. This analysis highlights the potential problems of individual developing nations implementing rabies control programmes in the absence of a regional programme.
Author Summary
Rabies virus (RABV) is widespread throughout Africa, with the domestic dog being the principal vector. Dog rabies is estimated to cause 24,000 human deaths per year in Africa, however, this estimate is still considered to be conservative. Two sub-Saharan African RABV lineages (Africa 1 and 2) are thought to circulate in western and central Africa. We confirmed the presence of RABV in a cohort of 76 brain samples obtained from rabid animals in Ghana collected from 2007 to 2009. In addition we developed and tested a novel molecular diagnostic assay for the detection of RABV, which offers an alternative RABV diagnostic tool for African laboratories. Our analysis of the genetic sequences obtained confirmed all viruses to be RABV, however, unlike previous studies we detected two sub-Saharan African RABV viruses (Africa 1 and 2) in this cohort, which included a single virus previously undetected in West Africa. We suggest that there has been repeated introduction of new RABVs into Ghana over a prolonged period from other West African countries and more recently from eastern Africa. These observations further highlight the problems of individual developing nations implementing rabies control programmes at a local, rather than regional level.
doi:10.1371/journal.pntd.0001001
PMCID: PMC3071360  PMID: 21483707
22.  What Are the Factors Associated With Acetabular Correction in Perthes-like Hip Deformities? 
Background
Perthes-like hip deformities encompass variable proximal femoral abnormalities and associated acetabular dysplasia that can be reconstructed with contemporary hip preservation procedures. Nevertheless, the necessity and indications for surgical correction of associated acetabular dysplasia have not been established.
Questions/Purposes
We determined whether patient-specific factors (sex, age, BMI, previous surgery, hip pain and function) and/or structural deformity characteristics (radiographic parameters of acetabular morphology) were associated with our indications for acetabular reorientation in surgical reconstruction of Perthes-like hip deformities.
Methods
We compared patient-specific characteristics and radiographic parameters of acetabular morphology in 94 patients (97 hips) with residual Perthes deformities who underwent joint preservation surgery without or with a periacetabular osteotomy (PAO) as part of the reconstruction.
Results
Patient sex, BMI, preoperative Harris hip score, and previous hip surgery were not associated with our indications for a combined femoral and PAO procedure. Radiographic parameters associated with the indication for a PAO included the lateral center-edge angle, anterior center-edge angle, acetabular inclination, and acetabulum-head index. No or mild secondary osteoarthritis and joint congruency were associated with the indication for a PAO as part of the reconstruction.
Conclusions
Contemporary hip preservation surgery for residual Perthes deformities covers a wide spectrum of procedures. We believe a PAO should be considered in the surgical treatment plan for symptomatic patients having radiographic parameters indicating acetabular dysplasia, no or mild secondary osteoarthritis, and adequate joint congruity.
Level of Evidence
Level III, prognostic study. See Instructions for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-012-2507-0
PMCID: PMC3492615  PMID: 22895688
23.  Radiological study of the sacroiliac joints in vertebral ankylosing hyperostosis. 
Annals of the Rheumatic Diseases  1982;41(3):225-231.
A radiological study of the sacroiliac joints was undertaken in 54 patients (32 males, 22 females) with vertebral ankylosing hyperostosis (VAH) and in 46 control patients (24 males, 22 females) matched for age and sex. The ages ranged from 38 to 90 years. The radiographs were taken in anteroposterior, oblique, and craniocaudal projections. The films were read for cranial, ventral, and caudal capsular ossifications, for ventral and caudal osteophytes, and for bone sclerosis. Cranial and/or ventral capsular ossifications were found in 28 (87.5%) males with VAH and in 4 (16.6%) control males (p less than 0.0005), but only in 2 females with VAH and no control female. Sacroiliac capsular ossifications in males with VaH are frequent from the onset, but complete bridging of the joint is not reached before the sixth decade. Women, either VAH or control, have more sacroiliac osteophytes than men. There were 11 out of 22 control women with osteophytes versus 4 out of 24 men (p less than 0.025). The incidence of osteophytes does not seem to increase with age after 50 years. Our findings support the idea of VAH being a distinct entity and not a major form of osteophytosis.
Images
PMCID: PMC1000915  PMID: 7092335
24.  Relationships of hip joint volume ratios with degrees of joint laxity and degenerative disease from youth to maturity in a canine population predisposed to hip joint osteoarthritis 
Objective
To assess relationships of acetabular volume (AV), femoral head volume (FV), and portion of the femoral head within in the acetabulum (FVIA) with each other and with degrees of hip joint laxity and degenerative joint disease from youth to maturity in dogs predisposed to developing hip joint osteoarthritis (OA).
Animals
46 mixed-breed half- or full-sibling hound-type dogs.
Procedures
The distraction index (DI), AV, FV, FVIA, and degree of osteoarthritis (OA score) were quantified in 1 hip joint at 16, 32, and 104 weeks of age. Relationships among variables were evaluated within and between ages. Ratios corresponding to OA scores were compared within ages. Differences among 16-week ratios corresponding to 32-week OA scores and among 16- and 32-week ratios corresponding to 104-week OA scores were evaluated.
Results
Significant positive relationships existed between FV and AV across ages as well as between FVIA/FV and FVIA/AV and between DI and OA score across and within most ages. Such relationships also existed within these variables across most ages. Negative relationships of DI and OA scores with FVIA/FV and FVIA/AV within and among all ages were significant. Sixteen-week AVs, FVs, and FVIAs were greater and FV/AVs and OA scores were less than 32- and 104-week values. The 32-week FVIA/FV was less than 16- and 104-week values, and the 32-week FVIA/AV was less than the 104-week value. The FVIA/FV and FVIA/AV were lower and the DI was higher with higher OA scores within and among most ages.
Conclusions and Clinical Relevance
Structural volumes in lax canine hip joints changed predictably relative to each other during growth, despite degenerative changes. Measures developed in this study may augment current diagnosis and treatment strategies for hip dysplasia in dogs.
doi:10.2460/ajvr.72.3.376
PMCID: PMC3711502  PMID: 21355741
25.  Total hip replacement in developmental dysplasia using an oval-shaped cementless press-fit cup 
International Orthopaedics  2012;36(7):1355-1361.
Purpose
Acetabular roof deficiency due to subluxation of the femoral head (Hartofilakidis type II) increases the complexity of total hip arthroplasty. In these cases some form of support is usually required, to reach stable fixation of the acetabular component. Pursuing this aim, the oval-shaped cementless cranial socket could be an alternative to conventional treatment options.
Methods
Between 1998 and 2008, 37 patients (40 hips) underwent primary total hip arthroplasty using the cranial socket (mean follow-up 5.6 years, range 26 to 133 months). In a retrospective study we compared these clinical and radiological results with the results of a matched control group consisting of 35 patients (40 hips) treated with a standard cementless hemispherical cup in combination with bulk femoral autografting (mean follow-up 6.9 years, range 30 to 151 months).
Results
There were no statistically significant differences in the HHS (p = 0.205) or the SF-36 (p = 0.26) between both groups. There was no prosthesis failure due to septic or aseptic loosening. Time of surgery was significantly shorter in the cranial socket group (p < 0.001). The acetabular component could be placed in the ideal rotational hip centre in 24 (60%) hips in the cranial socket group and 32 (80%) hips in the control group, respectively.
Conclusions
Our study indicates, that the cranial socket can be an alternative treatment option for the reconstruction of acetabular deficiency in osteoarthritis secondary to developmental dysplasia.
doi:10.1007/s00264-012-1510-0
PMCID: PMC3385904  PMID: 22382394

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