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Biomedical subjects

C P Case

Publications and source records attributed to C P Case.

At least 19 recordsLinked to original sources
PubMed2006

Effects of hTERT on metal ion-induced genomic instability.

There is currently a great interest in delayed chromosomal and other damaging effects of low-dose exposure to a variety of pollutants which appear collectively to act through induction of stress-response pathways related to oxidative stress and ageing. These have been studied mostly in the radiation field but evidence is accumulating that the mechanisms can also be triggered by chemicals, especially heavy metals. Humans are exposed to metals, including chromium (Cr) (VI) and vanadium (V) (V), from the environment, industry and surgical implants. Thus, the impact of low-dose stress responses may be larger than expected from individual toxicity projections. In this study, a short (24 h) exposure of human fibroblasts to low doses of Cr (VI) and V (V) caused both acute chromosome damage and genomic instability in the progeny of exposed cells for at least 30 days after exposure. Acutely, Cr (VI) caused chromatid breaks without aneuploidy while V (V) caused aneuploidy without chromatid breaks. The longer-term genomic instability was similar but depended on hTERT positivity. In telomerase-negative hTERT- cells, Cr (VI) and V (V) caused a long lasting and transmissible induction of dicentric chromosomes, nucleoplasmic bridges, micronuclei and aneuploidy. There was also a long term and transmissible reduction of clonogenic survival, with an increased beta-galactosidase staining and apoptosis. This instability was not present in telomerase-positive hTERT+ cells. In contrast, in hTERT+ cells the metals caused a persistent induction of tetraploidy, which was not noted in hTERT- cells. The growth and survival of both metal-exposed hTERT+ and hTERT- cells differed if they were cultured at subconfluent levels or plated out as colonies. Genomic instability is considered to be a driving force towards cancer. This study suggests that the type of genomic instability in human cells may depend critically on whether they are telomerase-positive or -negative and that their sensitivities to metals could depend on whether they are clustered or diffuse.

Apoptosis↗
PubMed2006

Biological effects of metal-on-metal hip replacements.

The advantages seen by patients receiving total hip arthroplasties and the implications of the release of both metal particles and soluble metal ions are discussed. This paper describes some of the early changes that have been observed in metal-on-metal hip arthroplasties, in terms of both changes in metal levels in blood and chromosome changes.

Bone Neoplasms↗
PubMed2005

Effect of synovial fluid, phosphate-buffered saline solution, and water on the dissolution and corrosion properties of CoCrMo alloys as used in orthopedic implants.

The corrosion and dissolution of high- and low-carbon CoCrMo alloys, as used in orthopedic joint replacements, were studied by immersing samples in phosphate-buffered saline (PBS), water, and synovial fluid at 37 degrees C for up to 35 days. Bulk properties were analyzed with a fine ion beam microscope. Surface analyses by X-ray photoelectron spectroscopy and Auger electron spectroscopy showed surprisingly that synovial fluid produced a thin oxide/hydroxide layer. Release of ions into solution from the alloy also followed an unexpected pattern where synovial fluid, of all the samples, had the highest Cr concentration but the lowest Co concentration. The presence of carbide inclusions in the alloy did not affect the corrosion or the dissolution mechanisms, although the carbides were a significant feature on the metal surface. Only one mechanism was recognized as controlling the thickness of the oxide/hydroxide interface. The analysis of the dissolved metal showed two mechanisms at work: (1) a protein film caused ligand-induced dissolution, increasing the Cr concentration in synovial fluid, and was explained by the equilibrium constants; (2) corrosion at the interface increased the Co in PBS. The effect of prepassivating the samples (ASTM F-86-01) did not always have the desired effect of reducing dissolution. The release of Cr into PBS increased after prepassivation. The metal-synovial fluid interface did not contain calcium phosphate as a deposit, typically found where samples are exposed to calcium rich bodily fluids.

Biocompatible Materials↗
PubMed2005

Metal-specific differences in levels of DNA damage caused by synovial fluid recovered at revision arthroplasty.

Previous research has shown an increase in chromosomal aberrations in patients with worn implants. The type of aberration depended on the type of metal alloy in the prosthesis. We have investigated the metal-specific difference in the level of DNA damage (DNA stand breaks and alkali labile sites) induced by culturing human fibroblasts in synovial fluid retrieved at revision arthroplasty. All six samples from revision cobalt-chromium metal-on-metal and four of six samples from cobalt-chromium metal-on-polyethylene prostheses caused DNA damage. By contrast, none of six samples from revision stainless-steel metal-on-polyethylene prostheses caused significant damage. Samples of cobalt-chromium alloy left to corrode in phosphate-buffered saline also caused DNA damage and this depended on a synergistic effect between the cobalt and chromium ions. Our results further emphasise that epidemiological studies of orthopaedic implants should take account of the type of metal alloy used.

Aged↗
PubMed2005

An unusual lymphocytic perivascular infiltration in tissues around contemporary metal-on-metal joint replacements.

BACKGROUND: Metal-on-metal bearing surfaces have been reintroduced for use during total hip replacement. To assess tissue reactions to various types of articulations, we studied the histological appearance of periprosthetic tissues retrieved from around metal-on-metal and metal-on-polyethylene total hip replacements and compared these findings with the appearance of control tissues retrieved at the time of primary arthroplasty. METHODS: Periprosthetic tissues were obtained at the time of revision of twenty-five cobalt chromium-on-cobalt chromium, nine cobalt chromium-on-polyethylene, and ten titanium-on-polyethylene total hip arthroplasties. Control tissues were obtained from nine osteoarthritic hips at the time of primary total hip arthroplasty. Each tissue sample was processed for routine histological analysis, and sections were stained with hematoxylin and eosin. Quantitative stereological analysis was performed with use of light microscopy. RESULTS: Tissue samples obtained from hips with metal-on-metal implants displayed a pattern of well-demarcated tissue layers. A prominent feature, seen in seventeen of twenty-five tissue samples, was a pattern of perivascular infiltration of lymphocytes. In ten of the tissue samples obtained from hips with metal-on-metal prostheses, there was also an accumulation of plasma cells in association with macrophages that contained metallic wear-debris particles. The surfaces of tissues obtained from hips with metal-on-metal prostheses were more ulcerated than those obtained from hips with other types of implants, particularly in the region immediately superficial to areas of perivascular lymphocytic infiltration. The lymphocytic infiltration was more pronounced in samples obtained at the time of revision because of aseptic failure than in samples retrieved at the time of autopsy or during arthrotomy for reasons other than aseptic failure. Total-joint-replacement and surface-replacement designs of metal-on-metal prostheses were associated with similar results. Tissue samples obtained from hips with metal-on-polyethylene implants showed far less surface ulceration, much less distinction between tissue layers, no pattern of lymphocytic infiltration, and no plasma cells. The inflammation was predominantly histiocytic. Tissues retrieved from hips undergoing primary joint replacement showed dense scar tissue and minimal inflammation. CONCLUSIONS AND CLINICAL RELEVANCE: The pattern and type of inflammation seen in periprosthetic tissues obtained from hips with metal-on-metal and metal-on-polyethylene implants are very different. At the present time, we do not know the prevalence or clinical implications of these histologic findings, but we suggest that they may represent a novel mode of failure for some metal-on-metal joint replacements.

Biocompatible Materials↗
PubMed2004

Wear debris from hip or knee replacements causes chromosomal damage in human cells in tissue culture.

Wear debris was extracted from 21 worn hip and knee replacements. Its mutagenic effects were tested on human cells in tissue culture using the micronucleus assay and fluorescent in situ hybridisation. The extracted wear debris increased the level of micronuclei in a linear dose-dependent manner but with a tenfold difference between samples. The concentration of titanium +/- vanadium and aluminium within the wear debris was linearly related both to the level of centromere-positive micronuclei in tissue culture, indicating an aneuploid event, and to the level of aneuploidy in vivo in peripheral blood lymphocytes. The concentration of cobalt and chromium +/- nickel and molybdenum in the wear debris correlated with the total index of micronuclei in tissue culture, both centromere-positive and centromere-negative i.e. both chromosomal breakage and aneuploidy events. The results show that wear debris can damage chromosomes in a dose-dependent manner which is specific to the type of metal. The results from studies in vitro correlate with those in vivo and suggest that the wear debris from a worn implant is at least partly responsible for the chromosomal damage which is seen in vivo.

Adult↗
PubMed2003

Particulate debris from a titanium metal prosthesis induces genomic instability in primary human fibroblast cells.

Previous studies detected both lethal and cumulative chromosomal aberrations in bone marrow and peripheral blood of patients with worn hip and knee replacements. This study shows that wear debris from a worn titanium metal on high-density polyethylene hip replacement also produces chromosomal instability and reproductive failure in cell culture. The progeny of these treated cells also displayed chromosomal instability, mainly consisting of chromatid breaks and minutes, and reproductive failure as determined by clonogenic survival many generations postexposure. These delayed effects are similar to those caused by the heavy metals cadmium and nickel and to those seen for low-dose radiation. These findings may have important implications with regard to the long-term risks of joint replacement surgery. This highlights the need for long-term epidemiological studies of patients with surgical implants.

Cell Division↗
PubMed2001

Increased chromosome translocations and aneuploidy in peripheral blood lymphocytes of patients having revision arthroplasty of the hip.

The long-term biological effects of wear debris are unknown. We have investigated whether there is any evidence of cumulative mutagenic damage in peripheral blood lymphocytes of patients undergoing revision arthroplasty of predominantly metal-on-plastic total hip replacements compared with those at primary arthroplasty. There was a threefold increase in aneuploidy and a twofold increase in chromosomal translocations which could not be explained by the confounding variables of smoking, gender, age and diagnostic radiographs. In the patients with TiVaAl prostheses there was a fivefold increase in aneuploidy but no increase in chromosomal translocations. By contrast, in patients with cobalt-chrome prostheses there was a 2.5-fold increase in aneuploidy and a 3.5-fold increase in chromosomal translocations. In six patients with stainless-steel prostheses there was no increase in either aneuploidy or chromosomal translocations. Our results suggest that future epidemiological studies of the putative long-term risks of joint replacement should take into account the type of alloy used in the prosthesis.

Aged↗
PubMed2001

Development of a routine method for the determination of trace metals in whole blood by magnetic sector inductively coupled plasma mass spectrometry with particular relevance to patients with total hip and knee arthroplasty.

BACKGROUND: Joint-replacement surgery has revolutionized the treatment of osteoarthritis and is still the most effective therapy. A recent clinical trend reintroducing metal-on-metal bearing surfaces has in turn stimulated a requirement for accurate measurement of the concentrations of relevant metals in both pre- and postoperative patients. Thus, there is a need for cost-effective, multielement methods for trace metal analysis in whole blood to monitor possible increases in wear metal concentrations. METHODS: A method was developed to allow routine analysis of whole blood samples for molybdenum, cobalt, chromium, and nickel. Sample preparation consisted of a simple 1:10 dilution of whole blood with a solution of 10 mL/L Triton X-100, 0.0002 mol/L EDTA, and 0.01 mol/L ammonium hydroxide. Final determination was performed by a double-focusing magnetic sector inductively coupled plasma mass spectrometer operated in medium-resolution mode (resolution, 3400). Online addition of rhodium was used for internal standardization. RESULTS: Detection limits in whole blood were 0.06 microg/L for chromium, cobalt, and molybdenum and 0.30 microg/L for nickel. Base concentrations of 0.22, 0.17, 0.62, and 0.99 microg/L for chromium, cobalt, molybdenum, and nickel, respectively, in whole blood have been found. Polyatomic interferences on all four elements have been shown to be resolved from the analyte masses by use of a resolution of >3000. CONCLUSIONS: The simple, rapid method of sample preparation is effective in minimizing potential contamination and enables 60 samples (run time, 8 h) to be analyzed before cleaning the instrument is necessary. A resolution >3000 was sufficient to separate polyatomic interferences from the masses of interest. The method was used to analyze a large number of blood samples taken from primary patients awaiting total hip arthroplasty. The method is sensitive enough to provide base concentrations for chromium, cobalt, and molybdenum in whole blood. The results for nickel were compromised by high signals for blank samples.

Arthroplasty, Replacement, Hip↗
PubMed2000

Nerve injury-associated kinase: a sterile 20-like protein kinase up-regulated in dorsal root ganglia in a rat model of neuropathic pain.

Partial injury of the rat sciatic nerve elicits a variety of characteristic chemical, electrophysical and anatomical changes in primary sensory neurons and constitutes a physiologically relevant model of neuropathic pain. To elucidate molecular mechanisms that underlie the physiology of neuropathic pain, we have used messenger RNA differential display to identify genes that exhibit increased ipsilateral expression in L4/5 dorsal root ganglia, following unilateral partial ligation of the rat sciatic nerve. One set of partial complementary DNA clones identified in this screen was found to encode a protein kinase, nerve injury-associated kinase. Cloning of the full-length human nerve injury-associated kinase complementary DNA, together with recombinant expression analysis, reveal nerve injury-associated kinase to be a functional member of a subgroup of sterile 20-like protein kinases characterised by the presence of a putative carboxy terminal autoregulatory domain. Induction of nerve injury-associated kinase expression in dorsal root ganglia in the rat neuropathic pain model was confirmed by quantitative reverse transcription-polymerase chain reaction, and RNA in situ hybridization analysis revealed enhanced levels of nerve injury-associated kinase within neurons.Together, our data implicate nerve injury-associated kinase as a novel upstream component of an intracellular signalling cascade that is up-regulated in dorsal root ganglia neurons in response to sciatic nerve injury.

Amino Acid Sequence↗
PubMed2000

Identification of differentially expressed genes in dorsal root ganglia following partial sciatic nerve injury.

Partial sciatic nerve injury, a model of neuropathic pain, elicits a variety of neurochemical, electrophysiological and neuroanatomical changes in primary sensory neurons. We have used the technique of messenger RNA differential display to identify genes with altered expression in these neurons which may contribute to the development of aberrant sensation following such peripheral nerve damage. This approach identified 14 distinct complementary DNA clones, representing transcripts with increased ipsilateral expression in L4/5 dorsal root ganglia, two weeks after unilateral partial ligation of the rat sciatic nerve. Both Zucker diabetic fatty rats and their lean counterparts were used in this study but none of the transcripts identified showed an induction that was confined to one of the two groups. The majority of the clones did not show significant sequence similarity to previously reported genes and therefore may represent novel messenger RNA sequences or, alternatively, unknown regions of partially characterised messenger RNAs. Two of the clones represented transcripts for the known proteins muscle LIM protein and acidic epididymal glycoprotein, neither of which had previously been associated with expression in the nervous system. Reverse transcriptase-polymerase chain reaction analysis and in situ hybridization confirmed that the messenger RNA expression of both muscle LIM protein and acidic epididymal glycoprotein was induced in an ipsilateral-specific manner. Their localisations, examined with in situ hybridization in L5 dorsal root ganglia, were limited in each case to a sub-population of neuronal profiles. Those neuronal profiles that demonstrated muscle LIM protein hybridization were distributed across the profile size range, whereas the distribution of acidic epididymal glycoprotein-positive profiles appeared to be skewed towards smaller profiles. The induction of muscle LIM protein and acidic epididymal glycoprotein in dorsal root ganglia may play an important functional role in the adaptive response of primary sensory neurons following partial sciatic nerve injury.

Animals↗
PubMed2000

Changes in the proportions of peripheral blood lymphocytes in patients with worn implants.

We compared the peripheral blood and periprosthetic tissues of 53 patients at revision arthroplasty with those of 30 patients at primary arthroplasty to determine whether there is a systemic difference in lymphocytes in patients with worn hip implants. The absolute number and relative proportion of lymphocytes bearing CD2, CD3, CD4, CD8, CD16, CD19, HLA-DR, kappa and lambda antigens were compared with the levels of IL-1beta, IL-6 and PGE2 in the pseudosynovial membrane as well as with a semiquantitative estimate of metal and polyethylene particles, necrosis and chronic inflammation and the total concentration of metals within the periprosthetic tissues. There was a significant increase in the relative proportion of CD2-positive T-cells and CD16-positive natural killer cells in the peripheral blood at revision arthroplasty compared with primary arthroplasty and an increased proportion of CD8-positive T-cells and a decreased ratio of CD4 to CD8 (helper inducer/suppressor cytotoxic cells). Three control patients, who went on to have revision surgery, had values at primary arthroplasty which were similar to those of patients at the time of revision surgery. These differences did not correlate with the local concentration of metal, plastic or cement or inflammatory response or the type of prosthesis. An inverse correlation was noted between the necrosis in the periprosthetic tissue and both the local production of IL-6 and the absolute numbers of T-cells in peripheral blood. We conclude that there may be several cell-mediated systemic immune responses to aseptic loosening, at least one of which may be directly related to events in the periprosthetic tissues. We cannot exclude the possibility that the changes in the proportion of CD8-positive cells reflected a predisposition, rather than a reaction, to loosening of the implant.

Aged↗
PubMed1998

Characterization of wear debris associated with aseptic loosening of a canine hip prosthesis.

A 12-month-old Golden Retriever bitch underwent unilateral hip arthroplasty following a diagnosis of coxofemoral osteoarthritis secondary to hip dysplasia. The hip prosthesis underwent aseptic loosening and was removed 6 months after implantation. Synovial biopsies taken at that time revealed scattered foci of granulomatous inflammation associated with intra-cytoplasmic and extracellular particulate material. Electron microscopical analyses demonstrated that this material contained cobalt, chromium, titanium and zirconium, which was probably wear debris from the loosened prosthesis. In human patients with hip arthroplasty, widespread dissemination of wear debris from loosened prostheses occasionally occurs, with an increased prevalence of neoplasia. A similar phenomenon may be predicted to occur with the increasing use of hip arthroplasty in the dog.

Animals↗
PubMed1997

Tumors around implants.

In 1989, A. G. Apley recommended cautious surveillance of malignant tumors that developed in association with orthopaedic implants. This retrospective review of the Bristol Bone Tumour Register between 1980 and 1992 reports on 240 malignant soft tissue sarcomas. Eighteen developed in the thigh region of patients more than 50 years old, and 4 of these developed in the soft tissues around a hip arthroplasty.

Aged↗
PubMed1996

Preliminary observations on possible premalignant changes in bone marrow adjacent to worn total hip arthroplasty implants.

Previous epidemiologic studies have suggested that there may be a risk of malignancy, especially lymphoma and leukemia, after joint replacement, but the followup has been relatively short. This is a preliminary study to see if there is any biologic basis for such a risk. Blood and bone marrow samples from 71 patients at revision arthroplasty of a loose or worn prosthesis and 30 control patients at primary arthroplasty were analyzed with cytogenetic techniques and molecular biology. There was a higher chromosomal aberration rate in cells adjacent to the prosthesis at revision surgery compared with iliac crest marrow from the same patients or with femoral bone marrow at primary arthroplasty. Clonal expansion of lymphocytes without a serum paraprotein was seen in 2 of 21 patients at revision arthroplasty performed more than 10 years after primary arthroplasty. The results of this preliminary study suggest that future epidemiologic studies should concentrate on patients with longer postoperative intervals to see if there is any risk that would be pertinent to a young patient at primary arthroplasty.

Aged↗
PubMed1996

Postmortem diagnosis of Factor V Leiden from paraffin wax embedded tissue.

Activated protein C resistance resulting from Factor V Leiden is an important inherited thrombophilia disorder which is found in 3.5% of people in the UK. The genetic defect can be detected using the PCR and the diagnosis can be made postmortem from paraffin wax embedded tissue. The presence of Factor V Leiden should be sought in all cases of unexplained sudden death resulting from venous thromboembolism.

Journal Article↗