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Occupational and environmental exposure to Co and Cr has been previously linked to a wide array of inflammatory and degenerative conditions and cancer. Recently, significant health concerns have been raised by the high levels of Cr and Co ions and corrosion products released by biomedical implants. Herein, we set to analyze the biological responses associated with Co and Cr toxicity. Histological, ultrastructural, and elemental analysis, performed on Cr and Co exposed patients reveal the presence of corrosion products, metallic wear debris and metal ions at varying concentrations. Metallic ions and corrosion products were also generated in vitro following macrophage phagocytosis of metal alloys. Ex vivo redox proteomic mapped several oxidatively damaged proteins by Cr(III) and Co(II)-induced Fenton reaction. Importantly, a positive correlation between the tissue amounts of Cr(III) and Co(II) ions and tissue oxidative damage was observed. Immobilized- Cr(III) and Co(II) affinity chromatography indicated that metal ions can also directly bind to several metallo and non-metalloproteins and, as demonstrated for aldolase and catalase, induce loss of their biological function. Altogether, our analysis reveals several biological mechanisms leading to tissue damage, necrosis, and inflammation in patients with Cr and Co-associated adverse local tissue reactions.

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 IFNinducible 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.alternative macrophages | kidney disease | polyinosinic: polycytidylic acid | systemic lupus erythematosus | tissue repair

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The study compared the OARSI osteoarthritis cartilage histopathology assessment system with the biomechanical quality of human in vivo cartilage samples. In a prospective cohort study, 84 patients (100 knees) with varus deformity of the knee were included between May, 2010 and January, 2012. Osteochondral samples underwent biomechanical and histologic analysis. The dynamic modulus significantly (p < 0.001) decreased with each advancing grade of degeneration from OARSI Grade 0 (surface intact) to OARSI Grade 4 (erosion). For the aggregate modulus, there were significant (p < 0.001) differences between OARSI Grade 0 and OARSI Grade 1 as well as between OARSI Grade 1 and OARSI Grade 2. From OARSI Grade 2 to OARSI Grade 5, no differences in aggregate modulus occurred. The new OARSI grading system provides useful information about the functional properties of cartilage. There is a significant difference in cartilage stiffness between samples with intact surface and no signs of degeneration (OARSI Grade 0) and samples with intact surface and early signs of arthritis (OARSI Grade 1). Surgeons performing joint preserving procedures have to be aware that in knees with an intact cartilage surface (OARSI Grade 0/1), significant differences in the biomechanical properties may exist.

Trichloroethylene was administered by inhalation, 7 hours daily, 5 days weekly, for 8 weeks, at concentrations of 600, 100 and 0 ppm, to Sprague-Dawley rats and Swiss mice; and for 104 weeks to Sprague-Dawley rats; and for 78 weeks to Swiss and B6C3F1 mice at concentrations of 600, 300, 100 and 0 ppm. The animals were kept under observation until spontaneous death. In the experiments reported herein, 3768 animals were studied. Under the experimental conditions, trichloroethylene appears to be carcinogenic in rats and mice (particularly in male Swiss mice). The most relevant finding was the dose-related increased incidence of Leydig cell tumors in male rats, and the onset of few renal tubuli adenocarcinomas at the highest dose, always in rats (4/130 males and 1/130 females). The renal tubuli adenocarcinomas were preceded by, and associated with, a characteristic lesion of the kidney: tubuli cell karyomegaly (megalonucleocytosis).

Defective placentation and subsequent placental insufficiency lead to maternal and fetal adverse pregnancy outcome (APO), but their pathologic mechanisms are unclear, and treatment remains elusive. The mildly hypertensive BPH/5 mouse recapitulates many features of human APO 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 VEGF 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.

BackgroundAdverse 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.MethodsConsecutive 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.ResultsOur 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.ConclusionsALTR 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.