Hip joint replacement surgery for idiopathic osteoarthritis aggregates in families

In order to determine whether there is a genetic component to hip or knee joint failure due to idiopathic osteoarthritis (OA), we invited patients (probands) undergoing hip or knee arthroplasty for management of idiopathic OA to provide detailed family histories regarding the prevalence of idiopathic OA requiring joint replacement in their siblings. We also invited their spouses to provide detailed family histories about their siblings to serve as a control group. In the probands, we confirmed the diagnosis of idiopathic OA using American College of Rheumatology criteria. The cohorts included the siblings of 635 probands undergoing total hip replacement, the siblings of 486 probands undergoing total knee replacement, and the siblings of 787 spouses. We compared the prevalence of arthroplasty for idiopathic OA among the siblings of the probands with that among the siblings of the spouses, and we used logistic regression to identify independent risk factors for hip and knee arthroplasty in the siblings. Familial aggregation for hip arthroplasty, but not for knee arthroplasty, was observed after controlling for age and sex, suggesting a genetic contribution to end-stage hip OA but not to end-stage knee OA. We conclude that attempts to identify genes that predispose to idiopathic OA resulting in joint failure are more likely to be successful in patients with hip OA than in those with knee OA.     

Hip joint replacement surgery for idiopathic osteoarthritis aggregates in families

In order to determine whether there is a genetic component to hip or knee joint failure due to idiopathic osteoarthritis (OA), we invited patients (probands) undergoing hip or knee arthroplasty for management of idiopathic OA to provide detailed family histories regarding the prevalence of idiopathic OA requiring joint replacement in their siblings. We also invited their spouses to provide detailed family histories about their siblings to serve as a control group. In the probands, we confirmed the diagnosis of idiopathic OA using American College of Rheumatology criteria. The cohorts included the siblings of 635 probands undergoing total hip replacement, the siblings of 486 probands undergoing total knee replacement, and the siblings of 787 spouses. We compared the prevalence of arthroplasty for idiopathic OA among the siblings of the probands with that among the siblings of the spouses, and we used logistic regression to identify independent risk factors for hip and knee arthroplasty in the siblings. Familial aggregation for hip arthroplasty, but not for knee arthroplasty, was observed after controlling for age and sex, suggesting a genetic contribution to end-stage hip OA but not to end-stage knee OA. We conclude that attempts to identify genes that predispose to idiopathic OA resulting in joint failure are more likely to be successful in patients with hip OA than in those with knee OA.     

Studies in Osteoarthritis of the Hip: Part I, * Classification

A definition and classification of primary OA hip is presented based on radiological criteria. Most cases of unilateral idiopathic OA hip remain unilateral over the years and the majority of these show a distinct radiological pattern with articular cartilage loss in the superolateral area of the joint. In contrast, OA hip with loss of cartilage in the medial area is usually bilateral. A supermedial form appears to be an intermediate type, but is less well defined.It is suggested that superolateral and medial forms of OA hip are fundamentally different in nature. Leg-length disparity, to be discussed in a subsequent section, is related to the superolateral type.     

Linkage of early-onset osteoarthritis and chondrocalcinosis to human chromosome 8q.

Calcium pyrophosphate-deposition disease (CPDD), also called "chondrocalcinosis" or "pseudogout," is a disorder characterized by the deposition of calcium-containing crystals in joint tissue, which leads to arthritis-like symptoms. The presence of these crystals in joint tissue is a common finding in the elderly, and, in this population, there is a poor correlation with joint pain. In contrast, early-onset CPDD has been described in several large families in which the disease progresses to severe degenerative osteoarthritis (OA). In these families, an autosomal dominant mode of inheritance is observed, with an age at onset between the 2d and 5th decades of life. In this report, we describe a large New England family with early-onset CPDD and severe degenerative OA. We found genetic linkage between the disease in this family and chromosome 8q, with a multipoint lod score of 4.06. These results suggest that a defective gene at this location causes the disease in this family.     

Autosomal dominant avascular necrosis of femoral head in two Taiwanese pedigrees and linkage to chromosome 12q13

Avascular necrosis of the femoral head (ANFH) is a debilitating disease that commonly leads to destruction of the hip joint in adults. The etiology of ANFH is unknown, but previous studies have indicated that heritable thrombophilia (increased tendency to form thrombi) and hypofibrinolysis (reduced ability to lyse thrombi), alcohol intake, and steroid use are risk factors for ANFH. We recently identified two families with ANFH showing autosomal dominant inheritance. By applying linkage analysis to a four-generation pedigree, we excluded linkage between the family and three genes related to thrombophilia and hypofibrinolysis: protein C, protein S, and plasminogen activator inhibitor. Furthermore, by a genomewide scan, a significant two-point LOD score of 3.45 (recombination fraction [theta] = 0) was obtained between the family with ANFH and marker D12S85 on chromosome 12. High-resolution mapping was conducted in a second family with ANFH and replicated the linkage to D12S368 (pedigree I: LOD score 2.47, theta = 0.05; pedigree II: LOD score 2.81, theta = 0.10). When an age-dependent-penetrance model was applied, the combined multipoint LOD score was 6.43 between D12S1663 and D12S85. Thus, we mapped the candidate gene for autosomal dominant ANFH to a 15-cM region between D12S1663 and D12S1632 on chromosome 12q13.     

Genome Scan for Predisposing Loci for Distal Interphalangeal Joint Osteoarthritis: Evidence for a Locus on 2q

The genetic contribution to common forms of osteoarthritis (OA) is well established but poorly understood. We performed a genome scan, using 302 markers for loci predisposing to distal interphalangeal joint (DIP) OA. To minimize genetic heterogeneity in our study sample, we identified siblings with a severe, radiologically defined phenotype from the nationwide registers of Finland. In the initial genome scan, linkage analysis in 27 sibships gave a pairwise LOD score (Z) >1.00 with nine of the screening markers. In the second stage, additional markers and family members were genotyped in these chromosomal regions. On 2q12-q13, IL1R1 resulted in Z=2.34 at recombination fraction (theta) 0, allowing a dominant mode of inheritance. Association analysis of markers D2S2264, IL1R1, D2S373, and D2S1789 jointly provided some evidence for a shared haplotype among the affected individuals (P value of.012). Also, multipoint nonparametric linkage analysis yielded a P value of.0001 near the locus IL1R1 and P=.0007 approximately 20 cM telomeric near marker D2S1399, which, in two-point analysis, gave Z=1.48 (straight theta=. 02). This chromosomal region on 2q harbors the interleukin 1 gene cluster and, thus, represents a good candidate region for inflammatory and autoimmune disorders. Three additional chromosomal regions-4q26-q27, 7p15-p21, and Xcen-also provided some evidence for linkage, and further analyses would be justified to clarify their potential involvement in the genetic predisposition to DIP OA.     

Post-traumatic osteoarthritis: the role of stress induced chondrocyte damage

Post-traumatic osteoarthritis is the form of osteoarthritis (OA) that develops following joint injury. Although its end-stage is indistinguishable from idiopathic OA, many patients with post-traumatic OA are younger than those with idiopathic OA, and they have a well-defined precipitating insult. Clinical and experimental studies suggest that excessive acute impact energy or chronic mechanical overload cause the degeneration of the articular surface responsible for post-traumatic OA. Yet, the mechanisms by which excessive mechanical force causes OA remain unknown. For these reasons it has not been possible to develop effective methods of preventing or decreasing the risk of post-traumatic OA. We hypothesized that mechanical loading that exceeds the tolerance of the articular surface causes chondrocyte damage due to oxidative stress. Our in vitro tests of human articular cartilage samples showed that shear stress causes chondrocyte death and that anti-oxidants decrease the shear stress induced cell death. These observations suggest that specific patterns of loading are particularly damaging to articular surfaces and that improved treatments of joint injuries may include mechanical methods of minimizing shear stresses and biologic methods of minimizing oxidative damage.     

Body mass indices in patients with disabling hip osteoarthritis

Hip osteoarthritis (OA) is a degenerative joint disease that results in substantial morbidity. The disease may be preventable in some instances by reducing risk factors associated with the disease. We undertook a study to determine whether being overweight or obese, a health risk that applies to younger and older age groups, is commonly associated with hip joint OA. The body mass indices (BMIs) of 1021 males and females ranging in age from 23 to 94 years and requiring surgery for end-stage hip joint OA were analyzed to find the prevalence of high body weights at the time of surgery. Being overweight was defined as having a BMI of 25-29.9 kg/m2 and being obese as having a BMI >30 kg/m2. BMIs indicative of overweight were recorded for 68% of the patients surveyed. Of 35 patients aged 30-39 years, 53.3% had BMIs >25, with a mean of 28.8, which nearly reaches the lower limit defined for obesity. On average, patients who had had previous surgery and complications warranting reimplantation of new surgical devices had BMIs in the obese range. Our findings suggest that a high percentage of patients with end-stage hip OA are overweight, including younger adults and those with symptoms of 3-6 months' duration. Moreover, patients whose BMIs are in the obese range may be at increased risk for removal and reimplantation of their prosthesis.     

Body mass indices in patients with disabling hip osteoarthritis

Hip osteoarthritis (OA) is a degenerative joint disease that results in substantial morbidity. The disease may be preventable in some instances by reducing risk factors associated with the disease. We undertook a study to determine whether being overweight or obese, a health risk that applies to younger and older age groups, is commonly associated with hip joint OA. The body mass indices (BMIs) of 1021 males and females ranging in age from 23 to 94 years and requiring surgery for end-stage hip joint OA were analyzed to find the prevalence of high body weights at the time of surgery. Being overweight was defined as having a BMI of 25–29.9 kg/m² and being obese as having a BMI >30 kg/m². BMIs indicative of overweight were recorded for 68% of the patients surveyed. Of 35 patients aged 30–39 years, 53.3% had BMIs >25, with a mean of 28.8, which nearly reaches the lower limit defined for obesity. On average, patients who had had previous surgery and complications warranting reimplantation of new surgical devices had BMIs in the obese range. Our findings suggest that a high percentage of patients with end-stage hip OA are overweight, including younger adults and those with symptoms of 3–6 months' duration. Moreover, patients whose BMIs are in the obese range may be at increased risk for removal and reimplantation of their prosthesis.     

Activation of β-catenin in Col2-expressing chondrocytes leads to osteoarthritis-like defects in hip joint

Although osteoarthritis (OA) in the hip joint is a common and debilitating degenerative disease, the precise molecular mechanisms underlying its pathological process remains unclear. This study sets out to investigate whether β-catenin plays a critical role in hip OA pathogenesis. Here, we showed overexpressed β-catenin protein in human OA cartilage tissues. Then, we analyzed β-cat(ex3)^Col2ER mice, in which β-catenin gene was conditionally activated in femoral head chondrocytes. At 2 months of age, β-cat(ex3)^Col2ER mice already showed a phenotype of severe cartilage degeneration in the femoral head. More changes observed in β-cat(ex3)^Col2ER mice with age included subchondral sclerosis and osteophyte formation along joint margins, resembling a hip OA phenotype in humans. In addition, cartilage degradation and chondrocyte apoptosis as the results of β-catenin activation possibly contributed to this hip OA-like phenotype. Overall our findings provide direct evidence about the importance of β-catenin in hip OA pathogenesis.     

A progressive autosomal recessive cataract locus maps to chromosome 9q13-q22

Cataracts are the leading cause of blindness in most countries. Although most hereditary cases appear to follow an autosomal dominant pattern of inheritance, autosomal recessive inheritance has been clearly documented and is probably underrecognized. We studied a large family-from a relatively isolated geographic region-whose members were affected by autosomal recessive adult-onset pulverulent cataracts. We mapped the disease locus to a 14-cM interval at a novel disease locus, 9q13-q22 (between markers D9S1123 and D9S257), with a LOD score of 4.7. The study of this progressive and age-related cataract phenotype may provide insight into the cause of the more common sporadic form of age-related cataracts.     

Autozygosity mapping,to chromosome 11q25, of a rare autosomal recessive syndrome causing histiocytosis,joint contractures,and sensorineural deafness.

We describe a highly consanguineous family, originating from Pakistan, displaying histiocytosis, joint contractures, and sensorineural deafness. The form of histiocytosis exhibited by this family does not fit readily into any of the recognized classes of this disease. It appears to represent a novel form of familial histiocytosis demonstrating autosomal recessive inheritance. Using autozygosity mapping, we have identified a homozygous region of approximately 1 cM at chromosome 11q25, in affected individuals. A maximum two-point LOD score of 3.42 (recombination fraction straight theta = .00) was obtained with marker D11S968. This is the first genetic locus to be described that is involved in the molecular pathogenesis of histiocytosis.     

Hip joint moments in symptomatic vs. asymptomatic people with mild radiographic hip osteoarthritis

Our primary objective was to examine external hip joint moments during walking in people with mild radiographic hip osteoarthritis (OA) with and without symptoms and disease-free controls. Three groups were compared (symptomatic with mild radiographic hip OA, n = 12; asymptomatic with mild radiographic hip OA, n = 13; OA-free controls, n = 20). Measures of the external moment (peak and impulse) in the sagittal, frontal and transverse plane during walking were determined. Variables were compared according to group allocation using mixed linear regression models that included individual gait trials, with group allocation as fixed effect and walking speed as a random effect. Participants with evidence of radiographic disease irrespective of symptoms walked 14–16% slower compared to disease-free controls (p = 0.002). Radiographic disease without symptoms was not associated with any altered measures of hip joint moment compared to asymptomatic OA-free controls once speed was taken into account (p ≥ 0.099). People with both mild radiographic disease and symptoms had lower external peak hip adduction moment (p = 0.005) and lower external peak internal rotation moment (p < 0.001) accounting for walking speed. Among angular impulses, only the presence of symptoms was associated with a reduced hip internal rotation impulse (p = 0.002) in the symptomatic group. Collectively, our observations suggest that symptoms have additional mechanical associations from radiographic disease alone, and provide insight into potential early markers of hip OA. Future research is required to understand the implications of modifying walking speed and/or the external hip adduction and internal rotation moment in people with mild hip OA.     

Mechanical contributors to sex differences in idiopathic knee osteoarthritis

The occurrence of knee osteoarthritis (OA) increases with age and is more common in women compared with men, especially after the age of 50 years. Recent work suggests that contact stress in the knee cartilage is a significant predictor of the risk for developing knee OA. Significant gaps in knowledge remain, however, as to how changes in musculoskeletal traits disturb the normal mechanical environment of the knee and contribute to sex differences in the initiation and progression of idiopathic knee OA. To illustrate this knowledge deficit, we summarize what is known about the influence of limb alignment, muscle function, and obesity on sex differences in knee OA. Observational data suggest that limb alignment can predict the development of radiographic signs of knee OA, potentially due to increased stresses and strains within the joint. However, these data do not indicate how limb alignment could contribute to sex differences in either the development or worsening of knee OA. Similarly, the strength of the knee extensor muscles is compromised in women who develop radiographic and symptomatic signs of knee OA, but the extent to which the decline in muscle function precedes the development of the disease is uncertain. Even less is known about how changes in muscle function might contribute to the worsening of knee OA. Conversely, obesity is a stronger predictor of developing knee OA symptoms in women than in men. The influence of obesity on developing knee OA symptoms is not associated with deviation in limb alignment, but BMI predicts the worsening of the symptoms only in individuals with neutral and valgus (knock-kneed) knees. It is more likely, however, that obesity modulates OA through a combination of systemic effects, particularly an increase in inflammatory cytokines, and mechanical factors within the joint. The absence of strong associations of these surrogate measures of the mechanical environment in the knee joint with sex differences in the development and progression of knee OA suggests that a more multifactorial and integrative approach in the study of this disease is needed. We identify gaps in knowledge related to mechanical influences on the sex differences in knee OA.     

Evidence in favor of linkage to human chromosomal regions 18q, 5q and 13q for bicuspid aortic valve and associated cardiovascular malformations

The aim of this study was to identify regions of the genome that harbor genes influencing inheritance of bicuspid aortic valve (BAV) and/or associated cardiovascular malformation (CVM). Aortic valve disease is an important clinical problem, which often results in valve replacement, the second most common cardiac surgery in the United States. In every age group, a majority of cases of valve disease involves a BAV. BAV is the most common CVM with a reported prevalence of 1–2%. Heritability studies indicate that BAV determination is almost entirely genetic. We used a family-based genome-wide linkage analysis with microsatellite markers. Parametric and nonparametric analyses were performed with the software GENEHUNTER and SOLAR (Sequential Oligogenic Linkage Analysis Routines). Thirty-eight families (353 subjects) with BAV and/or associated CVM were assessed. Each participant underwent a standardized echocardiographic examination. The highest LOD score, 3.8, occurred on chromosome 18q between markers D18S68 and D18S1161. Two other chromosomal regions, 5q15–21 (between D5S644 and D5S2027) and 13q33-qter (between D13S1265 and 13qter), exhibited suggestive evidence of linkage (LOD > 2.0). Further, two previously reported linkage peaks on 9q34 and 17q24 were replicated in family specific analyses. No significant X chromosome linkage peaks were identified. In this genome-wide scan we demonstrate for the first time, that BAV and/or associated CVM exhibit linkage to chromosomes 18q, 5q and 13q. These regions likely contain genes whose mutation results in BAV and/or associated CVM indicating their important role in valvulogenesis and cardiac development. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Lisa J. Martin and Vijaya Ramachandran have contributed equally to this work.     

Childhood absence epilepsy with tonic-clonic seizures and electroencephalogram 3-4-Hz spike and multispike-slow wave complexes: linkage to chromosome 8q24.

Childhood absence epilepsy (CAE), a common form of idiopathic generalized epilepsy, accounts for 5%-15% of childhood epilepsies. To map the chromosomal locus of persisting CAE, we studied the clinical and electroencephalographic traits of 78 members of a five-generation family from Bombay, India. The model-free affected-pedigree member method was used during initial screening with chromosome 6p, 8q, and 1p microsatellites, and only individuals with absence seizures and/or electroencephalogram 3-4-Hz spike- and multispike-slow wave complexes were considered to be affected. Significant P values of .00000-.02 for several markers on 8q were obtained. Two-point linkage analysis, assuming autosomal dominant inheritance with 50% penetrance, yielded a maximum LOD score (Zmax) of 3.6 for D8S502. No other locus in the genome achieved a significant Zmax. For five smaller multiplex families, summed Zmax was 2.4 for D8S537 and 1.7 for D8S1761. Haplotypes composed of the same 8q24 microsatellites segregated with affected members of the large family from India and with all five smaller families. Recombinations positioned the CAE gene in a 3.2-cM interval.     

Gait and neuromuscular pattern changes are associated with differences in knee osteoarthritis severity levels

Knee osteoarthritis (OA) is a multifactoral, progressive disease process of the musculoskeletal system. Mechanical factors have been implicated in the progression of knee OA, but the role of altered joint mechanics and neuromuscular control strategies in progressive mechanisms of the disease have not been fully explored. Previous biomechanical studies of knee OA have characterized changes in joint kinematics and kinetics with the disease, but it has been difficult to determine if these biomechanical changes are involved in the development of disease, are in response to degenerative changes in the joint, or are compensatory mechanisms in response to these degenerative changes or other related factors as joint pain. The goal of this study was to explore the association between biomechanical changes and knee OA severity in an effort to understand the changing role of biomechanical factors in the progression of knee OA. A three-group cross-sectional model was used that included asymptomatic subjects, subjects clinically diagnosed with moderate knee OA and severe knee OA subjects just prior to total joint replacement surgery. Principal component analysis and discriminant analysis were used to determine the combinations of electromyography, kinematic and kinetic waveform pattern changes at the knee, hip and ankle joints during gait that optimally separated the three levels of severity. Different biomechanical mechanisms were important in discriminating between severity levels. Changes in knee and hip kinetic patterns and rectus femoris activation were important in separating the asymptomatic and moderate OA gait patterns. In contrast, changes in knee kinematics, hip and ankle kinetics and medial gastrocnemius activity were important in discriminating between the moderate and severe OA gait patterns.     

论股骨头坏死误诊的现状及分析

股骨头坏死是一种常见的疾病,在30岁至60岁年龄段的人群中较为常见,临床的症状包括疼痛以及髋部不适等,股骨头坏死在早期很难发现,由于没有得到准确的诊断,耽误了最佳的治疗时间和有效的治疗,随着病情的发展,最终将会造成股骨头变形以及塌陷,从而引起骨性关节炎,对髋关节功能的影响是很大的,甚至会丧失髋关节的基本功能。股骨头坏死的病状体征和早期症状存在一定的隐蔽性,因此,造成误诊的情况频繁发生。此外,有些疾病的症状表现为髋关节疼痛,最后反而容易被误诊为股骨头坏死。     

Protein modification by deamidation indicates variations in joint extracellular matrix turnover

As extracellular proteins age, they undergo and accumulate nonenzymatic post-translational modifications that cannot be repaired. We hypothesized that these could be used to systemically monitor loss of extracellular matrix due to chronic arthritic diseases such as osteoarthritis (OA). To test this, we predicted sites of deamidation in cartilage oligomeric matrix protein (COMP) and confirmed, by mass spectroscopy, the presence of deamidated (Asp(64)) and native (Asn(64)) COMP epitopes (mean 0.95% deamidated COMP (D-COMP) relative to native COMP) in cartilage. An Asp(64), D-COMP-specific ELISA was developed using a newly created monoclonal antibody 6-1A12. In a joint replacement study, serum D-COMP (p = 0.017), but not total COMP (p = 0.5), declined significantly after replacement demonstrating a joint tissue source for D-COMP. In analyses of 450 participants from the Johnston County Osteoarthritis Project controlled for age, gender, and race, D-COMP was associated with radiographic hip (p < 0.0001) but not knee (p = 0.95) OA severity. In contrast, total COMP was associated with radiographic knee (p < 0.0001) but not hip (p = 0.47) OA severity. D-COMP was higher in soluble proteins extracted from hip cartilage proximal to OA lesions compared with remote from lesions (p = 0.007) or lesional and remote OA knee (p < 0.01) cartilage. Total COMP in cartilage did not vary by joint site or proximity to the lesion. This study demonstrates the presence of D-COMP in articular cartilage and the systemic circulation, and to our knowledge, it is the first biomarker to show specificity for a particular joint site. We believe that enrichment of deamidated epitope in hip OA cartilage indicates a lesser repair response of hip OA compared with knee OA cartilage.     

Studies in Osteoarthritis of the Hip: Part II, * Osteoarthritis of the hip and leg-length disparity

An x-ray method is described for the determination of leg-length inequality in the standing subject, Its precision is compared to that of other methods in current use. The geometrical considerations which are inherent in any radiographic method of leg-length determination are summarized. Sixty-seven patients with OA hip were studied; 62 were considered to be idiopathic and 36 of these idiopathic cases were superolateral in type. Measurements in these 36 patients showed significant leg-length disparity, most of the diseased hips being found on the side of the longer leg. If allowance is made for shortening due to disease, the frequency and bias of the disparity are highly significant. The strong association between OA hip of this type and a long leg suggests a causal relationship.