Showing papers by "Nuffield Orthopaedic Centre published in 2000"
TL;DR: The ODI remains a valid and vigorous measure and has been a worthwhile outcome measure, and the process of using the ODI is reviewed and should be the subject of further research.
Abstract: Study design The Oswestry Disability Index (ODI) has become one of the principal condition-specific outcome measures used in the management of spinal disorders. This review is based on publications using the ODI identified from the authors' personal databases, the Science Citation Index, and hand searches of Spine and current textbooks of spinal disorders. Objectives To review the versions of this instrument, document methods by which it has been validated, collate data from scores found in normal and back pain populations, provide curves for power calculations in studies using the ODI, and maintain the ODI as a gold standard outcome measure. Summary of background data It has now been 20 years since its original publication. More than 200 citations exist in the Science Citation Index. The authors have a large correspondence file relating to the ODI, that is cited in most of the large textbooks related to spinal disorders. Methods All the published versions of the questionnaire were identified. A systematic review of this literature was made. The various reports of validation were collated and related to a version. Results Four versions of the ODI are available in English and nine in other languages. Some published versions contain misprints, and many omit the scoring system. At least 114 studies contain usable data. These data provide both validation and standards for other users and indicate the power of the instrument for detecting change in sample populations. Conclusions The ODI remains a valid and vigorous measure and has been a worthwhile outcome measure. The process of using the ODI is reviewed and should be the subject of further research. The receiver operating characteristics should be explored in a population with higher self-report disabilities. The behavior of the instrument is incompletely understood, particularly in sensitivity to real change.
4,482 citations
TL;DR: Patients' ability to identify correctly a marked lumbar interspace was assessed, and the risk of accidentally selecting a higher interspace than intended for intrathecal injection implies that spinal cord trauma is more likely when higher interspaces are selected.
Abstract: Anaesthetists' ability to identify correctly a marked lumbar interspace was assessed in 100 patients undergoing spinal magnetic resonance imaging scans. Using ink, one anaesthetist marked an interspace on the lower spine and attempted to identify its level with the patient in the sitting position. A second anaesthetist attempted to identify the level with the patient in the flexed lateral position. A marker capsule was taped over the ink mark and a routine scan performed. The actual level of markers ranged from one space below to four spaces above the level at which the anaesthetist believed it to be. The marker was one space higher than assumed in 51% of cases and was identified correctly in only 29%. Accuracy was unaffected by patient position (sitting or lateral), although it was impaired by obesity (p = 0.001) and positioning of the markers high on the lower back (p < 0.001). The spinal cord terminated below L(1) in 19% of patients. This, together with the risk of accidentally selecting a higher interspace than intended for intrathecal injection, implies that spinal cord trauma is more likely when higher interspaces are selected.
366 citations
TL;DR: This review focuses on recent developments in Na+, K+-ATPase research, and in particular reportsof expression of isoforms in various tissues and experiments aimed atucidating the intrinsic structural features of iso forms important forNa+, K-atPase function.
Abstract: Na+, K+-ATPase is ubiquitously expressed in the plasma membrane of all animal cells where it serves as the principal regulator of intracellular ion homeostasis. Na+, K+-ATPase is responsible for generating and maintaining transmembrane ionic gradients that are of vital importance for cellular function and subservient activities such as volume regulation, pH maintenance, and generation of action potentials and secondary active transport. The diversity of Na+, K+-ATPase subunit isoforms and their complex spatial and temporal patterns of cellular expression suggest that Na+, K+-ATPase isozymes perform specialized physiological functions. Recent studies have shown that the alpha subunit isoforms possess considerably different kinetic properties and modes of regulation and the beta subunit isoforms modulate the activity, expression and plasma membrane targeting of Na+, K+-ATPase isozymes. This review focuses on recent developments in Na+, K+-ATPase research, and in particular reports of expression of isoforms in various tissues and experiments aimed at elucidating the intrinsic structural features of isoforms important for Na+, K+-ATPase function.
314 citations
TL;DR: It is indicated that histological examination of periprosthetic tissues should form part of the investigative protocol to distinguish between aseptic and septic loosening.
Abstract: An assessment of clinical and laboratory findings is generally required to distinguish between septic and aseptic loosening of a hip implant. In order to evaluate the diagnostic utility of histological and microbiological investigative techniques to differentiate between these two conditions, we analysed their results in 617 patients with hip implant loosening. Histology and microbiology study confirmed the clinical diagnosis of septic loosening in approximately 98% and 89%, respectively. The clinical diagnosis of aseptic loosening was confirmed by histology in 99% of cases. In all but 2 of 81 cases of septic loosening, in which an organism was isolated on microbiological culture, the histological diagnosis of septic loosening was made on the basis of the degree of the acute inflammatory infiltrate (i.e. the presence of 1 or more neutrophil polymorphs per high power field (× 400) on average after examination of at least 10 high power fields) in periprosthetic tissues. In 10 patients for whom there was a strong clinical suspicion of septic loosening but no organisms were isolated on microbiological culture, the histological findings, using the above criteria, were in keeping with the clinical diagnosis of septic loosening. As almost 11% of cases of septic loosening would not have been diagnosed by microbiological investigation alone, our findings indicate that histological examination of periprosthetic tissues should form part of the investigative protocol to distinguish between aseptic and septic loosening.
199 citations
TL;DR: To determine the cruciate ligament forces occurring during typical rehabilitation exercises, a combination of non-invasive measurements with mathematical modelling of the lower limb and the "dynamically determinate one-sided constraint" analysis procedure was used.
194 citations
TL;DR: The significant individual variation in the position of the sural nerve in relation to the achilles tendon should be borne in mind when placing sutures in the proximal part of the aChilles tendon.
Abstract: Sural nerve injury is a complication of Achilles Tendon (TA) rupture. We dissected 30 cadaveric lower limbs to describe the course of the sural nerve in relation to the TA. At the level of insertion of the TA into the calcaneum, the sural nerve was a mean 18.8 mm from the lateral border of the TA. The proximal course of the nerve was towards the midline such that it crossed the lateral border of the TA at a mean distance of 9.8 cm from the calcaneum. The significant individual variation in the position of the sural nerve in relation to the achilles tendon should be borne in mind when placing sutures in the proximal part of the achilles tendon. Percutaneous sutures should not be placed in the lateral half of the TA.
185 citations
TL;DR: It was concluded that passive knee flexion can be described by a coupled path, although the exact shape of the path is very sensitive to load and varies between knees, knee rotations and translations were always coupled to flexion, and internal tibial rotation with flexion was always observed.
176 citations
TL;DR: The findings suggest that the interplay between pathogenesis and a single virulence determinant is unlikely to be a uniform process across a spectrum of infections, and confirms the need to extend the study of staphylococcal pathogenesis from the laboratory to non-uniform populations of clinically relevant isolates.
163 citations
TL;DR: It is concluded that a reversible part of the bone loss is related to the pregnancy itself and knowledge that the bone density increases after an affected pregnancy, combined with the known rarity of recurrent symptoms in subsequent pregnancies, is important in prognosis.
Abstract: Osteoporosis in pregnancy is a rare clinical problem of unknown cause. If the bone loss results from the pregnancy alone it should improve toward normal after delivery; in contrast, where bone density was low before pregnancy, due to some other secondary cause, significant postpartum improvement might not be expected. Thirteen women (age 23-37 years) with pregnancy-associated osteoporosis presenting with either pain in the back and vertebral collapse (8 subjects) or pain in the hip (5 subjects) had consecutive dual-energy X-ray absorptiometry measurements of bone mineral density (BMD) for up to 8 years after an affected pregnancy. The BMD results were expressed as a Z-score in relation to an age-matched mean. The mean initial (0-6 months postpartum) BMD was low in both groups and at both sites. In the back pain group the mean spine Z-score (Ll-L4) was -3.34 (range -2.25 to -4.66) and mean total hip Z-score was -2.41 (range -1.44 to -3.82). In the hip pain group the mean spine Z-score was -2.00 (range -1.48 to -2.65) and mean hip Z-score was -2.19 (range -1.12 to -3.26). Subsequent mean hip and spine BMD increased significantly toward the lower end of the normal range. We conclude that a reversible part of the bone loss is related to the pregnancy itself. A low BMD before pregnancy cannot be excluded. Knowledge that the bone density increases after an affected pregnancy, combined with the known rarity of recurrent symptoms in subsequent pregnancies, is important in prognosis.
155 citations
TL;DR: A number of difficulties arose, most associated with age-related declines in sensory, perceptual, cognitive and communication abilities, and these difficulties are described, together with the steps that need to be taken to eliminate, or at least ameliorate, them.
131 citations
TL;DR: The findings suggest that the increase in osteoclast numbers seen in Paget's disease results not from an increase in the number of circulating precursors in peripheral blood but rather from an increased sensitivity of osteoprotegerin-expressing osteoblastic cells and human macrophage colony-stimulating factor to the humoral factors, 1,25(OH)(2)D(3) and RANKL, which regulate osteOClast formation.
TL;DR: FEMs developed from orthogonal radiographs of a diaphyseal tibial fracture and its reparative tissue at four different time points during healing indicated the presence of stress concentrations medial and lateral to the fracture gap, which probably caused tissue damage during normal activity levels.
TL;DR: It is shown that macrophages isolated from the synovium of RA patients are capable of differentiating into osteoclastic bone‐resorbing cells; this process is OPGL‐ and M‐CSF‐dependent and is modulated by corticosteroids.
Abstract: Osteoprotegerin ligand (OPGL) is a newly discovered molecule which is essential for osteoclast differentiation. Both OPGL and its soluble decoy receptor, osteoprotegerin (OPG), which inhibits osteoclast formation, are known to be produced by osteoblasts and inflammatory cells found in the rheumatoid arthritis (RA) synovium. In this study, RA synovial macrophages were incubated in the presence or absence of OPGL, macrophage-colony stimulating factor (M-CSF), and dexamethasone for various time points. The results indicated that osteoclast formation from RA synovial macrophages is OPGL-dependent and that OPGL and M-CSF are the only humoral factors required for RA synovial macrophage-osteoclast differentiation. OPG was found to inhibit osteoclast formation by RA synovial macrophages in a dose-dependent manner. This study has shown that macrophages isolated from the synovium of RA patients are capable of differentiating into osteoclastic bone-resorbing cells; this process is OPGL- and M-CSF-dependent and is modulated by corticosteroids. Cellular (T and B cells, dendritic cells) and humoral factors in RA synovium and bone may influence osteoclast formation and bone resorption by controlling OPGL/OPG production.
TL;DR: MRI can be used to define more precisely the anatomy of the extensor mechanism and its relationship to the femur and tibia, in both a static and dynamic setting, in this way, patients with anterior knee pain can be classified more accurately and the outcomes of treatment more reliably assessed.
Abstract: Between January 1995 and Jul 1997, 474 patients with anterior knee pain resistant to conservative treatment were referred for MR of the knee. The MR examination consisted of routine sequences with an additional patellofemoral dynamic examination using a technique that has been developed at this institution. The dynamic study examines both knees simultaneously, with the patient supine and the quadriceps loaded. No gating or restraint apparatus is needed. Patellar subluxation or tilt was present in 188(40 %) of cases, bilateral in 104 and unilateral in 84 cases (right 39, left 45). It was classified as mild in 51 %, moderate in 39 % and severe in 10 %. Subluxation was more prevalent in females than males (42 % vs. 37 %) and this was most obvious in the severe group where 68 % were female. In 90 knees selected at random, four measurements of patellofemoral morphology were obtained using reconstructed images from a volume gradient echo sequence. These measurements were correlated with the degree of subluxation or tilt. A tibial tubercle distance greater than 20 mm, a femoral sulcus angle greater than 150 degrees, sulcus depth less than 4 mm were specific for subluxation but no measurement proved to be sufficiently sensitive to preclude a tracking study. MRI can be used to define more precisely the anatomy of the extensor mechanism and its relationship to the femur and tibia, in both a static and dynamic setting. In this way, patients with anterior knee pain can be classified more accurately and the outcomes of treatment more reliably assessed.
TL;DR: The FOP phenotype is linked to markers located in the 4q27-31 region (LOD score 3.10 at recombination fraction 0), and crossover events localize the putative FOP gene within a 36-cM interval which contains at least one gene involved in the bone morphogenetic protein-signaling pathway.
Abstract: Fibrodysplasia ossificans progressiva (FOP) is a severely disabling, autosomal-dominant disorder of connective tissue and is characterized by postnatal progressive heterotopic ossification of muscle, tendon, ligament, and fascia and by congenital malformation of the great toes. To identify the chromosomal location of the FOP gene, we conducted a genomewide linkage analysis, using four affected families with a total of 14 informative meioses. Male-to-male transmission of the FOP phenotype excluded X-linked inheritance. Highly polymorphic microsatellite markers covering all human autosomes were amplified by use of PCR. The FOP phenotype is linked to markers located in the 4q27-31 region (LOD score 3.10 at recombination fraction 0). Crossover events localize the putative FOP gene within a 36-cM interval bordered proximally by D4S1625 and distally by D4S2417. This interval contains at least one gene involved in the bone morphogenetic protein–signaling pathway.
TL;DR: This study has used specific affinity purified polyclonal antibodies to the functional glucocorticoid receptor α (GRα) to investigate its expression in both developing and adult human bone using sections of neonatal rib, calvarial, and vertebral bones, tibial growth plates from adolescents, and iliac crest biopsies from adults who were to undergo liver transplantation.
Abstract: Glucocorticoids have well-documented effects on the skeleton, although their mechanism of action is still poorly understood. The actions of glucocorticoids on bone cells are mediated, in part, directly via specific receptors. The presence of these receptors has been demonstrated in both rodent and human osteoblastic cells in vitro, but their presence in human bone in vivo has not been reported. In this study, we have used specific affinity purified polyclonal antibodies to the functional glucocorticoid receptor alpha (GRalpha) to investigate its expression in both developing and adult human bone using sections of neonatal rib, calvarial, and vertebral bones, tibial growth plates from adolescents, and iliac crest biopsies from adults who were to undergo liver transplantation. In the tibial growth plates, GRalpha was predominantly expressed in the hypertrophic chondrocytes within the cartilage. In the primary spongiosa, the receptor was highly expressed by osteoblasts at sites of bone modeling. Within the bone marrow, receptors were also detected in mononuclear cells and in endothelial cells of blood vessels. In the neonatal rib and vertebrae, GRalpha was widely distributed at sites of endochondral bone formation in resting, proliferating, mature, and hypertrophic chondrocytes. They were also highly expressed in osteoblasts at sites of bone modeling. At sites of intramembranous ossification in neonatal calvarial bone and rib periosteum, GRa was widely expressed in cells within the fibrous tissue and in osteoblasts at both the bone-forming surface and at modeling sites. In the iliac crests from adults, GRalpha was predominantly expressed in osteocytes. The receptors were not detected in osteoclasts. Our results show for the first time the presence of the functional GRalpha in human bone in situ and suggest that the actions of glucocorticoids on bone may be mediated, in part, directly via the GR at different stages of life. The absence of receptor expression in osteoclasts also suggests that the effects of glucocorticoids on bone resorption may be mediated indirectly.
TL;DR: The incidence of progressive osteoarthritis within the knee was very low after UKR and overcorrection of the deformity be avoided, and changes in alignment may be indicative of minor polyethylene wear or of subsidence of the tibial component.
Abstract: Failure of a unicompartmental knee replacement (UKR) may be caused by progressive osteoarthritis of the knee and/or failure of the prosthesis. Limb alignment can influence both of these factors. We have examined the fate of the other compartments and measured changes in leg alignment after UKR. A total of 50 UKRs was carried out on 45 carefully selected patients between 1989 and 1992. At operation, deliberate attempts were made to avoid overcorrection of the deformity. Four patients died, one patient was lost to follow-up and two knees were revised before review which was at a minimum of five years. Standard long-leg weight-bearing anteroposterior views of the knee and skyline views of the patellofemoral joint were taken before and at eight months and five years after operation. The radiographs of the remaining 43 knees were reviewed twice by blind and randomised assessment to measure the progression of osteoarthritis within the joints. Overcorrection of the deformity in the coronal plane was avoided in all but two knees. Only one showed evidence of progression of osteoarthritis within the patellofemoral joint, and this was only identified in one of the four assessments. Deterioration in the state of the opposite tibiofemoral compartment was not seen. Varus deformity tended to recur. Recurrent varus of 2 degrees was observed between eight months and five years after operation. There was no correlation between the postoperative tibiofemoral angle and the extent of recurrent varus recorded at five years. Changes in alignment may be indicative of minor polyethylene wear or of subsidence of the tibial component. The incidence of progressive osteoarthritis within the knee was very low after UKR. Patients should be carefully selected and overcorrection of the deformity be avoided.
TL;DR: Internal fixation with the use of plates is safe for displaced, unstable fractures in children, although in small children, or in those in whom there has been, or is, infection of the screw tracks, a new period of treatment using external fixation may be needed.
Abstract: We reviewed 173 patients undergoing distraction osteogenesis to determine the incidence, location and timing of fractures occurring as a complication of the procedure.
There were 17 fractures in 180 lengthened segments giving an overall rate of fracture of 9.4%. Unexpectedly, the pattern and location of the fractures were very variable; six were within the regenerate itself, six at the junction between the regenerate and the original bone and five at distant sites in the limb. Of those occurring in the regenerate, five were noted to be associated with compression and partial collapse of the regenerate. In three patients collapse and deformity developed gradually in the distracted segment over the six months after removal of the frame.
The method of treatment of these fractures should be chosen to take into account multiple factors, which are additional and often different from those to be considered during management of acute traumatic injuries. Internal fixation appears to be most appropriate for displaced fractures, although in small children, or in those in whom there has been, or is, infection of the screw tracks, a new period of treatment using external fixation may be needed. Fixation by intramedullary nailing was associated with a risk of infection, even if screw tracks were assessed as healthy at the time of insertion of the nail. Internal fixation with the use of plates is safe for displaced, unstable fractures in children.
TL;DR: This article found that as many as 15.5% of synovial CD8+ Tcells may be specific for a single epitope from an Epstein-Barr virus lyticcycle protein.
Abstract: CD8+ T cells dominate the lymphocyte population insynovial fluid in chronic inflammatory arthritis. It is known that theseCD8+ T cells are often clonally or oligoclonally expanded, but theirspecificity and their relevance to the pathogenesis of joint disease hasremained unclear. We found that as many as 15.5% of synovial CD8+ Tcells may be specific for a single epitope from an Epstein-Barr virus lyticcycle protein. The virus-specific T cells within the joint showed increasedexpression of markers of activation and differentiation compared with those inthe periphery, and retained their functional capacity to secreteproinflammatory cytokines on stimulation. These activated, virus-specificCD8+ T cells could therefore interact with synoviocytes, either bycell-cell contact or by a cytokine network, and play a 'bystander'role in the maintenance of inflammation in patients with arthritis.
TL;DR: 11 candidate genes as susceptibility loci for osteoarthritis (OA) were examined using one or more intragenic or closely linked microsatellite marker to reveal suggestive linkage of the type IX collagen gene COL9A1 to a subset of 132 families that contained affected females who were concordant for hip OA (female-hip).
Abstract: Objective. To examine 11 candidate genes as susceptibility loci for osteoarthritis (OA). Methods. A total of 481 families have been ascertained in which at least two siblings have had joint replacement surgery of the hip, or knee, or hip and knee for idiopathic OA. Each candidate gene was targeted using one or more intragenic or closely linked microsatellite marker. The linkage data were analysed unstratified and following stratification by sex and by joint replaced (hip or knee). Results. The analyses revealed suggestive linkage of the type IX collagen gene COL9A1 (6q12-q13) to a subset of 132 families that contained affected females who were concordant for hip OA (female-hip) with a P-value of 0.00053 and logarithm of the odds (LOD) score of 2.33 [corrected P-value of 0.0016, corrected LOD score of 1.85]. Conclusions. COL9A1 may therefore be a susceptibility locus for female hip OA. In addition, there was weak evidence of linkage to HLA/COL11A2 (6p21.3) in female hip OA with a corrected P-value of 0.016. K : Osteoarthritis, Linkage, Affected sibling pairs, COL9A1.
TL;DR: This study provides the first clinical rationale for ablation of rapidly enlarging exostoses to reduce growth disturbance and suggests that the growth retardation in HME may result from the local effects of enlarging osteochondromas rather than a skeletal dysplasia effect.
Abstract: Hereditary multiple exostoses (HME) is traditionally described as a skeletal dysplasia. However, the discovery that the EXT family of tumour suppressor genes are responsible for HME suggests that it is more appropriate to classify HME as a familial neoplastic trait. In a clinical and radiographic analysis of paired bone length and exostoses number and dimensions in a HME cohort, the local presence of osteochondromas was consistently associated with growth disturbance. In particular, an inverse correlation between osteochondroma size and relative bone length (p<0.01) was found. These data suggest that the growth retardation in HME may result from the local effects of enlarging osteochondromas rather than a skeletal dysplasia effect. This study provides the first clinical rationale for ablation of rapidly enlarging exostoses to reduce growth disturbance.
TL;DR: Systems of classification are useful in decision-making and evaluation of outcome only if there is agreement and consistency among observers and this study casts doubt on these aspects of the systems currently available for fractures of the distal humerus.
Abstract: We assessed the inter- and intraobserver variation in classification systems for fractures of the distal humerus. Three orthopaedic trauma consultants, three trauma registrars and three consultant musculoskeletal radiologists independently classified 33 sets of radiographs of such fractures on two occasions, each using three separate systems. For interobserver variation, the Riseborough and Radin system produced 'moderate' agreement (kappa = 0.513), but half of the fractures were not classifiable by this system. For the complete AO system, agreement was 'fair' (kappa = 0.343), but if only AO type and group or AO type alone was used, agreement improved to 'moderate' and 'substantial', respectively (kappa = 0.52 and 0.66). Agreement for the system of Jupiter and Mehne was 'fair' (kappa = 0.295). Similar levels of intraobserver variation were found. Systems of classification are useful in decision-making and evaluation of outcome only if there is agreement and consistency among observers. Our study casts doubt on these aspects of the systems currently available for fractures of the distal humerus.
TL;DR: The view that stable dysplastic hips will correct with growth and that there is no sustained benefit from early splintage is supported.
Abstract: A prospective trial was carried out to assess the outcome of children aged from 2 to 6 weeks with stable but dysplastic hips, treated with abduction splintage or by observation. Forty-four patients with 63 dysplastic hips were entered into the study and allocated into the two treatment groups at random. The ultrasound measured percentage acetabular cover in the splinted group improved in the first 3 months from an average of 32.8 to 54.3%. In the unsplinted group, the increase in cover was from 36.7 to 48.6%. The changes in cover for the splinted group were significantly more than those for the unsplinted group (p < 0.003) There was, however, no significant difference between the two groups in acetabular angle measurements on plain radiographs taken at 3 months. At 24 months, similarly, there was no significant difference in the acetabular angles of the two groups. These results support the view that stable dysplastic hips will correct with growth and that there is no sustained benefit from early splintage.
TL;DR: Correspondence should be sent to W. Gillespie, DeanDunedin School of Medicine, PO Box 913, Dunedin, New Zealand.
Abstract: W. Gillespie, DeanDunedin School of Medicine, PO Box 913, Dunedin, New Zealand.D. Murray, MD, FRCS, FRCS (Orth), Professor of Orthopaedic SurgeryNuffield Orthopaedic Centre, Windmill Road, Headington, Oxford OX37LD, UK.P. J. Gregg, MD, FRCS, Professor of Orthopaedic SurgeryThe Medical School, University of Newcastle upon Tyne, Newcastle uponTyne NE2 4HH, UK.D. Warwick, MD, FRCS, FRCS (Orth), Consultant Orthopaedic SurgeonSouthampton University Hospitals NHS Trust, Tremona Road, South-ampton SO16 6YD, UK.Correspondence should be sent to W. Gillespie©2000 British Editorial Society of Bone and Joint Surgery0301-620X/00/410452 $2.00
TL;DR: The results confirm previous observations in the southern German population of association between TNF promoter region polymorphisms and AS, but the lack of association in the English population suggests that these polymorphisms themselves are unlikely to be directly involved.
Abstract: The objective of this study was to investigate TNF promoter region polymorphisms for association with susceptibility to ankylosing spondylitis (AS). The TNF -238 and -308 polymorphisms were genotyped in 306 English AS cases and 204 ethnically matched healthy B27-positive controls, and 96 southern German AS cases, 58 B27-positive and 251 B27-negative ethnically matched controls. Additionally, the TNF -376 polymorphism was genotyped in the southern German cases and controls. In the southern German AS patients a significant reduction in TNF -308.2 alleles was seen, compared with B27 positive controls (odds ratio 0.4, P= 0.03, 95% confidence interval 0.2-0.9), but no difference in allele frequencies was observed at TNF -238. Significant association between AS and both TNF -238 and TNF -308 was excluded in the English cases. These results confirm previous observations in the southern German population of association between TNF promoter region polymorphisms and AS, but the lack of association in the English population suggests that these polymorphisms themselves are unlikely to be directly involved. More likely, a second, non-HLA-B, MHC locus is involved in susceptibility to AS in these two populations.
TL;DR: The results suggest that osteoblasts and chondrocytes within the regenerate originate from the same pool of progenitor cells, and the differentiation of these cells and the expression of types I and II collagen genes are altered by different rates of distraction.
TL;DR: It is concluded that mutations in the coding region of noggin are not associated with FOP, and elevated levels of bone morphogenetic protein 4 occur in lymphoblastoid cells and in lesional cells of patients with Fop.
Abstract: Fibrodysplasia ossificans progressiva (FOP) is an extremely rare and disabling genetic disorder characterized by congenital malformation of the great toes and by progressive heterotopic endochondral ossification in predictable anatomical patterns. Although elevated levels of bone morphogenetic protein 4 (BMP4) occur in lymphoblastoid cells and in lesional cells of patients with FOP, mutations have not been identified in the BMP4 gene, suggesting that the mutation in FOP may reside in a BMP4-interacting factor or in another component of the BMP4 pathway. A powerful antagonist of BMP4 is the secreted polypeptide noggin. A recent case report described a heterozygous 42-bp deletion in the protein-coding region of the noggin gene in a patient with FOP. In order to determine if noggin mutations are a widespread finding in FOP, we examined 31 families with 1 or more FOP patients. Linkage analysis with an array of highly polymorphic microsatellite markers closely linked to the noggin gene was performed in four classically-affected multigenerational FOP families and excluded linkage of the noggin locus to FOP (the multipoint lod score was -2 or less throughout the entire range of markers). We sequenced the noggin gene in affected members of all four families, as well as in 18 patients with sporadic FOP, and failed to detect any mutations. Single-strand conformation polymorphism (SSCP) analysis of 4 of these patients plus an additional 9 patients also failed to reveal any mutations. Among the samples analyzed by SSCP and DNA sequencing was an independently obtained DNA sample from the identical FOP patient previously described with the 42-bp noggin deletion; no mutation was detected. Examination of the DNA sequences of 20 cloned noggin PCR products, undertaken to evaluate the possibility of a somatic mutation in the noggin gene which could be carried by a small subset of white blood cells, also failed to detect the presence of the reported 42-bp deletion. We conclude that mutations in the coding region of noggin are not associated with FOP.
TL;DR: Thesex bias in AS is not explained by X-chromosome-encoded genetic effects, and the disease model best explaining the sex bias in occurrence and transmission of AS is a polygenic model with a higher susceptibility threshold in females.
Abstract: Objective. Ankylosing spondylitis (AS) affects 0.25-1.0% of the population, and its etiology is incompletely understood. Susceptibility to this highly familial disease (lambda(s) = 58) is primarily genetically determined. There is a significant sex bias in AS, and there are differences in recurrence risk to the offspring of affected mothers and fathers, suggesting that there may be an X-linked recessive effect. We undertook an X-chromosome linkage study to determine any contribution of the X-chromosome to AS susceptibility.Methods. A linkage study of the X-chromosome using 234 affected sibling pairs was performed to investigate this hypothesis.Results. No linkage of the X-chromosome with susceptibility to AS was found. Model-free multipoint linkage analysis strongly excluded any significant genetic contribution (lambda greater than or equal to 1.5) to AS susceptibility encoded on the X-chromosome (logarithm of odds [LOD] < -2.0). Smaller genetic effects (lambda greater than or equal to 1.3) were also found to be unlikely (LOD < -1.0).Conclusion. The sex bias in AS is not explained by X-chromosome-encoded genetic effects. The disease model best explaining the sex bias in occurrence and transmission of AS is a polygenic model with a higher susceptibility threshold in females.
TL;DR: It is found that, unlike osteoclast precursors in monocyte and other tissue macrophage populations, the addition of M-CSF to medium is not required for osteocline differentiation.
Abstract: A macrophage infiltrate is commonly found in enlarging subchondral cysts in osteoarthrosis (OA) and the surrounding bone. To determine whether osteoclast differentiation by these cells contributes to the increase in the number of osteoclasts and bone resorption that accompanies OA cyst enlargement, we isolated macrophages from the wall of OA cysts and co-cultured them with osteoblast-like UMR106 cells in the presence or absence of 1,25(OH) 2 D 3 and M-CSF. After 14 days of incubation, co-cultures of UMR106 cells and cyst-derived macrophages showed evidence of osteoclast differentiation by expression of TRAP, VNR and formation of numerous lacunar pits. We found that, unlike osteoclast precursors in monocyte and other tissue macrophage populations, the addition of M-CSF to medium is not required for osteoclast differentiation. Our findings suggest that macrophage-osteoclast differentiation is one means whereby the osteolysis associated with the enlargement of OA cysts could be effected.