Synchrotron-based characterization of arthroprosthetic CoCrMo particles in human bone marrow.

Particles released from cobalt-chromium-molybdenum (CoCrMo) alloys are considered common elicitors of chronic inflammatory adverse effects. There is a lack of data demonstrating particle numbers, size distribution and elemental composition of bone marrow resident particles which would allow for implementation of clinically relevant test strategies in bone marrow models at different degrees of exposure. The aim of this study was to investigate metal particle exposure in human periprosthetic bone marrow of three types of arthroplasty implants. Periprosthetic bone marrow sections from eight patients exposed to CoCrMo particles were analyzed via spatially resolved and synchrotron-based nanoscopic X-ray fluorescence imaging. These analyses revealed lognormal particle size distribution patterns predominantly towards the nanoscale. Analyses of particle numbers and normalization to bone marrow volume and bone marrow cell number indicated particle concentrations of up to 1 × 1011 particles/ml bone marrow or 2 × 104 particles/bone marrow cell, respectively. Analyses of elemental ratios of CoCrMo particles showed that particularly the particles' Co content depends on particle size. The obtained data point towards Co release from arthroprosthetic particles in the course of dealloying and degradation processes of larger particles within periprosthetic bone marrow. This is the first study providing data based on metal particle analyses to be used for future in vitro and in vivo studies of possible toxic effects in human bone marrow following exposure to arthroprosthetic CoCrMo particles of different concentration, size, and elemental composition. Graphical abstract.

Prevention of Defective Placentation and Pregnancy Loss by Blocking Innate Immune Pathways in a Syngeneic Model of Placental Insufficiency.

Defective placentation and subsequent placental insufficiency lead to maternal and fetal adverse pregnancy outcome, but their pathologic mechanisms are unclear, and treatment remains elusive. The mildly hypertensive BPH/5 mouse recapitulates many features of human adverse pregnancy outcome, with pregnancies characterized by fetal loss, growth restriction, abnormal placental development, and defects in maternal decidual arteries. Using this model, we show that recruitment of neutrophils triggered by complement activation at the maternal/fetal interface leads to elevation in local TNF-α levels, reduction of the essential angiogenic factor vascular endothelial growth factor, and, ultimately, abnormal placentation and fetal death. Blockade of complement with inhibitors specifically targeted to sites of complement activation, depletion of neutrophils, or blockade of TNF-α improves spiral artery remodeling and rescues pregnancies. These data underscore the importance of innate immune system activation in the pathogenesis of placental insufficiency and identify novel methods for treatment of pregnancy loss mediated by abnormal placentation.

Nano-analyses of wear particles from metal-on-metal and non-metal-on-metal dual modular neck hip arthroplasty.

Increased failure rates due to metallic wear particle-associated adverse local tissue reactions (ALTR) is a significant clinical problem in resurfacing and total hip arthroplasty. Retrieved periprosthetic tissue of 53 cases with corrosion/conventional metallic wear particles from 285 revision operations for ALTR was selected for nano-analyses. Three major classes of hip implants associated with ALTR, metal-on-metal hip resurfacing arthroplasty (MoM HRA) and large head total hip replacement (MoM LHTHA) and non-metal-on-metal dual modular neck total hip replacement (Non-MoM DMNTHA) were included. The size, shape, distribution, element composition, and crystal structure of the metal particles were analyzed by conventional histological examination and electron microscopy with analytic tools of 2D X-ray energy dispersive spectrometry and X-ray diffraction. Distinct differences in size, shape, and element composition of the metallic particles were detected in each implant class which correlate with the histological features of severity of ALTR and variability in implant performance.

Multi-elemental nanoparticle exposure after tantalum component failure in hip arthroplasty: In-depth analysis of a single case.

Porous tantalum components are widely used for complex acetabular reconstructions in revision hip arthroplasty. Multiple other metal alloys such as titanium-aluminum-vanadium or cobalt-chromium-molybdenum are principally used in artificial joint setups. We report a case of tantalum component failure being both cause and effect of a multiple metal exposure. Our aims were to assess and to characterize associated particle exposure and biological consequences. Metal level quantification revealed substantial in vivo exposure to particulate and dissociated tantalum, zirconium, chromium, cobalt, molybdenum, titanium, aluminum and vanadium in periprosthetic compartments. Aside from micron-sized particles, nanoparticles of a broad size range and elemental composition were obtained. Histological exams verified a spectrum of necrotic changes in the periprosthetic tissues. In the presented case tantalum release was accompanied by concomitance of particles originating from other utilized metals. We conclude that an overall in vivo exposure assessment is mandatory for realistic appraisal of metal toxicity and associated risks.

Radiological and histological analysis of two replaced interphalangeal joints with active subchondral bone resorption in erosive hand osteoarthritis: a novel mechanism?

The aim of this study was to describe the histological features of erosive hand osteoarthritis (EHOA), which is considered an aggressive subset of hand osteoarthritis (OA) characterized by severe local inflammation and degeneration of the distal and proximal interphalangeal joints. Two patients with EHOA underwent replacement with a cement-free press fit ceramic prosthesis of a proximal interphalangeal joint (PIPJ). Clinical and radiological data were collected and histological examination was performed. Radiological examination with histological correlation showed complete erosion of the articular cartilage with focal presence of peripheral fibrocartilaginous resurfacing, sclerosis, and remodeling of the exposed bone, osteoclastic activity with resorptive lacunae in the subchondral bone and around degenerative fibromyxoid pseudocysts, coarse trabeculation of the cancellous bone, and marginal osteophytes. The synovial membrane showed non-specific mild hypertrophy and mildly cellular fibromyxoid stroma. The histological findings in patients with EHOA suggest a pathogenesis of cartilage resorption from the subchondral bone, via osteoclastic-mediated activity and formation of periarticular reactive fibrocartilaginous proliferation with partial resurfacing of the articular surface.

Valgus Stress Radiographs Predict Lateral-Compartment Cartilage Thickness but Not Cartilage Degeneration in Varus Osteoarthritis.

BACKGROUND: Intact cartilage in the lateral compartment is an important requirement for medial unicompartmental knee arthroplasty. This study sought to determine how measurements of joint space width in the lateral compartment on valgus stress radiographs compare to cartilage thickness as measured with a precise needle test, and whether cartilage thickness is a predictor of cartilage degeneration. METHODS: A consecutive series of 100 knees undergoing total knee arthroplasty for end-stage varus osteoarthritis was studied. Twenty-eight knees were retrospectively excluded because not all data were available, leaving 72 knees (61 patients; mean age, 67 years [49-87]). On calibrated valgus stress radiographs, lateral-compartment joint space width was measured. During surgery, osteochondral samples of the distal lateral femur and the lateral tibia plateau were harvested. Cartilage thickness and histology were assessed. Cartilage thickness of tibia and femur was defined as lateral-compartment cartilage thickness. RESULTS: Lateral-compartment joint space width on valgus stress radiographs and lateral-compartment cartilage thickness correlated well (rs = 0.671, P < .001). However, no correlation of cartilage histology according to the osteoarthritis cartilage histopathology assessment system, and cartilage thickness on the lateral tibia plateau (rs = -0.060, P = .614) and cartilage thickness on the distal lateral femur (rs = -0.128, P = .282) was observed. CONCLUSION: Valgus stress radiographs can assess combined cartilage thickness in the lateral compartment of the knee. Cartilage thickness, however, is a poor predictor of cartilage degeneration.

The Disappearing Phalanx: A Case Report of a Vascular Tumor of the Toe.

We report a unique case of an epithelioid hemangioma of the third middle phalanx in which the lesion replaced the phalanx, became symptomatic, and then required resection, bone grafting, and joint arthroplasty. To the best of our knowledge, this is the first report of an epithelioid hemangioma in the toe that was treated using this approach.

Histopathological characterization of corrosion product associated adverse local tissue reaction in hip implants: a study of 285 cases.

BACKGROUND: Adverse local tissue reaction (ALTR), characterized by a heterogeneous cellular inflammatory infiltrate and the presence of corrosion products in the periprosthetic soft tissues, has been recognized as a mechanism of failure in total hip replacement (THA). Different histological subtypes may have unique needs for longitudinal clinical follow-up and complication rates after revision arthroplasty. The purpose of this study was to describe the histological patterns observed in the periprosthetic tissue of failed THA in three different implant classes due to ALTR and their association with clinical features of implant failure. METHODS: Consecutive patients presenting with ALTR from three major hip implant classes (N = 285 cases) were identified from our prospective Osteolysis Tissue Database and Repository. Clinical characteristics including age, sex, BMI, length of implantation, and serum metal ion levels were recorded. Retrieved synovial tissue morphology was graded using light microscopy. Clinical characteristics and features of synovial tissue analysis were compared between the three implant classes. Histological patterns of ALTR identified from our observations and the literature were used to classify each case. The association between implant class and histological patterns was compared. RESULTS: Our histological analysis demonstrates that ALTR encompasses three main histological patterns: 1) macrophage predominant, 2) mixed lymphocytic and macrophagic with or without features of associated with hypersensitivity/allergy or response to particle toxicity (eosinophils/mast cells and/or lymphocytic germinal centers), and 3) predominant sarcoid-like granulomas. Implant classification was associated with histological pattern of failure, and the macrophagic predominant pattern was more common in implants with metal-on-metal bearing surfaces (MoM HRA and MoM LHTHA groups). Duration of implantation and composition of periprosthetic cellular infiltrates was significantly different amongst the three implant types examined suggesting that histopathological features of ALTR may explain the variability of clinical implant performance in these cases. CONCLUSIONS: ALTR encompasses a diverse range of histological patterns, which are reflective of both the implant configuration independent of manufacturer and clinical features such as duration of implantation. The macrophagic predominant pattern and its mechanism of implant failure represent an important subgroup of ALTR which could become more prominent with increased length of implantation.

Implant based differences in adverse local tissue reaction in failed total hip arthroplasties: a morphological and immunohistochemical study.

BACKGROUND: Adverse local tissue reaction (ALTR) is characterized by periprosthetic soft tissue inflammation composed of a mixed inflammatory cell infiltrate, extensive soft tissue necrosis, and vascular changes. Multiple hip implant classes have been reported to result in ALTR, and clinical differences may represent variation in the soft tissue response at the cellular and tissue levels. The purpose of this study was to describe similarities and differences in periprosthetic tissue structure, organization, and cellular composition by conventional histology and immunohistochemistry in ALTR resulting from two common total hip arthroplasty (THA) implant classes. METHODS: Consecutive patients presenting with ALTR from two major hip implant classes (N = 54 patients with Dual-Modular Neck implant; N = 14 patients with Metal-on-Metal implant) were identified from our prospective Osteolysis Tissue Database and Repository. Clinical characteristics including age, sex, BMI, length of implantation, and serum metal ion levels were recorded. Retrieved synovial tissue morphology was graded using light microscopy and cellular composition was assessed using immunohistochemistry. RESULTS: Length of implantation was shorter in the DMN group versus MoM THA group (21.3 [8.4] months versus 43.6 [13.8] months respectively; p < 0.005) suggesting differences in implant performance. Morphologic examination revealed a common spectrum of neo-synovial proliferation and necrosis in both groups. Macrophages were more commonly present in diffuse sheets (Grade 3) in the MoM relative to DMN group (p = 0.016). Perivascular lymphocytes with germinal centers (Grade 4) were more common in the DMN group, which trended towards significance (p = 0.066). Qualitative differences in corrosion product morphology were seen between the two groups. Immunohistochemistry showed features of a CD4 and GATA-3 rich lymphocyte reaction in both implants, with increased ratios of perivascular T-cell relative to B-cell markers in the DMN relative to the MoM group (p = 0.032). CONCLUSION: Our results demonstrate that both implant classes display common features of neo-synovial proliferation and necrosis with a CD4 and GATA-3 rich inflammatory infiltrate. Qualitative differences in corrosion product appearance, macrophage morphology, and lymphocyte distributions were seen between the two implant types. Our data suggests that ALTR represents a histological spectrum with implant-based features.

Does intraarticular inflammation predict biomechanical cartilage properties?

BACKGROUND: Intact cartilage in the lateral compartment is an important requirement for medial unicompartmental knee arthroplasty (UKA). Progression of cartilage degeneration in the lateral compartment is a common failure mode of medial UKA. Little is known about factors that influence the mechanical properties of lateral compartment cartilage. QUESTIONS/PURPOSES: The purposes of this study were to answer the following questions: (1) Does the synovial fluid white blood cell count predict the biomechanical properties of macroscopically intact cartilage of the distal lateral femur? (2) Is there a correlation between MRI grading of synovitis and the biomechanical properties of macroscopically intact cartilage? (3) Is there a correlation between the histopathologic assessment of the synovium and the biomechanical properties of macroscopically intact cartilage? METHODS: The study included 84 patients (100 knees) undergoing primary TKA for varus osteoarthritis between May 2010 and January 2012. All patients underwent preoperative MRI to assess the degree of synovitis. During surgery, the cartilage of the distal lateral femur was assessed macroscopically using the Outerbridge grading scale. In knees with an Outerbridge grade of 0 or 1, osteochondral plugs were harvested from the distal lateral femur for biomechanical and histologic assessment. The synovial fluid was collected to determine the white blood cell count. Synovial tissue was taken for histologic evaluation of the degree of synovitis. RESULTS: The mean aggregate modulus and the mean dynamic modulus were significantly greater in knees with 150 or less white blood cells/mL synovial fluid compared with knees with greater than 150 white blood cells/mL synovial fluid. There was no correlation among MRI synovitis grades, histopathologic synovitis grades, and biomechanical cartilage properties. CONCLUSIONS: The study suggests that lateral compartment cartilage in patients with elevated synovial fluid white blood cell counts has a reduced ability to withstand compressive loads. LEVEL OF EVIDENCE: Level III, diagnostic study. See the Instructions for Authors for a complete description of levels of evidence.

Proliferative lesions and metalloproteinase activity in murine lupus nephritis mediated by type I interferons and macrophages.

Glomerulonephritis is a major cause of morbidity in patients with systemic lupus erythematosus. Although substantial progress has been made in the identification of pathogenic triggers that result in autoantibody production, little is known about the pathogenesis of aggressive proliferative processes that lead directly to irreversible glomerular damage and compromise of renal function. In this study, we describe a model of polyinosinic: polycytidylic acid-accelerated lupus nephritis in NZB/W mice that is characterized by severe glomerular proliferative lesions with de novo crescent formation, findings that are linked with decreased survival and adverse outcomes in lupus. Proliferative glomerulonephritis was associated with infiltrating kidney macrophages and renal expression of IFN-inducible genes, matrix metalloproteinases (MMPs), and growth factors. Crescent formation and renal MMP and growth factor expression were dependent on renal macrophages that expressed Il10, MMPs, osteopontin, and growth factors, including Pdgfc and Hbegf. Infiltrating macrophages and renal MMP expression were induced by type I IFN. These findings reveal a role for type I IFNs and alternatively activated macrophages in aggressive proliferative lesions of lupus nephritis.

Noninfectious tissue interactions at periprosthetic interfaces.

The success of hip arthroplasty is based on modern materials in addition to the continuous development of surgical techniques and clinical experience gained over six decades. The biocompatible implant materials used in hip arthroplasty can be textured or coated with biomimetic surfaces to ensure durable component ingrowth and moderate host response. Material integrity plays a critical role in the durability of the stable interface between implant components and periprosthetic tissues. Inflammation at the interfaces due to the release of degradation products from the implant materials is one of the causes of hip arthroplasty failure. This review summarizes the implant materials currently used in hip arthroplasty, their preclinical testing and the postoperative neogenesis of periprosthetic tissues, and the interactions of periprosthetic bone and the implant materials at the periprosthetic interfaces.

Combination of cobalt, chromium and titanium nanoparticles increases cytotoxicity in vitro and pro-inflammatory cytokines in vivo.

Background: The mixture of different metallic nanoparticles released from intended and unintended wearing of orthopaedic implants such as the Co/Cr cup and head, Co/Cr sleeves or tapers and their interface with Ti stems in the case of hip prostheses are a leading cause of adverse inflammatory responses and cytotoxicity to the host. Methods: This study assessed the in vitro cytotoxic effects of three metallic nanoparticles (Co, Cr and Ti) separately and in combination on macrophages. The in vivo effects were also evaluated after peri-tibial soft tissue injection in mice. Results: The results demonstrated that Co, Cr, and Ti nanoparticles and their combination were phagocytosed by macrophages both in vitro and in vivo. High doses of nanoparticles from each individual metal caused a variable rate of cell death in vitro. However, the mixture of Co/Cr/Ti nanoparticles was more toxic than the Co, Cr or Ti metals alone at low doses. Intracellular distribution of Co, Cr, and Ti in the combined group was heterogeneous and associated with distinct morphological features. The results from in vivo experiments showed a significant increase in the mRNA levels of interleukin (IL)-1ß, IL-6, IL-8 and tumour necrosis factor (TNF)-α in peri-tibial soft tissue following the administration of Co alone as well as the combination of nanoparticles. Conclusion: This study demonstrated that the combination of Co/Cr/Ti nanoparticles was more cytotoxic than any of the individual metals in vitro and induced higher expression of genes encoding pro-inflammatory cytokines than single metals in vivo. The in vivo model utilised in this study might provide a useful tool for rapid assessment of the effects of unintended release of metal nanoparticles from implants in pre-/post-marketing studies. Translational potential of this article: This study highlights the importance of preclinical assessments of potential nanoparticles produced by wear and tear of metal implants using macrophages and animal models, in particular their combinational toxicity in addition to the assessments of the bulk metallic materials.

MRI findings in painful metal-on-metal hip arthroplasty.

OBJECTIVE: The objective of our study was to compare the frequency of osseous and soft-tissue abnormalities in patients presenting with hip pain after resurfacing arthroplasty and after total hip arthroplasty (THA), correlate the MRI findings with histologic results, and determine which MRI findings are predictive of aseptic lymphocytic vasculitis-associated lesions. MATERIALS AND METHODS: The MRI examinations of patients with metal-on-metal hip prostheses placed at resurfacing arthroplasty (n=31) or THA (n=29) were reviewed for osteolysis, synovitis, extracapsular disease, synovial pattern, and mode of decompression into adjacent bursae. Regional muscles and tendons were assessed for tendinosis, tear, atrophy, and edema. Histologic and operative findings were reviewed in 19 patients (20 hips) who underwent revision surgery. Chi-square tests were performed to detect differences between the resurfacing arthroplasty and THA groups. The Wilcoxon rank sum test was performed to detect differences in MRI findings in patients with and those without aseptic lymphocytic vasculitis-associated lesions. RESULTS: Synovitis was detected in 77.4% of resurfacing arthroplasty hips and 86.2% of THA hips. Extracapsular disease was present in 6.5% of resurfacing arthroplasty hips and 10.3% of THA hips. Osteolysis was detected in 9.7% of resurfacing arthroplasty hips and 24.1% of THA hips. There was no difference in the incidence of synovitis (p=0.51), osteolysis (p=0.17), or extracapsular disease (p=0.67) between the resurfacing arthroplasty and THA groups. Patients with aseptic lymphocytic vasculitis-associated lesions had higher volumes of synovitis (p=0.04) than patients without aseptic lymphocytic vasculitis-associated lesions. Extracapsular disease and muscle edema were seen only in patients with aseptic lymphocytic vasculitis-associated lesions. CONCLUSION: Synovitis is common in patients with metal-on-metal hip prostheses and occurs with a similar incidence after resurfacing arthroplasty and after THA; osteolysis and extracapsular disease are uncommon. The MRI signs most suggestive of aseptic lymphocytic vasculitis-associated lesions are high volumes of synovitis, extracapsular disease, and intramuscular edema.

Engraftment of peripheral blood mononuclear cells from systemic lupus erythematosus and antiphospholipid syndrome patient donors into BALB-RAG-2-/- IL-2Rγ-/- mice: a promising model for studying human disease.

OBJECTIVE: To construct a humanized mouse model of systemic lupus erythematosus (SLE) that resembles the human disease in order to define the pathophysiology and targets for treatments. METHODS: We infused peripheral blood mononuclear cells (PBMCs) from SLE patients into BALB- RAG-2-/- IL-2Rγ-/- double-knockout (DKO) mice, which lack T cells, B cells, and natural killer cells. PBMCs from 5 SLE patients and 4 normal donors were infused intravenously/intraperitoneally at a density of 3-5×10(6) cells per animal into nonirradiated 4-5-week-old mice. We evaluated the engraftment of human CD45+ cells and monitored the plasma levels of human IgG, anti-double-stranded DNA (anti-dsDNA) antibody, and anticardiolipin antibody (aCL), as well as proteinuria and kidney histology. RESULTS: There was 100% successful engraftment in 40 DKO mice infused with human PBMCs. In the PBMC fraction from SLE PBMC-infused DKO (SLE-DKO) mice and normal donor PBMC-infused DKO (ND-DKO) mice, an average of 41% and 53% human CD45+ cells, respectively, were observed at 4 weeks postengraftment, with 70-90% CD3+ cells. There were fewer CD3+CD4+ cells (mean±SEM 5.5±2.1%) and more CD3+CD8+ cells (79.4±3.6%) in the SLE-DKO mice as in the SLE patients from which the PBMCs were derived. CD19+ B cells and CD11c+ monocytic cells were found in the spleen, lung, liver, and bone marrow. There was no significant difference in plasma levels of human IgG and anti-dsDNA antibodies between SLE-DKO and ND-DKO mice. Levels of aCL were significantly higher in all SLE-DKO mice infused with PBMCs from an SLE patient who had high titers of aCL. SLE-DKO mice had proteinuria, human IgG deposits in the kidneys, and a shorter life span. In SLE-DKO mice engrafted with PBMCs from the aCL-positive patient, we found microthrombi and infiltration of CD3+, CD8+, and CD19+ cells in the glomeruli, recapitulating the human antiphospholipid syndrome in these mice. CONCLUSION: We established a novel humanized SLE-DKO mouse exhibiting many of the immunologic and clinical features of human SLE.

Multimodality treatment of a multifocal osteoblastoma-like tumor of the lower extremity.

Osteoblastoma-like tumor is a rare condition with limited information on its orthopedic management in the current medical literature. The tumor histologically resembles an osteoblastoma, although the radiographic features are similar to those observed in primary vascular lesions. The treatment in the previously reported cases involved aggressive procedures including amputation, en bloc resection, and chemotherapy because of the uncertainty regarding the biological behavior of the tumor. We present a case of this entity that was successfully treated by a combination therapy including intralesional curettage with adjuvant cryotherapy, in situ and intravenous administration of bisphosphonates and radioablation.

PDIA3 epitope-driven immune autoreactivity contributes to hepatic damage in type 2 diabetes.

A diet rich in saturated fat and carbohydrates causes low-grade chronic inflammation in several organs, including the liver, ultimately driving nonalcoholic steatohepatitis. In this setting, environment-driven lipotoxicity and glucotoxicity induce liver damage, which promotes dendritic cell activation and generates a major histocompatibility complex class II (MHC-II) immunopeptidome enriched with peptides derived from proteins involved in cellular metabolism, oxidative phosphorylation, and the stress responses. Here, we demonstrated that lipotoxicity and glucotoxicity, as driven by a high-fat and high-fructose (HFHF) diet, promoted MHC-II presentation of nested T and B cell epitopes from protein disulfide isomerase family A member 3 (PDIA3), which is involved in immunogenic cell death. Increased MHC-II presentation of PDIA3 peptides was associated with antigen-specific proliferation of hepatic CD4+ immune infiltrates and isotype switch of anti-PDIA3 antibodies from IgM to IgG3, indicative of cellular and humoral PDIA3 autoreactivity. Passive transfer of PDIA3-specific T cells or PDIA3-specific antibodies also exacerbated hepatocyte death, as determined by increased hepatic transaminases detected in the sera of mice subjected to an HFHF but not control diet. Increased humoral responses to PDIA3 were also observed in patients with chronic inflammatory liver conditions, including autoimmune hepatitis, primary biliary cholangitis, and type 2 diabetes. Together, our data indicated that metabolic insults caused by an HFHF diet elicited liver damage and promoted pathogenic immune autoreactivity driven by T and B cell PDIA3 epitopes.

A complete deficiency of Hyaluronoglucosaminidase 1 (HYAL1) presenting as familial juvenile idiopathic arthritis.

We describe a single consanguineous family with three affected children exhibiting knee and/or hip pain associated with swelling. Detailed clinical evaluation demonstrated diffuse joint involvement with an unusual proliferative synovitis on MRI. Synovial biopsies were notable for an infiltration of macrophages with abundant cytoplasm filled with faintly basophilic vacuoles. We used homozygosity mapping with a panel of 262,000 single nucleotide polymorphism markers to identify a homozygous stretch of 40.52 Mb on chromosome 3p22.3 - 3p13 that segregated with the arthropathy in the family. Of the 378 genes in the interval, the three hyaluronoglucosaminidase genes were considered good candidates based on the phenotype. Dideoxy sequencing identified a homozygous deletion in HYAL1, c.104delT, resulting in a premature termination codon, p.Val35AlafsX25, found in all three affected children. Enzymatic analysis confirmed total HYAL1 deficiency in the three affected children. This confirms the diagnosis of Mucopolysaccharidosis IX (MPS IX) which has only been described in a single patient to date. In contrast to the previously described MPS IX patient, our three patients display a phenotype limited to the joints, suggesting that this is the primary manifestation of HYAL1 deficiency.

Ceramic composite with gentamicin decreases persistent infection and increases bone formation in a rat model of debrided osteomyelitis.

Introduction: Current methods of managing osteomyelitic voids after debridement are inadequate and result in significant morbidity to patients. Synthetic ceramic void fillers are appropriate for non-infected bone defects but serve as a nidus of re-infection in osteomyelitis after debridement. CERAMENT G (CG) is an injectable ceramic bone void filler which contains gentamicin and is currently being evaluated for use in osteomyelitic environments after debridement due to its theoretical ability to serve as a scaffold for healing while eliminating residual bacteria after debridement through the elution of antibiotics. The goal of this study was to evaluate (1) the rate of persistent infection and (2) new bone growth of a debrided osteomyelitic defect in a rat model which has been treated with either gentamicin-impregnated ceramic cement (CERAMENT G) or the same void filler without antibiotics (CERAMENT, CBVF). Methods: Osteomyelitis was generated in the proximal tibia of Sprague Dawley rats, subsequently debrided, and the defect filled with either (1) CG ( n = 20 ), (2) CBVF ( n = 20 ), or (3) nothing ( n = 20 ). Each group was euthanized after 6 weeks. Infection was detected through bacterial culture and histology. Bone growth was quantified using microCT. Results: Infection was not detected in defects treated with CG as compared with 35 % of defects ( 7 / 20 ) treated with CBVF and 50 % ( 10 / 20 ) of empty defects ( p = 0.001 ). Bone volume in the defect of CG-treated rats was greater than the CBVF (0.21 vs. 0.17, p = 0.021 ) and empty groups (0.21 vs. 0.11, p < 0.001 ) at 6 weeks after implantation. Conclusions: Ceramic void filler with gentamicin (CERAMENT G) decreased the rate of persistent infection and increased new bone growth as compared to the same void filler without antibiotics (CERAMENT) and an empty defect in a rat model of debrided osteomyelitis.