[Chondrocalcinosis. Clinical impact of intra-articular calcium phosphate crystals]. / Chondrokalzinose. Klinische Bedeutung von intraartikulären Kalziumphosphatkristallen.

Calcium pyrophosphate dihydrate (CPPD) crystals are known to cause acute attacks of pseudogout in joints but crystal deposition has also been reported to be associated with osteoarthritis (OA). Aside from CPPD crystals, basic calcium phosphates (BCPs), consisting of carbonate-substituted hydroxyapatite (HA), tricalcium phosphate and octacalcium phosphate, have been found in synovial fluid, synovium and cartilage of patients with OA. Although CPPD crystals have been found to be associated with OA and are an important factor in joint disease, this has also recently been associated with a genetic defect. However, according to the most recent findings, the association of BCP crystals, such as apatite with OA is much stronger, as their presence significantly correlates with the severity of cartilage degeneration. Identification of BCP crystals in OA joints remains problematic due to a lack of simple and reliable methods of detection. The clinical and pathological relevance of cartilage mineralization in patients with OA is not completely understood. It is well established that mineralization of articular cartilage is often found close to hypertrophic chondrocytes. A significant correlation between the expression of type X collagen, a marker for chondrocyte hypertrophy and cartilage mineralization was observed. In the process of endochondral ossification, the link between hypertrophy and matrix mineralization is particularly well described. Hypertrophic chondrocytes in OA cartilage and at the growth line share certain features, not only hypertrophy but also a capability to mineralize the matrix. Recent data indicate that chondrocyte hypertrophy is a key factor in articular cartilage mineralization strongly linked to OA and does not characterize a specific subset of OA patients, which has important consequences for therapeutic strategies for OA.

Decreased levels of nucleotide pyrophosphatase phosphodiesterase 1 are associated with cartilage calcification in osteoarthritis and trigger osteoarthritic changes in mice.

OBJECTIVE: To analyse the function of nucleotide pyrophosphatase phosphodiesterase (NPP1), a member of the pyrophosphate pathway, in osteoarthritis (OA). METHODS: mRNA expression of NPP1, ANK ankylosing protein and tissue non-specific alkaline phosphatase was assessed by quantitative PCR. NPP1 protein levels were analysed in mouse and human cartilage samples. Bone metabolism was analysed by F18-positron emission tomography-scanning and µCT in ttw/ttw mice. Ttw/ttw mice are mice carrying a loss-of-function mutation in NPP1. Calcification of articular cartilage was assessed using von Kossa staining and OA severity using the Mankin score. Cartilage remodelling was investigated by type X collagen immunohistochemistry. RESULTS: Expression of NPP1, but not the other members of this pathway, inversely correlated with cartilage calcification and OA severity in mouse and humans. Proinflammatory cytokines downregulated the expression of NPP1, demonstrating an influence of inflammation on matrix calcification. Ttw/ttw mutant mice, carrying a loss-of-function mutation in NPP1, exhibit increased bone formation process in joints compared with wild types. Ttw/ttw mice also developed spontaneous OA-like changes, evaluated by histological analysis and in vivo imaging. Ectopic calcifications were associated with increased expression of collagen X in the cartilage. CONCLUSION: The authors conclude that OA is characterised by the reactivation of molecular signalling cascades involving proinflammatory cytokines, thereby regulating the pyrophosphate pathway which consequently leads to cartilage ossification, at least in part resembling endochondral ossification.

[Crystal arthropathies]. / Kristallarthropathien.

Crystal arthropathies represent a heterogenic group of skeletal diseases associated with the deposition of mineralised material within joints and periarticular soft tissues. Gout is the most common and pathogenetically best understood crystal arthropathy, followed by basic calcium phosphate and calcium pyrophosphate dihydrate deposition diseases, and, in very rare cases, calcium oxalate crystal arthropathy. These crystals are responsible for different rheumatic syndromes, including acute or chronic synovial inflammation, and also contribute to cartilage degeneration. This review gives an overview of the pathological and clinical changes of these arthropathies.

[Approach to painful hip resurfacing]. / Vorgehen bei schmerzhafter Kappenprothese.

Hip resurfacing in young patients has been increasingly performed within the last decade. In comparison to standard total hip arthroplasty the failure rate remains high. Age and implant size have a significant effect on the risk of revision for primary total resurfacing and the risk of revision increases with increasing age. At 7 years the cumulative revision rate for patients is 5% and females have more than twice the cumulative revision rate as males. Even in hip resurfacing arthroplasty which has been performed in a perfect manner, a certain percentage of patients suffer from persistent pain for various reasons, such as neck fracture, iliopsoas tendinopathy, metal hypersensitivity, such as aseptic lymphocytic vasculitis associated lesions (ALVAL) and aseptic loosening. Diagnostic work-up of the painful hip resurfacing is challenging even for experienced surgeons. Recommendations for the diagnostic procedure are described.

[Synovial chondromatosis]. / Synoviale Chondromatose.

Primary articular synovial chondromatosis is a benign, self-limiting neoplastic process in which hyaline cartilage nodules form in the synovial tissue. The disease most frequently affects the knee in men, followed by the elbow. The basic feature of this disease is a metaplastic maturation of the mesenchymal cells in the synovial membrane of a joint into cartilage. These cells mature into chondroblasts and form small nodules of cartilage in the synovial membrane. These nodules subsequently enlarge and detach to lie within the joint space. They become free within the joint as multiple small cartilaginous loose bodies nourished by the synovial fluid. The chondrocytes in the loose bodies continue to multiply, and the loose bodies grow in diameter. Calcification appears in the central zone of the loose bodies, and in some cases, enchondral ossification takes place. The operative therapy depends on the stage of the disease: synovectomy with removal of chondral fragments if active intrasynovial disease is present, and removal of the multiple chondral bodies alone in cases of late inactive disease with no synovial abnormalities. Malignant transformation is unusual and can be difficult to distinguish from benign disease.

[Crystal arthropathies]. / Kristallarthropathien.

Basic calcium phosphate (BCP) and calcium pyrophosphate dihydrate crystals are the most common types of pathologic crystals, followed by monosodium urate crystals and, in rare cases, calcium oxalate crystals. These crystals have been associated with a variety of quite different rheumatic syndromes. They are responsible for acute synovial inflammation and also contribute to cartilage degradation and bone lesions within the joint. Although understanding of the molecular mechanisms involved in generating the pathologic effects of these crystals has increased, the role of BCP crystals in particular remains poorly understood. The clinical implication of articular deposits of calcium-containing crystals in osteoarthritis is unknown. This review provides an overview of the clinical and pathological changes of these four different types of crystals.

Accuracy and precision in the detection of articular cartilage lesions using magnetic resonance imaging at 1.5 Tesla in an in vitro study with orthopedic and histopathologic correlation.

BACKGROUND: Magnetic resonance (MR) sequences for cartilage visualization have been the target of numerous studies, and the optimal sequence for cartilage imaging remains a matter of debate in the literature. PURPOSE: To compare MR findings with different MR sequences for the detection of cartilage lesions in fresh deep-frozen human cadaveric patellae in an in vitro setting. MATERIAL AND METHODS: Ten cadaveric patellae were imaged on a 1.5T MR scanner with a 2x2 channel carotid sandwich coil and a conventional knee coil, and compared with orthopedic findings and gold-standard histopathology. MR sequences were: a) fat-saturated (FS) proton density-weighted (PDw) turbo spin-echo (TSE) sequence (TR/TE 4000/39 ms); b) T2-weighted (T2w) double-echo steady-state (DESS) 3D water-excitation (we) sequence (TR/TE 17/4.7 ms); c) 3D-PDw-SPACE (sampling perfection with application-optimized contrasts using different flip-angle evolutions)-we sequence (TR/TE 1800/19 ms). Accuracy, Kendall's tau-b correlation, and weighted kappa coefficients were calculated. RESULTS: Accuracy for cartilage lesion detection with the FS PDw-TSE sequence and the carotid coil was 78.3%, and with the knee coil 73.9%. For the T2wDESS-3D-we sequence, the corresponding values were 69.5% and 65.2%, and for the 3D-PDw-SPACE-we sequence 65.2% and 60.8%, respectively. Kendall's tau-b correlation ranged between 0.508 for the 3D-PDw-SPACE-we sequence (knee coil) and 0.720 for the FS PDw-TSE sequence (carotid and knee coil). Weighted kappa coefficient was lowest for the 3D-PDw-SPACE-we sequence (knee coil) at 0.607, and highest for the carotid coil and FS PDw-TSE sequence at 0.779. CONCLUSION: The evaluated FS PDw-TSE sequences are superior in comparison to the T2wDESS-3D-we and 3D-PDw-SPACE-we sequences in the in vitro setting for the detection of cartilage lesions, and are comparable to results reported in the literature.

Translocation (3;21;8)(q21;q22;q22) in a patient with acute myeloid leukemia. A case report and review of prognostic indicators.

We report a patient with acute myeloid leukemia (AML) and t(3;21;8)(q21;q22;q22). This translocation has not been previously described in de novo or relapsed AML. The patient is a 25-year-old woman who presented with WBC 6.2 x 10(9)/L, Hgb 10.2 g/dL, Hct 28.4%, and platelets 67 x 10(9)/L. A bone marrow biopsy revealed a 70% hematopoietic cellularity with 65% blasts. Immunophenotyping showed aberrant expression of lymphoid-associated marker CD19. Cytogenetic analysis on a 72-hour culture of bone marrow cells supplemented with conditioned media was evaluated by G-banding at about the 400-band level. The patient's age, cytogenetics, WBC, and immunophenotype at diagnosis would seem to suggest a favorable prognosis, according to previous studies of prognostic indicators. She was treated with induction and consolidation chemotherapy, followed by myeloablative conditioning and autologous peripheral blood stem cell transplant (PBSCT). Despite multiple favorable prognostic factors, the patient relapsed 7 months after PBSCT. Translocation of chromosomes 8 and 21 is common in AML and is generally considered a good prognostic factor. We suspect that the effect of the 3q21 translocation in an otherwise favorable translocation of chromosomes 8 and 21 may be responsible for this patient's early relapse.

Translocation (12;15)(p13;q13) in a patient with relapsed acute myeloid leukemia.

We report a patient with a history of leukopenia who developed acute myeloid leukemia (AML) FAB M2 and was successfully treated with induction and consolidation chemotherapy. She relapsed 7 months after initial diagnosis. Peripheral blood cells at relapse showed a t(12;15)(p13;q13), which has not been previously described in de novo or relapsed AML.

Burkitt translocation (8;22)(q24;q11) in a patient with multiple myeloma.

The prevalence of chromosomal abnormalities in multiple myeloma (MM) has been difficult to detect by karyotyping primarily because of the low proliferative rate of malignant plasma cells. The reported incidences of abnormal karyotypes range from 24% to 63% in bone marrows obtained from MM patients, with the higher rates being seen in aggressive disease [1-8]. Detection of abnormal karyotypes in MM has been associated with a poor prognosis. We report a MM patient with an 8;22 Burkitt translocation, the first such reported case.

Technetium-99m sestamibi scanning in multiple myeloma stem cell transplantation.

We report the use of technetium-99m sestamibi (MIBI) in a patient with multiple myeloma (MM) undergoing peripheral blood stem cell (PBSC) transplantation. MIBI is a radionuclide agent that is preferentially taken up by malignant tumors. Plain radiographs in a MM patient, taken prior to PBSC transplantation, showed a large right humeral lytic lesion that correlated with increased uptake of MIBI at the same location. MIBI uptake, demonstrating active MM bone disease, was also evident in areas which were normal on plain radiographs. Three months after PBSC transplant, the lytic lesion had healed by plain radiographs and repeat MIBI scan showed no uptake. MIBI scanning results have a positive correlation with plain radiographs, and more importantly, demonstrate active MM bone disease not yet detectable by plain radiographs. If MIBI proves more sensitive in the detection of MM bone disease than plain radiographs or bone scanning with traditional isotopes, it will have a significant role in the detection of early disease and in monitoring disease progression during and after therapy.

Allan Levy: Loyalty to the Athlete.

New York Giants team physician Allan Levy places the welfare of the injured athlete ahead of the coach's desire to win.

Diagnosing and treating onychomycosis.

Onychomycosis is a particular concern for active people because they're exposed to fungi in locker rooms and because hot, sweaty feet enable the infection to flourish. A thorough physical exam and potassium hydroxide exam of debris from the nail plate can help rule out look-alike conditions and provide information that will guide drug therapy. Treatment with the new generation of onychomycosis medications-itraconazole, fluconazole, and terbinafine hydrochloride-is costly but produces impressive cure rates. Active patients need detailed instruction about preventive measures to avoid recurrence.

Perfusion culture system: Synovial fibroblasts modulate articular chondrocyte matrix synthesis in vitro.

OBJECTIVE: To investigate the interactions of chondrocyte metabolism by synovial cells and synovial supernatants in a new perfusion co-culture system. METHODS: Chondrocytes and synovial fibroblasts were obtained from knee joints of slaughtered adult cattle. For experimental studies chondrocytes and synovial fibroblasts were placed together into a perfusion chamber (co-culture) or were placed into two different perfusion culture containers, which were connected by a silicone tube (culturing of chondrocytes with synovial supernatants). A control setup was used without synovial cells. Chondrocyte proliferation was shown by measurement of DNA content. The proteoglycan synthesis was quantified using (35)SO(4)(2-)-labelling and the dimethylmethylene blue assay. (3)H-proline incorporation was used to estimate the protein biosynthesis. Type II collagen synthesis was measured by ELISA, furthermore extracellular matrix deposition was monitored immunohistochemically (collagen types I/II). Regarding to the role of reactive oxygen species LDH release before and after stimulation with hydrogen peroxide was measured. RESULTS: The proliferation of chondrocytes shows an increase in monoculture as well as in co-culture or in culture with synovial supernatants more than fivefold within 12 days. (3)H-proline incorporation as a marker for chondrocytes biosynthetic activity decreases in co-culture system and in culture with synovial supernatants. A similar effect is seen measuring total proteoglycan content as well as the (35)SO(4)(2-) incorporation in chondrocytes. Co-culturing and culturing with synovial supernatants lead to a significant decrease of proteoglycan release and content. Quantification of collagen type II by ELISA shows significant lower amounts of native collagen type II in the extracellular matrix of co-cultured chondrocytes as well as in culture with synovial supernatants. The membrane damage of chondrocytes by hydrogen peroxide is reduced when chondrocytes are co-cultured with synovial fibroblasts. CONCLUSION: The co-culture perfusion system is a new tool to investigate interactions of different cell types with less artificial interferences. Our results suggest that synovial supernatants and synovial fibroblasts modulate the biosynthetic activity and the matrix deposition of chondrocytes as well as the susceptibility to radical attack of reactive oxygen species.

Calcification of articular cartilage in human osteoarthritis.

OBJECTIVE: Hypertrophic chondrocyte differentiation is a key step in endochondral ossification that produces basic calcium phosphates (BCPs). Although chondrocyte hypertrophy has been associated with osteoarthritis (OA), chondrocalcinosis has been considered an irregular event and linked mainly to calcium pyrophosphate dihydrate (CPPD) deposition. The aim of this study was to determine the prevalence and composition of calcium crystals in human OA and analyze their relationship to disease severity and markers of chondrocyte hypertrophy. METHODS: One hundred twenty patients with end-stage OA undergoing total knee replacement were prospectively evaluated. Cartilage calcification was studied by conventional x-ray radiography, digital-contact radiography (DCR), field-emission scanning electron microscopy (FE-SEM), and synovial fluid analysis. Cartilage calcification findings were correlated with scores of knee function as well as histologic changes and chondrocyte hypertrophy as analyzed in vitro. RESULTS: DCR revealed mineralization in all cartilage specimens. Its extent correlated significantly with the Hospital for Special Surgery knee score but not with age. FE-SEM analysis showed that BCPs, rather than CPPD, were the prominent minerals. On histologic analysis, it was observed that mineralization correlated with the expression of type X collagen, a marker of chondrocyte hypertrophy. Moreover, there was a strong correlation between the extent of mineralization in vivo and the ability of chondrocytes to produce BCPs in vitro. The induction of hypertrophy in healthy human chondrocytes resulted in a prominent mineralization of the extracellular matrix. CONCLUSION: These results indicate that mineralization of articular cartilage by BCP is an indissociable process of OA and does not characterize a specific subset of the disease, which has important consequences in the development of therapeutic strategies for patients with OA.

[Periarticular mineralization of the finger]. / Die periartikuläre Mineralisation des Fingers.

Periarticular mineralization is a clinical disorder, which is typically found at the shoulder, knee and hip joint and only rarely diagnosed at the finger joints. Periarticular ossification is a different entity and has to be distinguished from periarticular mineralization. The typical symptoms of this disorder are pain and swelling of the joint that resolves spontaneously within 3-6 months. We report on a case of periarticular mineralization of the metacarpophalangeal (MCP) joint of a 39-year-old woman. Diagnosis was made by X-ray based on findings in the form of opaque mineralizations. There was no pain relief with conservative treatment and operative treatment was performed. Histological and electron microscope analysis of the mineralization showed hydroxyapatite crystals and chondrogenic metaplasia of the surrounding fibroblasts. The patient was symptom-free soon after treatment.Usually, the therapy of the periarticular mineralization is conservative; only exceptional cases with persistent pain and swelling need operative treatment. Acute periarticular mineralization of the hand is rare and often misdiagnosed as infectious arthritis.

The value of synovial biopsy, joint aspiration and C-reactive protein in the diagnosis of late peri-prosthetic infection of total knee replacements.

We analysed the serum C-reactive protein level, synovial fluid obtained by joint aspiration and five synovial biopsies from 145 knee replacements prior to revision to assess the value of these parameters in diagnosing late peri-prosthetic infection. Five further synovial biopsies were used for histological analysis. Samples were also obtained during the revision and incubated and analysed in an identical manner for 14 days. A total of 40 total knee replacements were found to be infected (prevalence 27.6%). The aspiration technique had a sensitivity of 72.5% (95% confidence interval (CI) 58.7 to 86.3), a specificity of 95.2% (95% CI 91.2 to 99.2), a positive predictive value of 85.3% (95% CI 73.4 to 100), a negative predictive value of 90.1% (95% CI 84.5 to 95.7) and an accuracy of 89%. The biopsy technique had a sensitivity of 100%, a specificity of 98.1% (95% CI 95.5 to 100), a positive predictive value of 95.2% (95% CI 88.8 to 100), a negative predictive value of 100% and an accuracy of 98.6%. C-reactive protein with a cut-off-point of 13.5 mg/l had a sensitivity of 72.5% (95% CI 58.7 to 86.3), a specificity of 80.9% (95% CI 73.4 to 88.4), a positive predictive value of 59.2% (95% CI 45.4 to 73.0), a negative predictive value of 88.5% (95% 81.0 to 96.0 CI) and an accuracy of 78.1%. We found that biopsy was superior to joint aspiration and C-reactive protein in the diagnosis of late peri-prosthetic infection of total knee replacements.