Loose Bodies Found in the Human Intra-Articular Space Showed Characteristics Similar to Endochondral Bone Formation.

OBJECTIVE: Loose bodies are free-floating tissues of cartilage and bone that can cause pain, swelling, the inability to straighten the knee, or intermittent locking of the knee. Loose bodies can arise from degenerative joint disease, flake fractures, osteochondritis dissecans, or chondromatosis. We hypothesized that loose bodies can be classified in stages with tissue characteristics similar to endochondral ossification. DESIGN: Loose bodies were harvested from patients undergoing joint replacement. Samples were processed for histology, gene expression analysis, and micro-computed tomography (µCT). Cartilage- and bone-related genes and proteins were selected for immunofluorescence stainings (collagen type I, II, and X, SOX9 [SRY-box transcription factor 9], and MMP13 [matrix metalloproteinase 13]) and gene expression analysis (FN [fibronectin], COL1A1, COL2A1, COL10A1, SOX9, MMP13, and aggrecan [ACAN]). RESULTS: Loose bodies were grouped in 4 stages: fibrous, (mineralized) cartilaginous, cartilage and bone, and bone. Hyaline-like cartilage tissue with Benninghoff arcades was present in stages 2 and 3. A transition from cartilaginous to mineralized tissue and bone trabecula was defined by an increase in COL1A1 and COL10A1 (stage 3 vs. 4: p = 0.047) positive area. Stage 4 showed typical trabecular bone tissue. The relative volume of calcified tissue (mineralized cartilage and bone tissue) decreased with stages (stages 1-2 vs. 3: p = 0.002; stage 1-2 vs. 4: p = 0.012). COL2A1 expression and stained area decreased from stages 1-2 to 4 (p = 0.010 and p = 0.004). ACAN expression decreased from stage 1-2 to stage 3 (p = 0.049) and stage 4 (p = 0.002). CONCLUSION: Loose bodies show tissue characteristics similar to endochondral ossification. They are probably a relevant substrate for regenerative therapeutic interventions in joint disease.

The histopathological synovitis score is influenced by biopsy location in patients with knee osteoarthritis.

INTRODUCTION: Osteoarthritis (OA) and rheumatoid arthritis (RA) represent the most common forms of arthritis, which are mainly caused by mechanical and inflammatory components, respectively. Determination of synovial inflammation in synovial biopsies via the histopathological Krenn score may be crucial for correct diagnosis and treatment. Specifically, it remains unclear whether synovitis scores differ among multiple biopsy locations within a single joint. MATERIALS AND METHODS: Eighty synovial samples were taken from four standardized regions of the knee in 20 patients (ten primary OA, ten secondary OA) undergoing total knee arthroplasty (TKA) or total synovectomy. The Krenn synovitis score (grade 0-9) was determined in a blinded manner by two expert pathologists in all biopsies. Next to the inter-rater reliability, we evaluated the agreement of the determined scores among the four biopsy locations within each knee. RESULTS: The inter-rater reliability between the two pathologists was very high (Cohen's kappa = 0.712; r = 0.946; ICC = 0.972). The mean synovitis score was significantly higher in knees with secondary than in primary OA (p = 0.026). Importantly, we found clear differences between the scores of the four different biopsy locations within the individual knee joints, with an average deviation of 10.6%. These deviations were comparable in knees with primary and secondary OA (p = 0.64). CONCLUSIONS: While we confirmed the synovitis score as a reliable and reproducible parameter to assess the histopathological synovitis grade in the knee, the considerable variability within the joint indicates that multiple synovial biopsies from different regions should be obtained to enable reliable results of the synovitis score.

General synovitis score and immunologic synovitis score reflect clinical disease activity in patients with advanced stage rheumatoid arthritis.

The purpose of this study was to investigate the relationship between clinical disease activity in patients with advanced stage rheumatoid arthritis (RA) on treatment with Disease Modifying Antirheumatic Drugs (DMARDs) and histopathological scores of synovial inflammation. To this end, synovial biopsies of 62 RA patients who underwent surgery for either synovectomy or total joint arthroplasty were assessed by a general synovitis score (GSS) and an immunologic synovitis score (IMSYC). The clinical disease activity index (CDAI) was significantly correlated with both the GSS and the IMSYC (r = 0.65, p = <0.001, r = 0.68, p = <0.001). Compared to patients with moderate and high disease activity, there was a significantly lower expression of T cell (CD3), B cell (CD20) and neutrophil (CD15) markers in synovial tissue of patients with low activity, but similar expression of the macrophage marker CD68. Subgroup analyses revealed no differences between small and large joints, seropositive and seronegative RA and patients with or without prednisolone treatment. However, we found a significantly stronger correlation of CDAI with IMSYC in patients undergoing arthroplasty (r = 0.82) than in patients undergoing synovectomy (r = 0.55). In addition, there was a stronger correlation of CDAI with GSS in patients treated with methotrexate (r = 0.86) than in patients with TNFα blockade (r = 0.55). In summary, the present study demonstrates that the histopathological scores GSS and IMSYC in general reflect clinical disease activity in patients with advanced stage rheumatoid arthritis, but that there is some heterogeneity between subgroups of patients within the cohort. In the future, molecular characterization of synovial inflammatory cell populations, including plasma cell infiltrates, will help to further defined clinically important subtypes of RA and treatment response.

Forefoot Reconstruction Following Metatarsal Head Resection Arthroplasty With a Plantar Approach-A 20-Year Follow-Up.

BACKGROUND: Rheumatoid arthritis (RA) can cause significant forefoot disorders. If forefoot deformity and pain are severe, surgical treatment can be considered. The aim of this study was to analyze the long-term outcomes of surgical forefoot correction per Tillmann, which involves resection of the metatarsal heads through a transverse plantar approach for the lesser toes and a dorsomedial approach to the great toe. METHODS: This retrospective study used patient-based questionnaires to analyze the revision rate, pain, use of orthoses, walking ability, forefoot function, and patient satisfaction of patients with RA who had undergone a complete forefoot correction of metatarsophalangeal (MTP) I to V. The study only included participants with RA before the era of biological agents and who were at least 20 years postoperatively. A total of 60 patients who had undergone 100 complete forefoot operations according to Tillmann 24.6 ± 3.5 years ago were included in this study. RESULTS: The data collected showed that 35 reoperations were performed on 26 of the patients. Deformity relapses were often documented for the hallux valgus. More than 60% of the patients were able to wear conventional shoes. The distances the participants were able to walk were significantly increased by wearing shoes when compared with walking barefoot (P < .01). CONCLUSION: While forefoot function remained difficult to assess, the majority of patients were able to use conventional shoes. This long-term follow-up study of patient-reported questionnaires completed more than 20 years after the Tillmann procedure showed that more than 80% of the patients remained satisfied with the outcome. LEVEL OF EVIDENCE: Level IV, retrospective cohort study.

The impact of physical activity on serum levels of inflammatory markers in rheumatoid arthritis: a systematic literature review.

This review aims to determine the specific effects of PA on systemic levels of interleukins and inflammatory markers. A systematic literature search was conducted in three computerized bibliographic databases (Medline, Embase, CENTRAL) to identify randomized controlled trials and matched case studies. Applied key words were: RA and PA including the terms exercise, exercise therapy, gymnastics and exercise movement techniques. Inclusion criteria were data on all types of proinflammatory interleukins (IL), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). For data synthesis, the populations, interventions and outcomes were described according to the PRISMA statement. A total of 1289 publications were found. Fifteen papers, related to 14 different study populations, met the inclusion criteria. No study revealed a significant change regarding IL or CRP levels in response to the intervention (PA). In three study populations, a significant reduction of the ESR was identified, but the effect from PA was not discernible from effects of changes of the anti-rheumatic medication in these studies. The strong variability in study designs, cohort size and types of physical training programs remains an obstacle in the assessment of the measurable effects of PA on inflammatory markers in patients with RA. At present, there is no sufficient evidence to conclude that PA has a significant impact on systemic levels of inflammatory markers in RA.

Th17 cell frequency is associated with low bone mass in primary sclerosing cholangitis.

BACKGROUND & AIMS: Osteoporotic fractures are a major cause of morbidity and reduced quality of life in patients with primary sclerosing cholangitis (PSC), a progressive bile duct disease of unknown origin. Although it is generally assumed that this pathology is a consequence of impaired calcium homeostasis and malabsorption, the cellular and molecular causes of PSC-associated osteoporosis are unknown. METHODS: We determined bone mineral density by dual-X-ray absorptiometry and assessed bone microstructure by high-resolution peripheral quantitative computed tomography in patients with PSC. Laboratory markers of liver and bone metabolism were measured, and liver stiffness was assessed by FibroScan. We determined the frequency of Th17 cells by the ex vivo stimulation of peripheral blood mononuclear cells in a subgroup of 40 patients with PSC. To investigate the potential involvement of IL-17 in PSC-associated bone loss, we analyzed the skeletal phenotype of mice lacking Abcb4 and/or Il-17. RESULTS: Unlike in patients with primary biliary cholangitis, bone loss in patients with PSC was not associated with disease duration or liver fibrosis. However, we observed a significant negative correlation between the bone resorption biomarker deoxypyridinoline and bone mineral density in the PSC cohort, indicating increased bone resorption. Importantly, the frequency of Th17 cells in peripheral blood was positively correlated with the urinary deoxypyridinoline level and negatively correlated with bone mass. We observed that Abcb4-deficient mice displayed a low-bone-mass phenotype, which was corrected by an additional Il-17 deficiency or anti-IL-17 treatment, whereas the liver pathology was unaffected. CONCLUSIONS: Our findings demonstrate that an increased frequency of Th17 cells is associated with bone resorption in PSC. Whether antibody-based IL-17 blockade is beneficial against bone loss in patients with PSC should be addressed in future studies. LAY SUMMARY: Primary sclerosing cholangitis (PSC) is a cholestatic liver disease characterized by progressive bile duct destruction. One serious complication of PSC is reduced bone mass resulting in increased fracture risk. Herein, we demonstrate that Th17 cells mediate bone loss in PSC by inducing bone resorption, which suggests that antibody-based IL-17 blockade might be beneficial for the treatment of bone loss in affected patients.

Calcification of the acetabular labrum of the hip: prevalence in the general population and relation to hip articular cartilage and fibrocartilage degeneration.

BACKGROUND: Meniscal calcification is considered to play a relevant role in the pathogenesis of osteoarthritis of the knee. Little is known about the biology of acetabular labral disease and its importance in hip pathology. Here, we analyze for the first time the calcification of the acetabular labrum of the hip (ALH) and its relation to hip cartilage degeneration. METHODS: In this cross-sectional post-mortem study of an unselected sample of the general population, 170 ALH specimens and 170 femoral heads from 85 donors (38 female, 47 male; mean age 62.1 years) were analyzed by high-resolution digital contact radiography (DCR) and histological degeneration grade. The medial menisci (MM) from the same 85 donors served as an intra-individual reference for cartilage calcification (CC). Scanning electron microscopy (SEM), energy dispersive analysis (ED) and Raman spectroscopy were performed for characterization of ALH CC. RESULTS: The prevalence of CC in the ALH was 100% and that in the articular cartilage of the hip (ACH) was 96.5%. Quantitative analysis revealed that the amount of ALH CC was higher than that in the ACH (factor 3.0, p < 0.001) and in the MM (factor 1.3, p < 0.001). There was significant correlation between the amount of CC in the fibrocartilage of the left and right ALH (r = 0.70, p < 0.001). Independent of age, the amount of ALH CC correlated with histological degeneration of the ALH (Krenn score) (r = 0.55; p < 0.001) and the ACH (Osteoarthritis Research Society International (OARSI), r = 0.69; p < 0.001). Calcification of the ALH was characterized as calcium pyrophosphate dihydrate deposition. CONCLUSION: The finding that ALH fibrocartilage is a strongly calcifying tissue is unexpected and novel. The fact that ALH calcification correlates with cartilage degeneration independent of age is suggestive of an important role of ALH calcification in osteoarthritis of the hip and renders it a potential target for the prevention and treatment of hip joint degeneration.

Labral calcification in end-stage osteoarthritis of the hip correlates with pain and clinical function.

The acetabular labrum of the hip (ALH) is recognized as a clinically important structure, but knowledge about the pathophysiology of this fibrocartilage is scarce. In this prospective study we determined the prevalence of ALH calcification in patients with end-stage osteoarthritis (OA) and analyzed the relationship of cartilage calcification (CC) with hip pain and clinical function. Cohort of 80 patients (70.2 ± 7.6years) with primary OA scheduled for total hip replacement. Harris Hip Score (HHS) was recorded preoperatively. Total ALH and femoral head (FH) were sampled intraoperatively. CC of the ALH and FH was analyzed by high-resolution digital contact radiography. Histological degeneration of the ALH (Krenn-Score) and FH (OARSI-Score) was determined. Multivariate linear regression model and partial correlation analyses were performed. The prevalence of cartilage calcification both in the ALH and FH was 100%, while the amount of CC in the ALH was 1.55 times higher than in the FH (p < 0.001). There was a significant inverse regression between the amount of calcification of both the ALH and the FH and preoperative HHS (ßALH = -2.1, p = 0.04), (ßFH = -2.9, p = 0.005), but pain was influenced only by ALH calcification (ßALH = -2.7, p = 0.008). Age-adjusted, there was a significant correlation between cartilage calcification and histological degeneration (ALH:rs = 0.53, p < 0.001/FH: rs = 0.30, p = 0.007). Fibrocartilage and articular cartilage calcification are inseparable pathological findings in end-stage osteoarthritis of the hip. Fibrocartilage calcification is associated with poor and painful hip function. CLINICAL SIGNIFICANCE: ALH fibrocartilage appears to be particularly prone to calcification, which may explain higher pain levels in individuals with a high degree of ALH calcification independent of age and histological degeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1248-1255, 2018.

Changes in cortical microarchitecture are independent of areal bone mineral density in patients with fragility fractures.

Dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) are commonly used to assess the areal bone mineral density (aBMD) and peripheral microstructure, respectively. While DXA is the standard to diagnose osteoporosis, HR-pQCT provides information about the cortical and trabecular architecture. Many fragility fractures occur in patients who do not meet the osteoporosis criterion (i.e., T-score≤-2.5). We hypothesize that patients with T-score above -2.5 and fragility fracture may have abnormal bone microarchitecture. Therefore, in this retrospective clinical study, HR-pQCT data obtained from patients with fragility fractures and T-scores≥-2.5 (n=71) were compared to corresponding data from patients with fragility fractures and T-scores≤-3.5 (n=56). Types of secondary osteoporosis were excluded from the study. To verify the dependency of alterations in bone microarchitecture and T-score, the association between HR-pQCT values and aBMD as reflected by the T-score at both proximal femora, was assessed. At the distal tibia, cortical thickness was lower (p<0.001), cortical porosity was similar (p=0.61), trabecular number was higher (p<0.001), and bone volume fraction (BV/TV) was higher (p<0.001) in patients with T-scores≥-2.5 than in patients with T-scores≤-3.5. Trabecular number and BV/TV correlated with T-score (r=0.68, p<0.001; r=0.61, p<0.001), whereas the cortical values did not. Our results thus demonstrate the importance of bone structure, as assessed by HR-pQCT, in addition to the standard DXA T-score in the diagnosis of osteoporosis.

Evaluation of bone microstructure in CRPS-affected upper limbs by HR-pQCT.

INTRODUCTION: Complex regional pain syndrome (CRPS) is a major complication after trauma, surgery, and/or immobilization of an extremity. The disease often starts with clinical signs of local inflammation and develops into a prolonged phase that is characterized by trophic changes and local osteoporosis and sometimes results in functional impairment of the affected limb. While the pathophysiology of CRPS remains poorly understood, increased local bone resorption plays an undisputed pivotal role. The aim of this retrospective clinical study was to assess the bone microstructure in patients with CRPS. METHODS: Patients with CRPS type I of the upper limb whose affected and unaffected distal radii were analyzed by high-resolution peripheral quantitative computed tomography (HR-pQCT) were identified retrospectively. The osteology laboratory data and dual-energy X-ray absorptiometry (DXA) images of the left femoral neck and lumbar spine, which were obtained on the same day as HR-pQCT, were extracted from the medical records. RESULTS: Five patients were identified. The CRPS-affected upper limbs had significantly lower trabecular numbers and higher trabecular thicknesses than the unaffected upper limbs. However, the trabecular bone volume to total bone volume and cortical thickness values of the affected and unaffected sides were similar. Trabecular thickness tended to increase with time since disease diagnosis. DISCUSSION: CRPS associated with significant alterations in the bone microstructure of the affected upper limb that may amplify as the duration of disease increases.

Microcalcification of lumbar spine intervertebral discs and facet joints is associated with cartilage degeneration, but differs in prevalence and its relation to age.

Cartilage calcification (CC) is associated with degeneration in non-vertebral joints, but little is known about CC and lumbar vertebral joints. The goal of this study was to analyze the prevalence of CC in lumbar facet joints (FJ) and intervertebral discs (IVD) and its relation to cartilage degeneration and age in a non-selected cohort of the general population. The segment L4/5 of 85 consecutive donors (mean age 61.9 years) was analyzed by high-resolution imaging digital-contact radiography (DCR). Quantification was achieved by measuring CC in % of total cartilage area. Histological degeneration of FJs and IVDs was determined by OARSI and Boos scores. Prevalence of CC was 36.5% for FJ (95%CI (0.26, 0.48)) and 100% for IVD (95%CI (0.96, 1.00)). The amount of IVD CC (3.36% SD ± 7.14) was 16.3 times higher (p < 0.001) than that of the FJ (0.23% SD ± 0.53) and independent of each other (p = 0.07). The amount of FJ CC correlated significantly with FJ and IVD degeneration (FJ r = 0.44, p = 0.01, IVD r = 0.49, p = 0.006) while the amount of IVD CC correlated only with IVD degeneration (r = 0.54, p < 0.001). Age correlated with IVD CC (rs = 0.35, p < 0.001), but not FJ CC (rs = 0.04, p = 0.85). We conclude that IVD fibrocartilage is particularly prone to calcification. A causal relationship between lumbar CC and degeneration is possible, but the clear differences in IVD fibrocartilage CC and FJ synovial joint CC in regard to prevalence and in relation to age point to a differential role of CC in single compartments of the respective motion segment in lumbar spine degeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2692-2699, 2017.

Hyaline cartilage calcification of the first metatarsophalangeal joint is associated with osteoarthritis but independent of age and BMI.

BACKGROUND: Hyaline cartilage calcification (CC) is associated with osteoarthritis (OA) in hip and knee joints. The first metatarsophalangeal joint (1stMTPJ) is frequently affected by OA, but it is unclear if CC occurs in the 1stMTPJ. The aim of the present study was to analyze the prevalence of CC of the 1stMTPJ in the general population by high-resolution digital contact radiography (DCR) and to determine its association with histological OA severity, age and body mass index (BMI). METHODS: 168 metatarsal heads of 84 donors (n = 47 male, n = 37 female; mean age 62.73 years, SD ±18.8, range 20-93) were analyzed by DCR for the presence of CC. Histological OA grade (hOA) by OARSI was analyzed in the central load-bearing zone of the first metatarsal head (1st MH). Structural equation modeling (SEM) was performed to analyze the interrelationship between CC, hOA, age and BMI. RESULTS: The prevalence of CC of 1stMH was 48.8 % (41/84) (95 %-CI [37.7 %, 60.0 %]), independent of the affected side (p = 0.42), gender (p = 0.41) and BMI (p = 0.51). The mean amount of CC of one MH correlated significantly with that of the contralateral side (rs = 0.4, 95 %-CI [0.26, 0.52], p < 0.001). The mean amount of CC (in % of total cartilage area) of the MH correlated significantly with the severity of hOA (rs = 0.51, 95 %-CI [0.32, 0.65], p < 0.001). SEM revealed significant associations between CC and hOA (r = 0.74, p < 0.001) and between hOA and age (ß = 0.62, p = 0.001), but not between CC and age (p = 0.15). There was no significant influence of BMI on either CC (p = 0.37) or hOA (p = 0.16). CONCLUSION: The observation that CC of the 1stMH is significantly associated with the severity of OA but independent of age and BMI, suggests an intimate relationship between CC and the pathogenesis of OA, the exact nature of which will have to be explored by future studies.

Articular cartilage calcification of the humeral head is highly prevalent and associated with osteoarthritis in the general population.

Articular cartilage calcification is considered a pathological albeit incompletely understood process which is known to be associated with osteoarthritis of the knee and hip. The goal of this study was to determine the prevalence of articular cartilage calcification of the shoulder as a non-weight-bearing joint and to analyze the interrelationship of calcification with age and histological severity of shoulder osteoarthritis in the general population. In a cross-sectional study of 180 humeral heads from 90 donors (n = 49 male, n = 41 female; mean age 62.7 years [20-93]), cartilage calcification of the humeral head was quantified by digital contact radiography (DCR). Histological OA grade (OARSI) was determined and structural equation modeling (SEM) was used to analyze the interrelationship of cartilage calcification, OARSI and age. The prevalence of articular cartilage calcification was 98.9% (95%CI: [93.96%, 99.97%]) and was independent of gender (p = 0.55). Cartilage calcification of one shoulder correlated significantly with that of the contralateral side (r = 0.61, 95%CI: [0.46, 0.73], p < 0.001). SEM demonstrated significant associations between histological OA grade and cartilage calcification (r = 0.55, p = 0.039), between histological OA grade and age (ß = 0.59, p < 0.001) but not between age and cartilage calcification (ß = 0.24, p = 0.116). In conclusion, the prevalence of shoulder cartilage calcification in the general population is higher than anticipated. The high prevalence, its concomitant bilateral manifestation and the association between the amount of cartilage calcification and OA severity, but not age, suggest that cartilage calcification is a systemically driven process with early onset in life and may be a causative factor in the pathogenesis of OA. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1984-1990, 2016.

Sunitinib treatment reduces tumor growth and limits changes in microvascular properties after minor surgical intervention in an in vivo model of secondary breast cancer growth in bone.

BACKGROUND AND OBJECTIVES: Surgical interventions can alter the balance between pro- and anti-angiogenic growth factors and thereby modulate tumor growth. Since the microcirculatory properties of tumors underlie organ-specific differences, the microhemodynamic characteristics of bone metastasis have not yet been fully described. Angiogenesis inhibitors are increasingly being used to treat advanced stages of cancer. We hypothesized that the anti-angiogenic drug sunitinib abrogates alterations in microvascular properties following a minor surgical intervention in an in vivo model of secondary breast cancer growth in the bone. METHODS: Intravital microscopy was performed over 25 days using a xenograft model of breast cancer tumor growth in the bone to determine changes in microvascular properties during sunitinib treatment. Mastectomy was performed on day 5 to evaluate the effect of a minor surgical trauma on tumor growth and microvascular properties. RESULTS: Anti-angiogenic therapy resulted in reduced tumor growth, decreased vascular density, and increased vascular diameters. Blood flow velocity remained constant while microvascular permeability temporarily increased after the surgical intervention. CONCLUSIONS: Administration of sunitinib reduced tumor growth and altered microcirculatory properties in a time-dependent manner. The observed dramatic increase in microvascular permeability after the surgical intervention may have implications for local tumor growth, and metastatic dissemination. J. Surg. Oncol. 2016;113:515-521. © 2016 Wiley Periodicals, Inc.

Deterioration of teeth and alveolar bone loss due to chronic environmental high-level fluoride and low calcium exposure.

OBJECTIVES: Health risks due to chronic exposure to highly fluoridated groundwater could be underestimated because fluoride might not only influence the teeth in an aesthetic manner but also seems to led to dentoalveolar structure changes. Therefore, we studied the tooth and alveolar bone structures of Dorper sheep chronically exposed to very highly fluoridated and low calcium groundwater in the Kalahari Desert in comparison to controls consuming groundwater with low fluoride and normal calcium levels within the World Health Organization (WHO) recommended range. MATERIALS AND METHODS: Two flocks of Dorper ewes in Namibia were studied. Chemical analyses of water, blood and urine were performed. Mineralized tissue investigations included radiography, HR-pQCT analyses, histomorphometry, energy-dispersive X-ray spectroscopy and X-ray diffraction-analyses. RESULTS: Fluoride levels were significantly elevated in water, blood and urine samples in the Kalahari group compared to the low fluoride control samples. In addition to high fluoride, low calcium levels were detected in the Kalahari water. Tooth height and mandibular bone quality were significantly decreased in sheep, exposed to very high levels of fluoride and low levels of calcium in drinking water. Particularly, bone volume and cortical thickness of the mandibular bone were significantly reduced in these sheep. CONCLUSIONS: The current study suggests that chronic environmental fluoride exposure with levels above the recommended limits in combination with low calcium uptake can cause significant attrition of teeth and a significant impaired mandibular bone quality. CLINICAL RELEVANCE: In the presence of high fluoride and low calcium-associated dental changes, deterioration of the mandibular bone and a potential alveolar bone loss needs to be considered regardless whether other signs of systemic skeletal fluorosis are observed or not.

Quality-Adjusted Life Years Gained by Hip and Knee Replacement Surgery and Its Aftercare.

OBJECTIVES: To determine the lifetime quality-adjusted life years (QALYs) gained by total joint arthroplasty (TJA), and assess the QALYs attributed to specific postoperative rehabilitation interventions. DESIGN: Secondary analysis of 2 multicenter, randomized controlled trials (RCTs) with 3-, 6-, 12-, and 24-month follow-up. SETTING: Two university hospitals, 2 municipal hospitals, and 1 rural hospital. PARTICIPANTS: Patients (N=827) who underwent total hip arthroplasty (THA) or total knee arthroplasty (TKA). INTERVENTIONS: RCT A: 465 patients were randomly assigned to receive aquatic therapy (pool exercises aimed at training of proprioception, coordination, and strengthening) 6 versus 14 days after THA or TKA. RCT B: 362 patients were randomly assigned to either perform or not perform ergometer cycling beginning 2 weeks after THA or TKA. MAIN OUTCOME MEASURE: QALYs, based on the Short Form-6 Dimensions utility, measured at baseline and 3, 6, 12, and 24 months' follow-up. RESULTS: After hip arthroplasty, the lifetime QALYs increased by 2.35 years in the nonergometer group, and by 2.30 years in the early aquatic therapy group. However, after knee arthroplasty, the lifetime QALYs increased by 1.81 years in the nonergometer group, and by 1.60 years in the early aquatic therapy group. By ergometer cycling, .55 additional QALYs could be gained after hip and .10 additional QALYs after knee arthroplasty, while the additional QALYs attributed to the timing of aquatic therapy were .12 years after hip and .01 years after knee arthroplasty. CONCLUSIONS: This analysis provides a sound estimate for the determination of the lifetime QALYs gained by THA and TKA. In addition, this analysis demonstrates that specific postoperative rehabilitation can result in an additional mean QALY gain of .55 years, which represents one fourth of the effect of surgery. Even if this is interpreted as a small effect at an individual level, it is important when extrapolated to all patients undergoing TJA. At a national level, these improvements appear to have a similar magnitude of QALY gain when compared with published data regarding medications to lower blood pressure in all persons with arterial hypertension.

Comparative immunohistochemical evaluation of the zonal distribution of extracellular matrix and inflammation markers in human meniscus in osteoarthritis and rheumatoid arthritis.

UNLABELLED: The purpose of our study was to analyze the distribution of the major extracellular matrix glycosaminoglycan hyaluronan (HA), its receptor CD44 and cells which influence (re)modeling of the extracellular matrix (T- and B-cells, macrophages, endothelial cells) in menisci obtained from patients suffering from rheumatoid arthritis or osteoarthritis in order to analyze whether these markers could be useful to differentiate between both arthropathies. Human menisci were sampled from patients undergoing total knee arthroplasty. Histological staining (H&E, PAS/Alcian Blue for neutral and charged carbohydrate residues) and (immuno)histochemistry were performed for detection of HA, CD44, sphingosine-1-phosphate receptor 1 (EDG-1) as a marker for endothelial cells, CD3 as a marker for T-cells, CD20 as a marker for B-cells and CD68 as a marker for macrophages. The extracellular matrix in the vascularized zone showed higher amounts of HA as well as acid carbohydrate residues in comparison to the poorly vascularized zones of the meniscus in both disease entities. EDG-1 positive endothelial cells were present in all zones, with fewer cells being detected in the inner zones of the rheumatoid menisci than in the osteoarthritic ones. Macrophages, T- and B-cells as well as CD44-positive cells were more prominent in the vascularized zone of the meniscus than in the poorly vascularized central zone. The distribution patterns of the extracellular matrix components as well as the CD44-positive cells and the inflammation markers in the peripheral zone resembled the distribution in synovial tissue, indicating that both synovia and meniscus were involved in pathological changes in osteoarthritis and rheumatoid arthritis. IN CONCLUSION: the distribution of extracellular glycoconjugates and of cells modulating their synthesis showed similar results in both arthropathies, not enabling a differentiation between rheumatoid arthritis and osteoarthritis but underlining the role of these markers in inflammation and degradation in human meniscus.