Quantitative analysis of wear and wear debris from metal-on-metal hip prostheses tested in a physiological hip joint simulator

Osteolysis and loosening of artificial joints caused by UHMWPE wear debris has prompted renewed interest in metal-on-metal (MOM) hip prostheses. This study investigated the wear and wear debris morphology generated by MOM prostheses in a physiological anatomical hip simulator for different carbon content cobalt chrome alloys. The low carbon pairings demonstrated significantly higher "bedding in" and steady state wear rates than the mixed and high carbon pairings. The in vitro wear rates reported here were up to one or two orders of magnitude lower than the clinical wear rates for first-generation MOM hip prostheses. Two methods for characterising the metal wear debris were developed, involving digestion, scanning electron microscopy and transmission electron microscopy. The metal wear particles characterised by the two methods were similar in size, 25-36 nm, and comparable to particles isolated from periprosthetic tissues from first and second-generation MOM hip prostheses. Due to the small size of the metal particles, the number of particles generated per year for MOM prostheses in vitro was estimated to be up to 100 times higher than the number of polyethylene particles generated per year in vivo. The volumetric wear rates were affected by the carbon content of the cobalt chrome alloy and the material combinations used. However, particle size and morphology was not affected by method of particle characterisation, the carbon content of the alloy or material combination.     

Comparison of the response of primary human peripheral blood mononuclear phagocytes from different donors to challenge with model polyethylene particles of known size and dose

The response of primary human peripheral blood mononuclear phagocytes to challenge with polyethylene particles of known size and dose was evaluated. Particles with mean sizes of 0.21, 0.49, 4.3, 7.2, and 88 microm were co-cultured with cells for 24 h prior to the assessment of cell viability and production of the osteolytic mediators IL-1beta, IL-6, TNFalpha, GM-CSF and PGE2. All particle fractions were evaluated at particle volume (microm3) to cell number ratios of 10:1 and 100:1 which were previously identified as being the most biologically active and clinically relevant. The heterogeneity of human individuals was clearly evident both in the profile and the magnitude of the response of the donors evaluated in this study (the response of donor 5 being 2- to 15-fold lower than that of the other donors). Only the sub-micrometre particles stimulated significantly enhanced cytokine secretion at the ratios tested: mean particle sizes of 0.49 and 0.21 microm being the most biologically active. Macrophages stimulated with particles outside this size range produced considerably lower levels of mediator. These results compared favourably with the results of earlier studies, which demonstrated that particles within the phagocytosable size range (0.1-10 microm) were the most biologically active. These results, therefore, confirm earlier findings and suggest that the size and volume of polyethylene particles are critical factors in macrophage activation. Furthermore, they suggest that the heterogeneity of human individuals may be another important factor in determining implant life and could provide the basis for a valuable diagnostic tool to identify those patients most at risk of implant loosening.     

Relative carriage rates of nuclear dehydrogenating clostridia in two populations of different colorectal cancer risk

Carriage of nuclear dehydrogenating clostridia has been associated with colon cancer and implicated in its aetiology. This study has compared the carriage of these organisms in a British population at high risk for the development of colon cancer with a low risk Nigerian population. Clostridia were found in all of the stools from both populations. Nuclear dehydrogenating clostridia were only found in the stools of the British subjects (32%). These results support the suggestion that the carriage rate of nuclear dehydrogenating clostridia in a population is related to the risk of colon cancer.     

Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability

X-linked spinal and bulbar muscular atrophy (SBMA) is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene. Disease-associated alleles (37-66 CAGs) change in length when transmitted from parents to offspring, with a significantly greater tendency to shift size when inherited paternally. As transgenic mice carrying human AR cDNAs with 45 and 66 CAG repeats do not display repeat instability, we attempted to model trinucleotide repeat instability by generating transgenic mice with yeast artificial chromosomes (YACs) carrying AR CAG repeat expansions in their genomic context. Studies of independent lines of AR YAC transgenic mice with CAG 45 alleles reveal intergenerational instability at an overall rate of approximately 10%. We also find that the 45 CAG repeat tracts are significantly more unstable with maternal transmission and as the transmitting mother ages. Of all the CAG/CTG repeat transgenic mice produced to date the AR YAC CAG 45 mice are unstable with the smallest trinucleotide repeat mutations, suggesting that the length threshold for repeat instability in the mouse may be lowered by including the appropriate flanking human DNA sequences. By sequence-tagged site content analysis and long range mapping we determined that one unstable transgenic line has integrated an approximately 70 kb segment of the AR locus due to fragmentation of the AR YAC. Identification of the cis - acting elements that permit CAG tract instability and the trans -acting factors that modulate repeat instability in the AR YAC CAG 45 mice may provide insights into the molecular basis of trinucleotide repeat instability in humans.      

The effect of 2,4-dinitrophenol and related compounds on bile secretion

1. 2,4-dinitrophenol, 2,4-dinitrophenetole, 2,4-dinitronaphthol, 4,6-dinitro-o-cresol, and to a lesser extent picric acid, produced an increase in bile flow and a rise in body temperature in the anaesthetized dog. The total biliary bromsulphalein (BSP) excretion in unit time was either slightly reduced, increased or remained at its pre-injection level.2. Picramic acid, the nitrochlorophenols and 2,4-dinitrobenzaldehyde caused a moderate increase in bile flow without an effect on the temperature of the animal.3. The three mononitrophenols, the five remaining isomeric dinitrophenols, isopicramic acid, the aminonitrophenols, phenol, 2,4-dinitroanisole, 2,4-dinitrobenzoic acid, 2,4-dinitrobenzene sulphonic acid, 2,4-dinitroresorcinol and 4-nitracatechol had little effect on bile secretion or body temperature.4. It thus appears that, in order for a compound of this type to have a pronounced effect on bile secretion, it is necessary to have nitro groups in positions 2 and 4 of the benzene ring, and a free or potential hydroxyl group.     

Limitations of the electrocardiographic response to exercise in predicting coronary-artery disease.

The electrocardiographic response to exercise was compared with the results of coronary angiography in 89 patients with Type II hyperlipoproteinemia who had previous myocardial infarction or typical angina or both (43 patients)(Group A), "atypical angina" (16 patients)(Group B)or positive electrocardiographic response to exercise without other evidence of cardiac disease (30 patients)(Group C). Thirty-nine of 43 in Group A had greater than or equal to 50 per cent stenosis, and 26 (67%) of these 39 had negative exercise tests. In Group B, five of the 16 had greater than or equal to 50% stenosis, and three had positive exercise tests (one patient had a false-positive test). In Group C, eleven of 30(37%) had greater than or equal to 50% stenosis; however, nine (30%) had minor stenosis (less than or equal to 50%), and 10(33%) normal coronary arteries. The diagnostic usefulness of exercise electrocardiography is limited. False-negative responses are frequent in patients with clinically suspected coronary disease, and false-positive responses frequent in asymptomatic patients.     

Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling

Oncogenic Ras transforms immortal rodent cells to a tumorigenic state, in part, by constitutively transmitting mitogenic signals through the mitogen-activated protein kinase (MAPK) cascade. In primary cells, Ras is initially mitogenic but eventually induces premature senescence involving the p53 and p16^INK4a tumor suppressors. Constitutive activation of MEK (a component of the MAPK cascade) induces both p53 and p16, and is required for Ras-induced senescence of normal human fibroblasts. Furthermore, activated MEK permanently arrests primary murine fibroblasts but forces uncontrolled mitogenesis and transformation in cells lacking either p53 or INK4a. The precisely opposite response of normal and immortalized cells to constitutive activation of the MAPK cascade implies that premature senescence acts as a fail-safe mechanism to limit the transforming potential of excessive Ras mitogenic signaling. Consequently, constitutive MAPK signaling activates p53 and p16 as tumor suppressors.     

Responses to intensive training and methandrostenelone administration: II. Hormonal,organ weights,muscle weights and body composition

The hormonal levels of the gonadotropins, the weight of selected organs and of the triceps surae as well as body composition were determined in Sprague Dawley rats at 3 and 6 weeks after intensive training with or without a methandrostenelone (Dianabol) supplement (0.35 mg/kg/day). The controls were sedentary rats of similar age and weight at the start of the experiment. The dianabol treated rats in the sedentary and exercise groups had a depression of plasma LH levels. There were no differences in body weight, specific gravity, lean body weight, fat or % fat between the two trained groups. Dianabol had no apparent effect on the measured parameters other than a depression of LH.     

Clinical value of ELISA assays for IgM and IgG rheumatoid factors.

The clinical value of enzyme linked immunosorbent assays (ELISA) assays for IgM and IgG rheumatoid factors was assessed in a series of studies using rabbit IgG as antigen. The tests were reproducible with intra-assay coefficients of variation of 6% and could be simply and rapidly performed. Normal ranges were established using 106 sera from healthy controls. In a cross sectional study of 208 rheumatoid patients these assays were compared with the Rose-Waaler and laser nephelometric assessments of rheumatoid factor. In some patients there were discrepancies between rheumatoid factor positivity determined by one method or another. IgM ELISA and Rose-Waaler titres showed a significant correlation (r = +0.58; p less than 0.001), but there was a low correlation between IgM and IgG ELISA (r = +0.27; p less than 0.001). There was no evidence to show that the measurement of IgM or IgG rheumatoid factor gave significantly more clinical information than traditional tests such as the Rose-Waaler or latex agglutination tests.