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1.  2- to 9-year outcome of stemmed total knee arthroplasty 
Acta Orthopaedica  2014;85(6):609-613.
Background and purpose —
There is an increase in demand for primary and revision total knee joint procedures. We studied implant survival and functional outcome of patients operated with a constrained condylar knee (CCK) or a rotating hinge implant (RH) as a primary or a revision total knee arthoplasty (TKA).
Patients and methods —
We evaluated clinically and radiographically 65 surgical procedures with a mean follow-up time of 5 (2–9) years (40 CCK and 25 RH). There were 24 primary TKAs—due to instability—and 41 revision TKAs, mostly due to aseptic loosening. Mean age at the index operation was 68 (31–88) years.
Results —
Overall, there were 12 failures, including 8 reoperations due to deep infection. The overall 5-year survival rate with reoperation as the endpoint was 82% (95% CI: 72–99). Radiolucent lines on either the femoral or the tibial side were seen in 36 cases. When comparing the cases that were operated as a primary TKA or as a revision TKA, function, health-related quality of life, and survival were similar. However, after primary TKA the patients generally had less pain and a higher proportion of patients were very satisfied or satisfied.
Interpretation —
Although a high rate of severe complications was observed, most patients improved in function after surgery regardless of whether it was a primary or a revision TKA. We found narrow radiolucent lines—mainly on the tibial side—in nearly half of the cases, but none of the implants were loose radiographically. Overall patient satisfaction and health-related quality of life were high, and a minority had problems with persistent pain.
doi:10.3109/17453674.2014.962411
PMCID: PMC4259026  PMID: 25238436
2.  Good stability but high periprosthetic bone mineral loss and late-occurring periprosthetic fractures with use of uncemented tapered femoral stems in patients with a femoral neck fracture 
Acta Orthopaedica  2014;85(4):396-402.
Background and purpose
We previously evaluated a new uncemented femoral stem designed for elderly patients with a femoral neck fracture and found stable implant fixation and good clinical results up to 2 years postoperatively, despite substantial periprosthetic bone mineral loss. We now present the medium-term follow-up results from this study.
Patients and methods
In this observational prospective cohort study, we included 50 patients (mean age 81 (70–92) years) with a femoral neck fracture. All patients underwent surgery with a cemented cup and an uncemented stem specifically designed for fracture treatment. Outcome variables were migration of the stem measured with radiostereometry (RSA) and periprosthetic change in bone mineral density (BMD), measured with dual-energy X-ray absorptiometry (DXA). Hip function and health-related quality of life were assessed using the Harris hip score (HHS) and the EuroQol-5D (EQ-5D). DXA and RSA data were collected at regular intervals up to 4 years, and data concerning reoperations and hip-related complications were collected during a mean follow-up time of 5 (0.2–7.5) years.
Results
At 5 years, 19 patients had either passed away or were unavailable for further participation and 31 could be followed up. Of the original 50 patients, 6 patients had suffered a periprosthetic fracture, all of them sustained after the 2-year follow-up. In 19 patients, we obtained complete RSA and DXA data and no component had migrated after the 2-year follow-up. We also found a continuous total periprosthetic bone loss amounting to a median of –19% (–39 to 2). No changes in HHS or EQ-5D were observed during the follow-up period.
Interpretation
In this medium-term follow-up, the stem remained firmly fixed in bone despite considerable periprosthetic bone mineral loss. However, this bone loss might explain the high number of late-occurring periprosthetic fractures. Based on these results, we would not recommend uncemented femoral stems for the treatment of femoral neck fractures in the elderly.
doi:10.3109/17453674.2014.931195
PMCID: PMC4105771  PMID: 24954490
3.  Age- and health-related quality of life after total hip replacement 
Acta Orthopaedica  2014;85(3):244-249.
Background
While age is a common confounder, its impact on health-related quality of life (HRQoL) after total hip replacement is uncertain. This could be due to improper statistical modeling of age in previous studies, such as treating age as a linear variable or by using age categories. We hypothesized that there is a non-linear association between age and HRQoL.
Methods
We selected a nationwide cohort from the Swedish Hip Arthroplasty Register of patients operated with total hip replacements due to primary osteoarthritis between 2008 and 2010. For estimating HRQoL, we used the generic health outcome questionnaire EQ-5D of the EuroQol group that consits or 2 parts: the EQ-5D index and the EQ VAS estimates.
Using linear regression, we modeled the EQ-5D index and the EQ VAS against age 1 year after surgery. Instead of using a straight line for age, we applied a method called restricted cubic splines that allows the line to bend in a controlled manner. Confounding was controlled by adjusting for preoperative HRQoL, sex, previous contralateral hip surgery, pain, and Charnley classification.
Results
Complete data on 27,245 patients were available for analysis. Both the EQ-5D index and EQ VAS showed a non-linear relationship with age. They were fairly unaffected by age until the patients were in their late sixties, after which age had a negative effect.
Interpretation
There is a non-linear relationship between age and HRQoL, with improvement decreasing in the elderly.
doi:10.3109/17453674.2014.916492
PMCID: PMC4062790  PMID: 24786908
4.  Measurement of the migration of a focal knee resurfacing implant with radiostereometry 
Acta Orthopaedica  2014;85(1):79-83.
Background and purpose
Articular resurfacing metal implants have been developed to treat full-thickness localized articular cartilage defects. Evaluation of the fixation of these devices is mandatory. Standard radiostereometry (RSA) is a validated method for evaluation of prosthetic migration, but it requires that tantalum beads are inserted into the implant. For technical reasons, this is not possible for focal articular resurfacing components. In this study, we therefore modified the tip of an articular knee implant and used it as a marker for RSA, and then validated the method.
Material and methods
We modified the tip of a resurfacing component into a hemisphere with a radius of 3 mm, marked it with a 1.0-mm tantalum marker, and implanted it into a sawbone marked with 6 tantalum beads. Point-motion RSA of the “hemisphere bead” using standard automated RSA as the gold standard was compared to manual measurement of the tip hemisphere. 20 repeated stereograms with gradual shifts of position of the specimen between each double exposure were used for the analysis. The tip motion was compared to the point motion of the hemisphere bead to determine the accuracy and precision.
Results
The accuracy of the manual tip hemisphere method was 0.08–0.19 mm and the precision ranged from 0.12 mm to 0.33 mm.
Interpretation
The accuracy and precision for translations is acceptable when using a small hemisphere at the tip of a focal articular knee resurfacing implant instead of tantalum marker beads. Rotations of the implant cannot be evaluated. The method is accurate and precise enough to allow detection of relevant migration, and it will be used for future clinical trials with the new implant.
doi:10.3109/17453674.2013.869654
PMCID: PMC3940996  PMID: 24286562
5.  Dual-mobility cups for revision due to instability are associated with a low rate of re-revisions due to dislocation 
Acta Orthopaedica  2012;83(6):566-571.
Background and purpose
Revision total hip arthroplasty (THA) due to recurrent dislocations is associated with a high risk of persistent instability. We hypothesized that the use of dual-mobility cups would reduce the risk of re-revision due to dislocation after revision THA.
Patients and methods
228 THA cup revisions (in 228 patients) performed due to recurrent dislocations and employing a specific dual-mobility cup (Avantage) were identified in the Swedish Hip Arthroplasty Register. Kaplan-Meier survival analysis was performed with re-revision due to dislocation as the primary endpoint and re-revision for any reason as the secondary endpoint. Cox regression models were fitted in order to calculate the influence of various covariates on the risk of re-revision.
Results
58 patients (25%) had been revised at least once prior to the index cup revision. The surgical approach at the index cup revision was lateral in 99 cases (44%) and posterior in 124 cases (56%). Median follow-up was 2 (0–6) years after the index cup revision, and by then 18 patients (8%) had been re-revised for any reason. Of these, 4 patients (2%) had been re-revised due to dislocation. Survival after 2 years with the endpoint revision of any component due to dislocation was 99% (95% CI: 97–100), and it was 93% (CI: 90–97) with the endpoint revision of any component for any reason. Risk factors for subsequent re-revision for any reason were age between 50–59 years at the time of the index cup revision (risk ratio (RR) = 5 when compared with age > 75, CI: 1–23) and previous revision surgery to the relevant joint (RR = 1.7 per previous revision, CI: 1–3).
Interpretation
The risk of re-revision due to dislocation after insertion of dual-mobility cups during revision THA performed for recurrent dislocations appears to be low in the short term. Since most dislocations occur early after revision THA, we believe that this device adequately addresses the problem of recurrent instability. Younger age and prior hip revision surgery are risk factors for further revision surgery. However, problems such as potentially increased liner wear and subsequent aseptic loosening may be associated with the use of such devices in the long term.
doi:10.3109/17453674.2012.742395
PMCID: PMC3555442  PMID: 23116439
6.  The risk of revision due to dislocation after total hip arthroplasty depends on surgical approach, femoral head size, sex, and primary diagnosis 
Acta Orthopaedica  2012;83(5):442-448.
Background and purpose
The effects of patient-related and technical factors on the risk of revision due to dislocation after primary total hip arthroplasty (THA) are only partly understood. We hypothesized that increasing the femoral head size can reduce this risk, that the lateral surgical approach is associated with a lower risk than the posterior and minimally invasive approaches, and that gender and diagnosis influence the risk of revision due to dislocation.
Patients and methods
Data on 78,098 THAs in 61,743 patients performed between 2005 and 2010 were extracted from the Swedish Hip Arthroplasty Register. Inclusion criteria were a head size of 22, 28, 32, or 36 mm, or the use of a dual-mobility cup. The covariates age, sex, primary diagnosis, type of surgical approach, and head size were entered into Cox proportional hazards models in order to calculate the adjusted relative risk (RR) of revision due to dislocation, with 95% confidence intervals (CI).
Results
After a mean follow-up of 2.7 (0–6) years, 399 hips (0.5%) had been revised due to dislocation. The use of 22-mm femoral heads resulted in a higher risk of revision than the use of 28-mm heads (RR = 2.0, CI: 1.2–3.3). Only 1 of 287 dual-mobility cups had been revised due to dislocation. Compared with the direct lateral approach, minimally invasive approaches were associated with a higher risk of revision due to dislocation (RR = 4.2, CI: 2.3–7.7), as were posterior approaches (RR = 1.3, CI: 1.1–1.7). An increased risk of revision due to dislocation was found for the diagnoses femoral neck fracture (RR = 3.9, CI: 3.1–5.0) and osteonecrosis of the femoral head (RR = 3.7, CI: 2.5–5.5), whereas women were at lower risk than men (RR = 0.8, CI: 0.7–1.0). Restriction of the analysis to the first 6 months after the index procedure gave similar risk estimates.
Interpretation
Patients with femoral neck fracture or osteonecrosis of the femoral head are at higher risk of dislocation. Use of the minimally invasive and posterior approaches also increases this risk, and we raise the question of whether patients belonging to risk groups should be operated using lateral approaches. The use of femoral head diameters above 28 mm or of dual-mobility cups reduced this risk in a clinically relevant manner, but this observation was not statistically significant.
doi:10.3109/17453674.2012.733919
PMCID: PMC3488169  PMID: 23039167
7.  Salvage of failed trochanteric and subtrochanteric fractures using a distally fixed, modular, uncemented hip revision stem 
Acta Orthopaedica  2012;83(5):488-492.
Background and purpose
Treatment options for failed internal fixation of hip fractures include prosthetic replacement. We evaluated survival, complications, and radiographic outcome in 30 patients who were operated with a specific modular, uncemented hip reconstruction prosthesis as a salvage procedure after failed treatment of trochanteric and subtrochanteric fractures.
Patients and methods
We used data from the Swedish Hip Arthroplasty Register and journal files to analyze complications and survival. Initially, a high proportion of trochanteric fractures (7/10) were classified as unstable and 12 of 20 subtrochanteric fractures had an extension through the greater trochanter. Modes of failure after primary internal fixation were cutout (n = 12), migration of the femoral neck screw (n = 9), and other (n = 9).
Results
Mean age at the index operation with the modular prosthesis was 77 (52–93) years and the mean follow-up was 4 (1–9) years. Union of the remaining fracture fragments was observed in 26 hips, restoration of proximal bone defects in 16 hips, and bone ingrowth of the stem in 25 hips. Subsidence was evident in 4 cases. 1 patient was revised by component exchange because of recurrent dislocation, and another 6 patients were reoperated: 5 because of deep infections and 1 because of periprosthetic fracture. The cumulative 3-year survival for revision was 96% (95% CI: 89–100) and for any reoperation it was 83% (68–93).
Interpretation
The modular stem allowed fixation distal to the fracture system. Radiographic outcome was good. The rate of complications, however—especially infections—was high. We believe that preoperative laboratory screening for low-grade infection and synovial cultures could contribute to better treatment in some of these patients.
doi:10.3109/17453674.2012.733917
PMCID: PMC3488175  PMID: 23083435
8.  Survival of uncemented acetabular monoblock cups 
Acta Orthopaedica  2012;83(3):214-219.
Background and purpose
Monoblock acetabular cups represent a subtype of uncemented cups with the polyethylene liner molded into a metal shell, thus eliminating—or at least minimizing—potential backside wear. We hypothesized that the use of mono​block cups could reduce the incidence of osteolysis and aseptic loosening, and thus improve survival compared to modular designs.
Patients and methods
We identified all 210 primary total hip arthroplasty (THA) procedures in the Swedish Hip Arthroplasty Register that used uncemented monoblock cups during the period 1999–2010. Kaplan-Meier and Cox regression analyses with adjustment for age, sex, and other variables were used to calculate survival rates and adjusted hazard ratios (HRs) of the revision risk for any reason. 1,130 modular cups, inserted during the same time period, were used as a control group.
Results
There was a nearly equal sex distribution in both groups. Median age at the index operation was 47 years in the monoblock group and 56 years in the control group (p < 0.001). The cumulative 5-year survival with any revision as the endpoint was 95% (95% CI: 91–98) for monoblock cups and 97% (CI: 96–98) for modular cups (p = 0.6). The adjusted HR for revision of monoblock cups compared to modular cups was 2 (CI: 0.8–6; p = 0.1). The use of 28-mm prosthesis heads rather than 22-mm heads reduced the risk of cup revision (HR = 0.2, CI: 0.1–0.5; p = 0.001).
Interpretation
Both cups showed good medium-term survival rates. There was no statistically significant difference in revision risk between the cup designs. Further review of the current patient population is warranted to determine the long-term durability and risk of revision of monoblock cup designs.
doi:10.3109/17453674.2012.688726
PMCID: PMC3369144  PMID: 22574820
9.  A modular cementless stem vs. cemented long-stem prostheses in revision surgery of the hip 
Acta Orthopaedica  2011;82(2):136-142.
Background and purpose
Modular cementless revision prostheses are being used with increasing frequency. In this paper, we review risk factors for the outcome of the Link MP stem and report implant survival compared to conventional cemented long-stem hip revision arthroplasties.
Patients and methods
We used data recorded in the Swedish Hip Arthroplasty Register. 812 consecutive revisions with the MP stem (mean follow-up time 3.4 years) and a control group with 1,073 cemented long stems (mean follow-up time 4.2 years) were included. Kaplan-Meier analysis was used to determine implant survival. The Cox regression model was used to study risk factors for reoperation and revision.
Results
The mean age at revision surgery for the MP stem was 72 (SD 11) years. Decreasing age (HR = 1.1, 95% CI: 1–1.1), multiple previous revisions (HR = 2.6, 95% CI: 1.1–6.2), short stem length (HR = 2.4, 95% CI: 1.1–5.2), standard neck offset (HR = 5, 95% CI: 1.5–17) and short head-neck length (HR = 5.3, 95% CI 1.4–21) were risk factors for reoperation. There was an overall increased risk of reoperation (HR = 1.7, 95% CI: 1.3–2.4) and revision (HR = 1.9, 95% CI: 1.2–3.1) for the MP prostheses compared to the controls.
Interpretation
The cumulative survival with both reoperation and revision as the endpoint was better for the cemented stems with up to 3 years of follow-up. Thereafter, the survival curves converged, mainly because of increasing incidence of revision due to loosening in the cemented group. We recommend the use of cemented long stems in patients with limited bone loss and in older patients.
doi:10.3109/17453674.2011.566145
PMCID: PMC3235281  PMID: 21434792
10.  Elevation of circulating HLA DR+ CD8+ T-cells and correlation with chromium and cobalt concentrations 6 years after metal-on-metal hip arthroplasty 
Acta Orthopaedica  2011;82(1):6-12.
Background and purpose
Following metal-on-metal hip arthroplasty (THA), immunological reactions including changes in lymphocyte populations, aseptic loosening, and lymphocytic pseudotumors occur. We hypothesized that changes in lymphocyte subpopulations would be associated with elevated metal ion concentrations.
Methods
A randomized trial involving 85 patients matched for age and sex and randomized to receiving metal-on-metal (n = 41) or metal-on-polyethylene total hip arthroplasty (n = 44) was conducted. 36 patients were eligible for follow-up after mean 7 (6–8) years. Concentrations of chromium and cobalt were analyzed by high-resolution inductively coupled plasma mass spectrometry. Leukocyte subpopulations and immunoglobulins in patient blood were measured using standard laboratory methods.
Results
Patients with a metal-on-metal hip had higher serum concentrations of chromium (1.05 vs. 0.36 μg/L; p < 0.001) and cobalt (0.86 vs. 0.24 μg/L; p < 0.001) than those with metal-on-polyethylene. The percentage of HLA DR+ CD8+ T-cells was higher in the metal-on-metal group (10.6 vs. 6.7%; p = 0.03) and correlated positively with chromium and cobalt concentrations in patient blood (Pearson's correlation coefficient: 0.39, p = 0.02; 0.36, p = 0.03, respectively). The percentage of B-cells was lower in the metal-on-metal group (p = 0.01). The two groups were similar with respect to immunoglobulin concentrations and Harris hip scores, and there were no radiographic signs of loosening.
Interpretation
We conclude that immunological alterations appear to be associated with increased cobalt and chromium concentrations. It is tempting to speculate that HLA DR+ CD8+ T-cells are involved in the pathogenesis of allergic reactions, implant loosening, and lymphocytic pseudotumors.
doi:10.3109/17453674.2010.548028
PMCID: PMC3229991  PMID: 21189110
11.  Neuropeptide Y innervation during fracture healing and remodeling 
Acta Orthopaedica  2010;81(5):639-646.
Background and purpose
Autonomic neuropeptide Y (NPY) is involved in local bone remodeling via the central nervous system. However, the role of peripheral neuronal NPY in fracture healing is not known. We investigated the relationship between bone healing and side-specific occurrence of NPY in angular and straight fractures.
Methods
Tibial fractures in Sprague-Dawley rats were fixed with intramedullary pins in straight alignment and anterior angulation. The samples were analyzed by radiography, histology, and immunohistochemistry (IHC) between 3 and 56 days postfracture.
Results
In the angular fractures, radiography and histology showed a 3.5-fold increase in callus thickness on the concave side compared to the convex side at day 21, whereas a 0.2-fold reduction in callus thickness was seen on the convex side between days 21 and 56. IHC showed regenerating NPY fibers in the callus and woven bone in both fractures at day 7. In angular fractures, a 5-fold increase in NPY fibers was observed on the concave side compared to the convex side at 7 days, whereas a 6-fold increase in NPY fibers was seen on the convex side between 21 and 56 days; only a 0.1-fold increase in NPY fibers was seen on the concave side during the same time period. In straight fractures, similar bony and neuronal changes were observed on both sides.
Interpretation
The increase in NPY innervation on the convex side appears to correlate with the loss of callus thickness on the same side in angular fractures. Our results highlight the probable function of the peripheral NPY system in local bone remodeling.
doi:10.3109/17453674.2010.504609
PMCID: PMC3214756  PMID: 20860441
12.  Effects of synovial fluid from aseptic prosthesis loosening on collagen production in osteoblasts 
International Orthopaedics  2008;33(3):873-877.
Synovial fluid from a loose prosthesis may act as a vehicle for factors that regulate bone turnover. The effect of such synovial fluid on osteoblasts has been studied. Synovial fluid obtained from patients who underwent revision hip arthroplasty because of aseptic prosthesis loosening was studied regarding the effect on protein synthesis, procollagen I mRNA expression, the secretion of procollagen I carboxyterminal propeptide (PICP) and osteocalcin in MG63 osteoblasts. Protein synthesis was increased and procollagen I mRNA expression was decreased by synovial fluid from patients with prosthesis loosening. Synovial fluid stimulated the total PICP in cell medium, but there was no change after correction for cell protein content in the cells. Synovial fluid in patients with prosthesis loosening has a general stimulatory effect on collagen formation and osteoblast proliferation because of a stimulatory effect on cell growth. Aseptic prosthesis loosening may be associated with an increase in bone formation.
doi:10.1007/s00264-008-0533-z
PMCID: PMC2903105  PMID: 18350290
13.  Distal femoral stem-bone anchorage of a cementless revision total hip arthroplasty 
Acta Orthopaedica  2009;80(3):298-302.
Background and purpose According to the manual of the cementless Link MP reconstruction prosthesis, a distal femoral stem-bone anchorage of at least 80 mm is necessary to gain implant stability. There have been no in vivo studies showing that this distance is either achieved in clinical practice or needed for clinically satisfying results. Thus, we assessed the femoral stem-bone anchorage of the MP prosthesis using CT.
Methods 14 patients with the MP stem were evaluated by CT scans at a median follow-up time of 12 months postoperatively. Femoral stem-bone anchorage was defined as adequate if 50% of the stem flutes or more had cortical bone contact. The length of anchorage was derived from the number of slices with adequate anchorage. Clinical outcome was assessed with VAS for pain and Harris hip score (HHS), both at 1 and 5 years of follow-up.
Results The median length of stem-bone anchorage was 33 mm (interquartile range 10–60), which was shorter than recommended (p = 0.002). Still, at the 1-year control, all patients were fully weight-bearing and only 1/14 complained about mild thigh pain. 7/14 patients did not experience any pain in the affected hip. The patients had a median of 85 points in the HHS. The clinical outcome at 5 years was unchanged.
Interpretation We found that it can be difficult to achieve a stem-bone anchorage of at least 80 mm for the MP Link prosthesis. However, this does not appear to be necessary to obtain stability and to achieve clinically satisfying results.
doi:10.3109/17453670903039403
PMCID: PMC2823214  PMID: 19593722
14.  Effects on osteoclast and osteoblast activities in cultured mouse calvarial bones by synovial fluids from patients with a loose joint prosthesis and from osteoarthritis patients 
Aseptic loosening of a joint prosthesis is associated with remodelling of bone tissue in the vicinity of the prosthesis. In the present study, we investigated the effects of synovial fluid (SF) from patients with a loose prosthetic component and periprosthetic osteolysis on osteoclast and osteoblast activities in vitro and made comparisons with the effects of SF from patients with osteoarthritis (OA). Bone resorption was assessed by the release of calcium 45 (45Ca) from cultured calvariae. The mRNA expression in calvarial bones of molecules known to be involved in osteoclast and osteoblast differentiation was assessed using semi-quantitative reverse transcription-polymerase chain reaction (PCR) and real-time PCR. SFs from patients with a loose joint prosthesis and patients with OA, but not SFs from healthy subjects, significantly enhanced 45Ca release, effects associated with increased mRNA expression of calcitonin receptor and tartrate-resistant acid phosphatase. The mRNA expression of receptor activator of nuclear factor-kappa-B ligand (rankl) and osteoprotegerin (opg) was enhanced by SFs from both patient categories. The mRNA expressions of nfat2 (nuclear factor of activated T cells 2) and oscar (osteoclast-associated receptor) were enhanced only by SFs from patients with OA, whereas the mRNA expressions of dap12 (DNAX-activating protein 12) and fcrγ (Fc receptor common gamma subunit) were not affected by either of the two SF types. Bone resorption induced by SFs was inhibited by addition of OPG. Antibodies neutralising interleukin (IL)-1α, IL-1β, soluble IL-6 receptor, IL-17, or tumour necrosis factor-α, when added to individual SFs, only occasionally decreased the bone-resorbing activity. The mRNA expression of alkaline phosphatase and osteocalcin was increased by SFs from patients with OA, whereas only osteocalcin mRNA was increased by SFs from patients with a loose prosthesis. Our findings demonstrate the presence of a factor (or factors) stimulating both osteoclast and osteoblast activities in SFs from patients with a loose joint prosthesis and periprosthetic osteolysis as well as in SFs from patients with OA. SF-induced bone resorption was dependent on activation of the RANKL/RANK/OPG pathway. The bone-resorbing activity could not be attributed solely to any of the known pro-inflammatory cytokines, well known to stimulate bone resorption, or to RANKL or prostaglandin E2 in SFs. The data indicate that SFs from patients with a loose prosthesis or with OA stimulate bone resorption and that SFs from patients with OA are more prone to enhance bone formation.
doi:10.1186/ar2127
PMCID: PMC1860076  PMID: 17316439
15.  Variability in synovial inflammation in rheumatoid arthritis investigated by microarray technology 
In recent years microarray technology has been used increasingly to acquire knowledge about the pathogenic processes involved in rheumatoid arthritis. The present study investigated variations in gene expression in synovial tissues within and between patients with rheumatoid arthritis. This was done by applying microarray technology on multiple synovial biopsies obtained from the same knee joints. In this way the relative levels of intra-patient and inter-patient variation could be assessed. The biopsies were obtained from 13 different patients: 7 by orthopedic surgery and 6 by rheumatic arthroscopy. The data show that levels of heterogeneity varied substantially between the biopsies, because the number of genes found to be differentially expressed between pairs of biopsies from the same knee ranged from 6 to 2,133. Both arthroscopic and orthopedic biopsies were examined, allowing us to compare the two sampling methods. We found that the average number of differentially expressed genes between biopsies from the same patient was about three times larger in orthopedic than in arthroscopic biopsies. Using a parallel analysis of the tissues by immunohistochemistry, we also identified orthopedic biopsies that were unsuitable for gene expression analysis of synovial inflammation due to sampling of non-inflamed parts of the tissue. Removing these biopsies reduced the average number of differentially expressed genes between the orthopedic biopsies from 455 to 171, in comparison with 143 for the arthroscopic biopsies. Hierarchical clustering analysis showed that the remaining orthopedic and arthroscopic biopsies had gene expression signatures that were unique for each patient, apparently reflecting patient variation rather than tissue heterogeneity. Subsets of genes found to vary between biopsies were investigated for overrepresentation of biological processes by using gene ontology. This revealed representative 'themes' likely to vary between synovial biopsies affected by inflammatory disease.
doi:10.1186/ar1903
PMCID: PMC1526587  PMID: 16507157

Results 1-15 (15)