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Biomedical subjects

J Fisher

Publications and source records attributed to J Fisher.

At least 37 records · Page 2Linked to original sources
PubMed2004

Expression of AML1-ETO in human myelomonocytic cells selectively inhibits granulocytic differentiation and promotes their self-renewal.

The t(8;21) translocation is one of the most frequent translocations in acute myeloid leukaemia (AML), giving rise to the AML1-ETO fusion protein (or RUNX1-CBF2T1). This abnormality is associated with myelocytic leukaemia with dysplastic granulopoiesis. Here, we demonstrate that when expressed in a normal human (CD34(+)) progenitor population, AML1-ETO selectively inhibits granulocyte colony formation but not monocyte colony formation. In bulk liquid culture, we found that though AML1-ETO transiently inhibited the proliferation of CD34(+) cells, it promoted long-term growth of myeloid cells for more than 80 days, suggesting that differentiation was inhibited. In support of this, cultures expressing AML1-ETO demonstrated enhanced retention of colony-forming capacity. Phenotypic examination of AML1-ETO cultures revealed a defect in granulocytic differentiation in terms of retention of CD34(+) cells within the culture and delayed CD11b upregulation. Morphologically, granulocyte terminal differentiation in AML1-ETO-expressing cells was inhibited by 83+/-5%, giving rise to a build-up of early to intermediate granulocytes that exhibited a number of morphological features associated with t(8;21) leukaemias. In contrast, AML1-ETO had little or no effect on monocytic differentiation. Taken together, these results suggest that expression of AML1-ETO selectively inhibits the differentiation of granulocytic cells and promoted extensive self-renewal, supporting a causal role for t(8;21) translocations in leukaemogenesis.

Antigens, CD34↗
PubMed2004

Estradiol negative feedback regulates nocturnal luteinizing hormone and follicle-stimulating hormone secretion in prepubertal female rhesus monkeys.

In recent years, animal models of puberty in children have focused on factors responsible for the developmental increase in gonadotropin secretion independent of gonadal negative feedback. Although the testis may play little if any role in timing the initial increase in gonadotropin secretion in the male, the situation may be different for the female. The present study tested the hypothesis that removal of endogenous estradiol by ovariectomy would produce an immediate increase in nocturnal but not daytime LH and FSH concentrations, an effect reversed by estradiol replacement. Morning (1000 and 1030 h) and evening (2200 and 2230 h) concentrations of bioactive LH and, in selected samples, immunoreactive FSH were evaluated in young juvenile female rhesus monkeys (n = 7) before and after ovariectomy at 13 months of age. Evening but not morning concentrations of gonadotropins were significantly increased within 2 wk of ovariectomy, whereas estradiol replacement returned these to presurgical levels and to those observed in age-matched, gonadally intact females (n = 7). By 145 d after ovariectomy, or approximately 17 months of age, evening as well as morning concentrations of LH were significantly higher than concentrations seen immediately after surgery. Estradiol replacement at approximately 18 months of age suppressed both morning and evening LH but not to the degree seen during a similar treatment after ovariectomy. These data support the hypothesis that, for the female, the developmental rise in diurnal gonadotropin secretion is controlled by a gonad-independent mechanism as well as a gonadal negative feedback inhibition. The importance of gonadal restraint on gonadotropin secretion in young juvenile females is evident only in samples obtained during the evening. These data underscore the notion that, for the female puberty, onset, at least in terms of gonadotropin secretion, is a misnomer and that puberty reflects a progression in multiple control mechanisms that ultimately time the attainment of fertility.

Animals↗
PubMed2004

Changes in the contact area during the bedding-in wear of different sizes of metal on metal hip prostheses.

In metal on metal hip prostheses, the contact mechanics can influence the lubrication and wear rate. In particular, during the bedding-in wear, the contact area gradually increases to an optimal value, and the wear rate reduces as the contact stress reduces and the lubrication conditions improve. Geometrical designs that reduce the volume of bedding-in wear as the optimal contact area develops are preferable. The objective of this study was to analyse the wear volume as a function of contact area during the bedding-in period, with the aim of identifying geometrical design configurations that give lower bedding-in wear. As the radial clearance was reduced, the bedding-in wear volume to reach an optimal contact area also reduced. For a fixed radial clearance, increasing the head diameter also reduced the bedding-in wear volume.

Computer Simulation↗
PubMed2003

Treatment of maternal mood disorder and infant behaviour disturbance in an Australian private mothercraft unit: a follow-up study.

Australia has a system of residential parentcraft services which offer brief admissions to mothers experiencing difficulties with infant care and postnatal mood disturbance. Most of these are state-funded public access services. In 1996 a comparable but differentiated service was opened in the private sector. Masada Private Hospital Mother Baby Unit accommodates five mother-infant pairs who are admitted to a five-night structured residential program. Care is provided by a multidisciplinary team comprising a paediatrician, general practitioner, clinical psychologist and specialist nurses. Complex maternal mood disorders as measured on standardised psychometric instruments include depression, anxiety and severe occupational fatigue. Their babies are unsettled, cry for prolonged periods, wake frequently at night and do not sleep well during the day. Many have feeding difficulties. The treatment program comprises both individualised training in infant care and settling strategies and psycho-educational groups offered in a supportive non-judgemental setting. One month post-discharge maternal mood is significantly improved and infant behaviour more manageable compared with functioning on admission.

Adult↗
PubMed2003

Biological response to wear debris generated in carbon based composites as potential bearing surfaces for artificial hip joints.

UHMWPE wear particles have been implicated in osteolysis, implant loosening, and long-term failure of total hip arthroplasties in vivo. This study examined four carbon-based composite materials as alternatives for UHMWPE in joint bearings. These materials were HMU-CVD, SMS-CVD, P25-CVD, and CFR-PEEK. New bearing materials should satisfy certain criteria: they should have good wear properties that at least match UHMWPE, and produce wear particles with low levels of biological activity. Of the four materials tested in multidirectional pin-on-plate tribological tests, SMS-CVD, P25-CVD, and CFR-PEEK showed lower volumetric wear factors than UHMWPE. P25-CVD had the lowest wear factor of 0.54 +/- 0.34 x 10(-7) mm(3)/Nm. Analysis of P25-CVD wear particles by transmission electron microscopy showed that the debris was very small, with the vast majority of particles being under 100 nm in size, which was similar in size to metal wear particles. The P25-CVD particles were isolated and cultured with L929 fibroblasts and U937 monocytic cells to assess their effect on cell viability. P25-CVD particles were significantly less cytotoxic (p < 0.01, ANOVA) to both cell types than CoCr metal wear particles. This work suggests that carbon-carbon composite materials may have potential for use in total hip replacement bearings. Of the materials tested P25-CVD had the lowest wear factor, and produced very small wear debris that had minimal cytotoxic effect on L929 and U937 cells in vitro. Therefore carbon-carbon composites, such as P25-CVD, may be important in the development of next-generation implants with lower wear rates and reduced cytotoxic potential.

Animals↗
PubMed2003

Comparison of the cytotoxicity of clinically relevant cobalt-chromium and alumina ceramic wear particles in vitro.

Concern over polyethylene wear particle induced aseptic loosening of metal-on-polyethylene hip prostheses has led to renewed interest in alternative materials such as metal-on-metal and alumina ceramic-on-alumina ceramic for total hip replacement. This study compared the effects of clinically relevant cobalt-chromium and alumina ceramic wear particles on the viability of U937 histiocytes and L929 fibroblasts in vitro. Clinically relevant cobalt-chromium wear particles were generated using a flat pin-on-plate tribometer. The mean size of the clinically relevant metal particles was 29.5+/-6.3 nm (range 5-200 nm). Clinically relevant alumina ceramic particles were generated in the Leeds MkII anatomical hip simulator from a Mittelmieier prosthesis using micro-separation motion. This produced particles with a bimodal size distribution. The majority (98%) of the clinically relevant alumina ceramic wear debris was 5-20 nm in size. The cytotoxicity of the clinically relevant wear particles was compared to commercially available cobalt-chromium (9.87 microm+/-5.67) and alumina ceramic (0.503+/-0.19 microm) particles. The effects of the particles on the cells over a 5 day period at different particle volume (microm(3)) to cell number ratios were tested and viability determined using ATP-Lite(TM). Clinically relevant cobalt-chromium particles 50 and 5 microm(3) per cell reduced the viability of U937 cells by 97% and 42% and reduced the viability of L929 cells by 95% and 73%, respectively. At 50 microm(3) per cell, the clinically relevant ceramic particles reduced U937 cell viability by 18%. None of the other concentrations of the clinically relevant particles were toxic. The commercial cobalt-chromium and alumina particles did not affect the viability of either the U937 histiocytes or the L929 fibroblasts.Thus at equivalent particle volumes the clinically relevant cobalt-chromium particles were more toxic then the alumina ceramic particles. This study has emphasised the fact that the nature, size and volume of particles are important in assessing biological effects of wear debris on cells in vitro.

Aluminum↗
PubMed2003

Effects of clinically relevant alumina ceramic wear particles on TNF-alpha production by human peripheral blood mononuclear phagocytes.

The recent introduction of microseparation of the components of ceramic-on-ceramic hip prostheses during hip simulations has produced clinically relevant wear rates, wear patterns and wear particles. This provided an opportunity to determine the response of primary human peripheral blood mononuclear cells to clinically relevant alumina ceramic wear particles in vitro. Alumina ceramic wear particles were generated in a hip joint simulator under microseparation conditions. The particles showed a bi-modal size distribution with nanometer sized (5-20nm) and larger particles (0.2->10 micrometer). The particles were cultured with human peripheral blood mononuclear cells obtained from six different donors at particle volume to cell number ratios of 1, 10, 100 and 500 micrometer(3). After 24h incubation the viability of the cells and the levels of TNF-alpha were determined. The response to the microseparation wear particles was compared to that of commercially available alumina powder with a uniform morphology and mean size of 0.5 micrometer. All six Donors PBMNC produced significantly elevated levels of TNF-alpha when stimulated with 100 micrometer(3) of the alumina powder per cell. Volumetric concentrations of 10 and 1.0 micrometer(3) per cell failed to stimulate a significant response by the cells from any of the six donors. Three of the six Donors PBMNC secreted significantly elevated levels of TNF-alpha when stimulated with 100 micrometer(3) of the microseparation wear particles, whereas the other three failed to respond to the wear debris at this concentration. All of the Donors PBMNC produced significantly elevated levels of TNF-alpha when stimulated with 500 micrometer(3) of the microseparation wear particles per cell. Thus, a greater volume of the microseparation wear particles was required to activate the PBMNC than the alumina powder. This was probably due to the microseparation wear particles having fewer particles in the critical size range (0.1-1 micrometer) for macrophage activation compared to the alumina powder. It can be concluded that alumina ceramic wear particles generated under microseparation conditions are capable of inducing osteolytic cytokine production by human mononuclear phagocytes. However, the volumetric concentration of the particles needed to generate this response is extremely high and given the low wear rates (<4mm(3) per million cycles) of ceramic-on-ceramic bearings, even under severe microseparation conditions, it is unlikely that this concentration threshold will be achieved in vivo.

Aluminum↗
PubMed2003

Population frequencies of single nucleotide polymorphisms (SNPs) in immuno-modulatory genes.

Inherited polymorphisms in immuno-modulatory genes may contribute to variations in immune function and genetic susceptibility for complex diseases, including cancer. We report results from a comprehensive study to discover novel single nucleotide polymorphisms (SNPs) and to estimate allelic frequency for both novel and known coding and regulatory region SNPs in genes encoding proteins that have been implicated in the immune response to tumors. We identified 12 novel nucleotide substitution variants and one deletion variant in 17 genes analyzed (TGFBETA;R, BETA;2M, IFNGAMMA;, TNFALPHA;, TNFALPHA;R, LTALPHA;, IL-6, IL-12, IL-2, IL-1ALPHA;, IL-1BETA;, IL-1RN, IL-10, CTLA4, CD40L, FAS and FASL). We determined the frequency of these novel polymorphisms, as well as 17 previously identified polymorphisms, in a control sample of 158 individuals, approximately half of which were Caucasian (n = 74) and half of which were African American (n = 84). Significant differences in allele frequencies were observed between the two racial groups for 13/17 genes tested. These allelic variations maybe associated with alterations in immune function and thus susceptibility to a number of complex disease states such as cancer.

Black or African American↗
PubMed2003

Taxanes synergize with the bispecific antibody MDXH447 to enhance antibody-dependent cell-mediated cytotoxicity.

The interaction between antibody based therapy and cytotoxic chemotherapy is complex. To explore these interactions we investigated, in vitro, the effects of IC20 growth inhibitory concentrations of taxanes on bispecific antibody-mediated tumor cell cytotoxicity. MDXH447 is a bispecific antibody with specificity for the high affinity IgG receptor (CD64) and the type I epidermal growth factor receptor type (EGF-R). A431 cells, an epidermoid carcinoma cell line that over expresses EGF-R, were exposed to a range of IC20 growth inhibitory concentrations of paclitaxel or docetaxel. Interferon gamma activated monocytes were armed with MDXH447 and a standard chromium release antibody-dependent cell-mediated cytotoxicity (ADCC) assay was performed. Using the Chou and Talalay median effect analysis, we found that MDXH447-mediated ADCC was enhanced when A431 target cells were pretreated with paclitaxel or docetaxel. Median effect analysis of these interactions supported a synergistic interaction (CI < 1). Pretreatment of A431 cells with taxanes did not increase EGF-R expression compared to untreated controls. A431 epidermoid carcinoma cells pretreated with IC20 growth inhibitory concentrations of taxanes enhanced interferon gamma activated monocyte mediated ADCC killing through MDXH447.

Antibodies, Bispecific↗
PubMed2003

Wear and deformation of ceramic-on-polyethylene total hip replacements with joint laxity and swing phase microseparation.

Wear of polyethylene and the resulting wear debris-induced osteolysis remains a major cause of long-term failure in artificial hip joints. There is interest in understanding engineering and clinical conditions that influence wear rates. Fluoroscopic studies have shown separation of the head and the cup during the swing phase of walking due to joint laxity. In ceramic-on-ceramic hips, joint laxity and microseparation, which leads to contact of the head on the superior rim of the cup, has led to localized damage and increased wear in vivo and in vitro. The aim of this study was to investigate the influence of joint laxity and microseparation on the wear of ceramic on polyethylene artificial hip joints in an in vitro simulator. Microseparation during the swing phase of the walking cycle produced contact of the ceramic head on the rim of the polyethylene acetabular cup that deformed the softer polyethylene cup. No damage to the alumina ceramic femoral head was found. Under standard simulator conditions the volume change of the moderately crosslinked polyethylene cups was 25.6 +/- 5.3 mm3/million cycles and this reduced to 5.6 +/- 4.2 mm3/million cycles under microseparation conditions. Testing under microseparation conditions caused the rim of the polyethylene cup to deform locally, possibly due to creep, and the volume change of the polyethylene cup when the head relocated was substantially reduced, possibly due to improved lubrication. Joint laxity may be caused by poor soft tissue tension or migration and subsidence of components. In ceramic-on-polyethylene acetabular cups wear was decreased with a small degree of joint laxity, while in contrast in hard-on-hard alumina bearings, microseparation accelerated wear. These findings may have significant implications for the choice of fixation systems to be used for different types of bearing couples.

Ceramics↗
PubMed2003

Microscopic asperity contact and deformation of ultrahigh molecular weight polyethylene bearing surfaces.

The effect of the roughness and topography of ultrahigh molecular weight polyethylene (UHMWPE) bearing surfaces on the microscopic contact mechanics with a metallic counterface was investigated in the present study. Both simple sinusoidal roughness forms, with a wide range of amplitudes and wavelengths, and real surface topographies, measured before and after wear testing in a simple pin-on-plate machine, were considered in the theoretical analysis. The finite difference method was used to solve the microscopic contact between the rough UHMWPE bearing surface and a smooth hard counterface. The fast Fourier transform (FFT) was used to cope with the large number of mesh points required to represent the surface topography of the UHMWPE bearing surface. It was found that only isolated asperity contacts occurred under physiological loading, and the real contact area was only a small fraction of the nominal contact area. Consequently, the average contact pressure experienced at the articulating surfaces was significantly higher than the nominal contact pressure. Furthermore, it was shown that the majority of asperities on the worn UHMWPE pin were deformed in the elastic region, and consideration of the plastic deformation only resulted in a negligible increase in the predicted asperity contact area. Microscopic asperity contact and deformation mechanisms may play an important role in the understanding of the wear mechanisms of UHMWPE bearing surfaces.

Computer Simulation↗
PubMed2003

In vitro analysis of the wear, wear debris and biological activity of surface-engineered coatings for use in metal-on-metal total hip replacements.

Extremely low wear rates have been reported for metal-on-metal total hip replacements, but concerns remain about the effects of metal ion release, dissolution rates and toxicity. Surface-engineered coatings have the potential to improve wear resistance and reduce the biological activity of the wear debris produced. The aim of this study was to examine the wear and wear debris generation from surface-engineered coatings: titanium nitride (TiN), chromium nitride (CrN) and chromium carbon nitride (CrCN) applied to a cobalt-chrome alloy (CoCr) substrate. The coatings were articulated against themselves in a simple geometry model. The wear particles generated were characterized and the cytotoxic effect on U937 macrophages and L929 fibroblasts assessed. The CrN and CrCN coatings showed a decrease in wear compared to the CoCr bearings and produced small (less than 40 nm in length) wear particles. The wear particles released from the surface engineered bearings also showed a decreased cytotoxic effect on cells compared to the CoCr alloy debris. The reduced wear volumes coupled with the reduced cytotoxicity per unit volume of wear indicate the potential for the clinical application of this technology.

Cell Survival↗
PubMed2003

Factors influencing faecal contamination in coastal marinas.

Recreational pleasure and fishing boats are potential sources of human faecal contamination because the sanitary wastes from boat occupants may be discharged into the surrounding water. The impacts of such faecal contamination from boats is potentially high in marinas where boats are often kept and occupied for varying periods of time. The nature and extent of such faecal contamination from boats in marinas of different design and use is still inadequately understood. In this study the levels of faecal coliform (FC) bacteria were measured in the waters of a confined and an open water marina over a 6 d period encompassing a holiday weekend. Levels of FC rose with increasing occupancy by boats and boaters during the study period and then declined again. FC levels were higher in waters of a confined or basin marina than in waters of an open or unconfined marina. In both confined and open water marinas, FC levels were highest in water samples collected near boats but they also became elevated on occasion in water samples taken a distance of 305 m from boats. Concentrations of FC in marina waters exceeded the standards and guidelines for shell-fishing and primary contact recreation waters. Therefore, greater consideration of human health risks from enteric microbes in marina waters and shellfish is recommended.

Animals↗
PubMed2002

Alumina-alumina artificial hip joints. Part I: a histological analysis and characterisation of wear debris by laser capture microdissection of tissues retrieved at revision.

The aims of this study were to investigate the tissues from uncemented Mittelmeier alumina ceramic-on-ceramic total hip replacements using histological methods and to isolate and characterise the ceramic wear debris using laser capture microdissection and electron microscopy. Tissues from around 10 non-cemented Mittelmeier alumina ceramic on ceramic THRs were obtained from patients undergoing revision surgery. Tissues were also obtained from six patients who were undergoing revisions for aseptic loosening of Charnley, metal-on-polyethylene prostheses. Tissue sections were analysed using light microscopy to determine histological reactions and also the location and content of alumina ceramic wear debris. Tissue samples were extracted from sections using laser capture microdissection and the characteristics of the particles subsequently analysed by TEM and SEM. The tissues from around the ceramic-on-ceramic prostheses all demonstrated the presence of particles, which could be seen as agglomerates inside cells or in distinct channels in the tissues. The tissues from the ceramic-on-ceramic retrievals had a mixed pathology with areas that had no obvious pathology, areas that were relatively rich in macrophages and over half of the tissues had in the region of 60% necrosis/necrobiosis. In comparison, the Charnley tissues showed a granulomatous cellular reaction involving a dense macrophage infiltrate and the presence of giant cells and < 30% necrosis/necrobiosis. The tissues from the ceramic prostheses also showed the presence of neutrophils and lymphocytes, which were not evident in the tissues from the Charnley retrievals. There were significantly more macrophages (p < 0.05), and giant cells (p < 0.01) in the Charnley tissues and significantly more neutrophils (p < 0.01) in the ceramic-on-ceramic tissues. TEM of the laser captured tissue revealed the presence of very small alumina wear debris in the size range 5-90 nm, mean size + SD of 24 +/- 19nm whereas SEM (lower resolution) revealed particles in the 0.05-3.2 microm size range. This is the first description of nanometre sized ceramic wear particles in retrieval tissues. The bi-modal size range of alumina ceramic wear debris overlapped with the size ranges commonly observed with metal particles (10-30 nm) and particles of ultra-high molecular weight polyethylene (0.1-1,000 microm). It is possible that the two size ranges of contributed to the mixed tissue pathology observed. It is speculated that the two types of ceramic wear debris are generated by two different wear mechanisms in vivo, under normal articulating conditions, relief polishing wear and very small wear debris is produced. while under conditions of microseparation of the head and cup and rim contact, intergranular and intragranular fracture and larger wear particles are generated.

Aluminum Oxide↗
PubMed2002

Alumina-alumina artificial hip joints. Part II: characterisation of the wear debris from in vitro hip joint simulations.

Until recently it was not possible to reproduce clinically relevant wear rates and wear patterns in in vitro hip joint simulators for alumina ceramic-on-ceramic hip prostheses. The introduction of microseparation of the prosthesis components into in vitro wear simulations produced clinically relevant wear rates and wear patterns for the first time. The aim of this study was to characterise the wear particles generated from standard simulator testing and microseparation simulator testing of hot isostatically pressed (HIPed) and non-HIPed alumina ceramic-on-ceramic hip prostheses, and compare these particles to those generated in vivo. Standard simulation conditions produced wear rates of approximately 0.1 mm3 per million cycles for both material types. No change in surface roughness was detected and very few wear features were observed. In contrast, when microseparation was introduced into the wear simulation, wear rates of between 1.24 (HIPed) and 1.74 mm3 per million cycles (non-HIPed) were produced. Surface roughness increased and a wear stripe often observed clinically on retrieved femoral heads was also reproduced. Under standard simulation conditions only nanometre-sized wear particles (2-27.5 nm) were observed by TEM, and it was thought likely that these particles resulted from relief polishing of the alumina ceramic. However, when microseparation of the prosthesis components was introduced into the simulation, a bi-modal distribution of particle sizes was observed. The nanometre-sized particles produced by relief polishing were present (1-35nm). however, larger micrometre-sized particles were also observed by both transmission electron microscopy (TEM) (0.021 microm) and scanning electron microscopy (SEM) (0.05-->10 microm). These larger particles were thought to originate from the wear stripe and were produced by trans-granular fracture of the alumina ceramic. In Part I of this study, alumina ceramic wear particles were isolated from the periprosthetic tissues from around Mittelmeier ceramic-on-ceramic hip prostheses. Characterisation of the particles by TEM and SEM revealed a bi-modal size distribution. SEM analysis revealed particles in the 0.05-3.2 microm size range. and TEM revealed particles in the 5-90 nm size range, indicating that microseparation of the prosthesis components may be a common event in vivo. This study (Part II) has revealed that the introduction of microseparation of the prosthesis components during the swing phase of the wear simulation reproduced clinically relevant wear rates, wear patterns and wear particles in in vitro hip joint simulators.

Aluminum Oxide↗
PubMed2002

Investigation of wear of knee prostheses in a new displacement/force-controlled simulator.

The performance of two knee simulators designed by ProSim (Manchester, UK) was evaluated by comparison of the wear seen in the press-fit condylar (PFC) Sigma (DePuy) knee prosthesis. Twelve specimens of the same design and manufacturing specification, were subjected to a wear test of 2 x 10(6) cycles duration using bovine serum as a lubricant. The anterior/posterior displacement and internal/external rotation inputs were based on the kinematics of the natural knee. International Standards Organization (ISO) standards were used for the flexion and axial load. The wear rates and wear scar areas were compared across all stations. The mean wear rates found were 17.6+/-5 mm3/10(6) cycles for stations 1 to 6 and 19.6+/-4 mm3/10(6) cycles for stations 7 to 12, resulting in an overall mean wear rate of 18.1+/-3 mm3/10(6) cycles. The differences between the two simulators were not significant. The average wear scar area seen on inserts from stations I to 6 was calculated at 32.4+/-1 per cent of the intended articulating surface. Similarly on stations 7 to 12 the average wear scar area was 30.7+/-3 per cent. The wear scars seen were a good physiological representation of those found from clinical explant data. This study has shown good repeatability from the simulator, both within and between the simulators.

Arthroplasty, Replacement, Knee↗