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Biomedical subjects

J Fisher

Publications and source records attributed to J Fisher.

At least 109 records · Page 6Linked to original sources
PubMed2000

Production of TNF-alpha and bone resorbing activity by macrophages in response to different types of bone cement particles.

We have compared the capacity of clinically relevant wear debris from seven different cement types to activate macrophages to produce TNF-alpha, IL-1beta, IL-6 and bone resorbing activity in vitro. The bone cements were: CMW 1 original (PMMA only); CMW 1RO (1 microm BaSO4; 9.2%); CMW copolymer bone cement 1 (10 microm BaSO4; 10%); CMW copolymer bone cement 2 (1 microm BaSO4; 10%); Palacos R (10 microm ZrO2; 15.6%); CMW Calcium phosphate cement 20% (10 microm tri-calcium phosphate; 20%) and CMW calcium phosphate cement 30% (10 microm tri-calcium phosphate; 30%). Cement debris was produced aseptically using a simple configuration wear test. The majority of particles were in the size range 0.1-0.5 microm for each cement type. The cement particles were co-cultured with the U937 macrophage cell line at ratios of 10 and 100 microm3 particle volumes to macrophage cell numbers for 24 h. At the 10:1 ratio the particles had no effect on the cells. At the 100:1 ratio, the major cytokine produced was TNF-alpha and there were no statistical differences between the different types of cement debris. The bone resorption activity of the co-culture supernatants was significantly greater than the control (U937 cells without particles) for particles of CMW 1RO, CMW copolymer bone cement 1, CMW copolymer bone cement 2 and Palacos R (P < 0.05, ANOVA). However there were no statistical differences between the levels of bone resoprtion evoked by these four cement types. The CMW1 original and CMW calcium phosphate containing cements failed to induce the macrophages to elaborate bone resorption activity at the 100:1 ratio. These data suggest that the addition of radio-opaque additives to bone cement may increase the capacity of the debris to induce osteolysis.

Acrylic Resins↗
PubMed2000

Distribution of hepatic venous blood in the total cavo-pulmonary connection: an in vitro study.

OBJECTIVES: The objective of this project was to quantify the effects of geometry on the distribution of hepatic blood to the lungs in patients with a total cavo-pulmonary connection. The basis for this work is the supposition that hepatic blood is necessary for proper lung function. METHODS: Plastic models of these connections were made with varying degrees of offset between the inferior and superior vena cava and attached to an in vitro flow loop. Dye was injected into the inferior vena cava and its concentration quantified in each pulmonary artery. These data were converted to percentage concentration and distribution of hepatic blood to each lung. RESULTS: With no offset between the vena cava, hepatic blood distribution and concentration to each lung was similar to normal. For an offset of one or more diameters, hepatic blood tended to flow preferentially towards the nearest pulmonary artery with the opposite pulmonary artery exhibiting a deficit (<10% of normal). CONCLUSIONS: Distribution of hepatic blood to each lung was found to be a function of vena cava offset and pulmonary artery flow split. Under normal conditions, 60% of blood towards the right pulmonary artery, the hepatic blood distribution to both lungs could be maintained above 50% of normal if the inferior vena cava was offset towards the left pulmonary artery. Offsetting the inferior vena cava towards the right pulmonary artery jeopardized the delivery of hepatic blood to one lung.

Blood Flow Velocity↗
PubMed2000

Quantitative analysis of polyethylene wear debris, wear rate and head damage in retrieved Charnley hip prostheses.

Submicrometer- and micrometer-sized ultra-high molecular weight polyethylene (UHMWPE) wear particles have been associated with osteolysis and failure of total artificial joints. Previous studies have isolated predominantly submicrometer-sized particles at the expense of larger particles (>10 microm). This study aimed to isolate and characterize quantitatively all sizes of UHMWPE wear particles generated in 18 Charnley hip prostheses. In addition, to analyze the wear debris with respect to the total volumetric wear of the cup and damage to the femoral head. Particle size distributions ranged from 0.1 to ->1000 microm. A significant proportion (3-82%) of the mass of the wear debris isolated was>10 microm. The mode of the frequency distribution of the particles was in the range 0.1-0.5 microm for all patients. However, analysis of the mass of wear debris as a function of its size allowed differentiation of the wear debris from different patients. Femoral head damage was associated with high volumetric wear and increased numbers of biologically active submicrometer-sized particles.

Journal Article↗
PubMed2000

Modeling of damage to articulating surfaces by third body particles in total joint replacements.

Numerous small scratches and some larger scratches have been observed on metallic femoral heads of explanted hip prostheses, with the larger scratches believed to be a major contributor to increased wear of the polyethylene acetabular cups. Previous work in our group has shown that smaller scratches, with a mean lip height up to 0.35 microm, can be caused by bone cement and bone particles up to 500 microm in size. However, the larger scratches were not readily replicated with these particles. Therefore in this study experimental and theoretical models have been developed to investigate the damage caused by harder metallic and ceramic particles. Small 10 microm diameter spherical metallic particles were also found to produce small fine scratches on the metallic counterface. However larger diameter spherical metal particles greater than 100 microm in diameter, which were embedded in polyethylene pins, caused severe sharp scratching of the metallic counterface with scratch lips greater than 0.5 microm. This level of damage, which was comparable to the severe damage found in vivo, was also simulated by a three body finite element model. Thus the larger metal particles led to the type of damage which was predicted to increase wear dramatically. This technique for simulating severe in vivo third body damage using spherical metal particles was found to be reproducible and reliable and will be used in the future in hip simulator testing to replicate third body damage and wear.

Journal Article↗
PubMed2000

The prediction of polyethylene wear rate and debris morphology produced by microscopic asperities on femoral heads.

Counterface damage in the form of scratches, caused by bone cement, bone or metallic particles, has been cited as a cause of increased wear of ultra-high molecular weight polyethylene (UHMWPE) acetabular cups. It is known that high levels of particulate wear debris lead to osteolysis. Surface damage was characterized in a series of explanted Charnley femoral heads. The heads had a mean scratch height of 1 microm with a mean aspect ratio (defined as height divided by half width) of 0.1. Wear discs were artificially scratched using these scratch geometries as a guide. In addition, the scratch geometries were incorporated into a finite element model of a stainless steel asperity repeatedly sliding over UHMWPE under conditions similar to those in an artificial hip joint. Wear tests showed a strong correlation between the average cross-sectional area of the scratch lip above the mean zero line and the measured wear factor. The finite element model predicted increases in the area of UHMWPE suffering plastic strain with increases in the cross-sectional area of the asperity above the mean line. Analysis of the wear debris showed the mode of the particle size was 0.01-0.5 microm for all cases. The morphology of the particles varied with aspect ratio of the asperity, with an increased percentage mass of submicrometer-sized debris with increased scratch lip aspect ratio. The finite element results predicted that the maximum surface strains would increase with increasing asperity aspect ratio. Examination of the worn UHMWPE pin surfaces showed an association between increased surface damage, probably due to high surface strains, and increased aspect ratio. The large areas of surface plastic strain predicted for asperities with high cross-sectional areas above the mean line offer an explanation for the positive correlation between wear rate and the average cross-sectional area of the scratch lip material. The higher surface strains predicted for the higher aspect ratios may explain the increased percentage mass of biologically active submicrometer-sized wear particles found for scratch lips with higher aspect ratios.

Journal Article↗
PubMed2000

Role of the melanocortin-4 receptor in metabolic rate and food intake in mice.

We evaluated the role of the melanocortin-4 receptor (MC-4R) in the control of metabolic rate and food intake in mice. Intraperitoneal administration of the non-selective MC-R agonist melanotan II (MT-II; a cyclic heptapeptide) increases metabolic rate in wildtype mice, while MC-4R knockout mice are insensitive to the effects of MT-II on metabolic rate. MC-4R knockout mice are also insensitive to the effects of MT-II on reducing food intake. We conclude that MC-4R can mediate control of both metabolic rate and food intake in mice. We infer that a role for MC-3R in mediating the acute effects of MT-II on basal metabolic rate and food intake in wildtype mice seems limited.

Animals↗
PubMed2000

The MEK inhibitor, PD98059, reduces survival but does not block acute myeloid leukemia blast maturation in vitro.

The appearance of blasts in acute myeloid leukemia (AML) reflects a shift from cellular processes inducing maturation and cell death to those favouring survival and accumulation. We have monitored changes in the growth factor signalling molecule MAPKinase, in the cytoprotective protein Bcl-2 and in the cell death protein Bax, during maturation of proliferating and non-proliferating AML blasts in vitro. Eighteen AML samples were cultured for 7 d in serum-free medium with or without a supplement of recombinant cytokines comprising c-kit ligand, IL3 and GMCSF. Maturation of AML blasts, as assessed by morphology on Romanowsky-stained slides of 7/18 samples and by changes in surface CD markers on all 18 leukemias, occurred in both the absence and presence of cytokines. Cell numbers decreased to a mean of 71% after 7 d of cytokine-free culture, but increased to 210% in cytokine-supplemented cultures. The proportion of CD15-positive cells, assessed by flow cytometry, increased over 7 d in 17/18 samples, from a mean of 22% to 68% in cytokine-free cultures and to 72% in cytokine-supplemented cultures (p = < 0.0001 for both). By immunofluorescence/flow cytometry, there was no significant change in Bcl-2 over 7 d of culture, while Bax increased, particularly in cytokine-free cultures (2.2-fold), which led to a significant decrease in the Bcl-2/Bax ratio. Immunoblotting demonstrated that ERK was briefly phosphorylated after seeding AML blasts into culture. PD98059, an inhibitor of MAPKinase kinase (MEK) which activates MAPKinase, inhibited this transient ERK phosphorylation but was unable to block maturation as measured by acquisition of CD15 in samples from 12 patients with low starting numbers of CD15-positive cells. PD98059, however, reduced cell numbers in 7-d liquid culture and, in cytokine-supplemented cultures, this was associated with a 1.3-fold increase in Bcl-2 (p = 0.012) and a 1.4-fold increase in Bax (p = 0.02). Overall, these data demonstrate that most leukemic populations can partially differentiate in vitro without the need for cytokines or inducers. The MAPKinase pathway is not required for this maturation, but it does maintain cell viability in the absence or presence of cytokines. A rise in Bcl-2 may not protect AML blasts in the face of elevated Bax.

Acute Disease↗
PubMed2000

Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass.

Genetic and pharmacological studies have defined a role for the melanocortin-4 receptor (Mc4r) in the regulation of energy homeostasis. The physiological function of Mc3r, a melanocortin receptor expressed at high levels in the hypothalamus, has remained unknown. We evaluated the potential role of Mc3r in energy homeostasis by studying Mc3r-deficient (Mc3r(-/-)) mice and compared the functions of Mc3r and Mc4r in mice deficient for both genes. The 4-6-month Mc3r-/- mice have increased fat mass, reduced lean mass and higher feed efficiency than wild-type littermates, despite being hypophagic and maintaining normal metabolic rates. (Feed efficiency is the ratio of weight gain to food intake.) Consistent with increased fat mass, Mc3r(-/-) mice are hyperleptinaemic and male Mc3r(-/-) mice develop mild hyperinsulinaemia. Mc3r(-/-) mice did not have significantly altered corticosterone or total thyroxine (T4) levels. Mice lacking both Mc3r and Mc4r become significantly heavier than Mc4r(-/-) mice. We conclude that Mc3r and Mc4r serve non-redundant roles in the regulation of energy homeostasis.

Adipose Tissue↗
PubMed2000

Determination of red cell volume in infants needing blood transfusion.

The total circulating red cell volume (RCV) is a better guide to the oxygen-carrying capacity of the blood in the whole circulation than is the haemoglobin concentration (Hb) or haematocrit in a blood sample. Pre- and post-transfusion RCV (and blood volume (BV)) may be determined by flow cytometry by exploiting antigen differences between transfused donor red cells and the recipient's red cells. This paper describes the use of red cell antigen differences of Duffy, Kidd, MN and RhD between donor and recipient. In 20 infants, transfused on 21 occasions, pretransfusion RCV ranged from 12 to 39 mL kg(-1) body weight. Only at one transfusion could no usable donor-recipient antigen differences be exploited. Measurement of RCV, used routinely, may determine the transfusion requirements of sick infants more accurately, with the aim of normalizing RCV and BV--securing euvolaemia--at the end of the transfusion. This may allow a complete correction of the RCV deficiency at the first occasion of transfusion. This approach may reduce donor exposures and also optimize oxygen transport and organ perfusion of the infant undergoing intensive management, perhaps leading ultimately to improved survival rates and fewer long-term complications of neonatal intensive care.

Autoantigens↗
PubMed2000

Newborn intraabdominal cystic lymphatic malformations.

Cystic lymphatic malformations are rare causes of abdominal masses in the newborn. Also known as mesenteric, omental, or retroperitoneal cysts, they can present in a variety of ways including, intestinal obstruction, volvulus, nonspecific abdominal pain, intracystic hemorrhage, or as an asymptomatic abdominal mass. Abdominal ultrasound scan provides a definitive diagnosis in most suspected cases. Complete resection is possible in most patients except those with extensive retroperitoneal involvement. Recurrence is unusual when complete resection is accomplished. Because most case series with complete data suggest that these entities are lymphatic malformations, the authors suggest the more specific term, cystic lymphatic malformations, be used to describe these lesions.

Cysts↗
PubMed2000

The in vitro hydrodynamic characteristics of the porcine pulmonary valve and root with regard to the ross procedure.

OBJECTIVE: The hydrodynamic parameters and leaflet motion of the porcine pulmonary root and valve and the performance of the pulmonary autograft implanted in subcoronary position or as a free-standing root were investigated at systemic and pulmonary pressures in vitro. METHODS: Ten fresh pulmonary and aortic roots (anulus diameter, 20-25 mm) were tested in a pulsatile flow simulator. Five free-sewn pulmonary valves were implanted in aortic roots in the subcoronary position, and 5 pulmonary roots were implanted as free-standing roots. The external diameter of the roots was measured at the sinotubular junction in a pressure range of 0 to 120 mm Hg. The transvalvular gradient and regurgitation were measured, and the effective orifice area was calculated. The leaflet motion was recorded on video tape. RESULTS: The fresh pulmonary roots were more compliant than their aortic counterparts (33% +/- 3. 0% vs 7% +/- 1.5% with dilatation at 0-30 mm Hg and 46% +/- 8.4% vs 35% +/- 7.8% with dilatation at 0-120 mm Hg). The pulmonary roots had a lower pressure drop at systemic than at pulmonary pressures. The pressure drops of the pulmonary roots were also lower than those of the aortic roots in the systemic pressure range. The leaflet opening of the pulmonary valve was triangular, with low bending deformation at all pressures. Implanting the free-sewn pulmonary valve in the subcoronary position or the pulmonary root as a free-standing root did not affect the hydrodynamic parameters and leaflet motion adversely. CONCLUSION: The pulmonary valve and root could easily withstand aortic pressures in vitro. A biphasic dilatation curve ensures that higher pressures did not overdilate the pulmonary root. Moreover, valve performance was better at systemic pressures.

Animals↗
PubMed2000

Structural equilibria in RNA as revealed by 19F NMR.

We have incorporated 5-fluorouridine into several sites within a 19-mer RNA modelled on the translational operator of the MS2 bacteriophage. The 19F NMR spectra demonstrate the different chemical shifts of helical and loop fluorouridines of the hairpin secondary structure. Addition of salt gives rise to a species in which the loop fluorouridine gains the chemical shift of its helical counterparts, due to the formation of the alternative bi-molecular duplex form. This is supported by UV thermal melting behaviour which becomes highly dependent on the RNA concentration. Distinct 19F NMR signals for duplex and hairpin forms allow the duplex-hairpin equilibrium constant to be determined under a range of conditions, enabling thermodynamic characterisation and its salt dependence to be determined. Mg2+ also promotes duplex formation, but more strongly than Na+, such that at 25 degrees C, 10 mM MgCl2 has a comparable duplex-promoting effect to 300 mM NaCl. A similar effect is observed with Sr2+, but not Ca2+ or Ba2+. Additional hairpin species are observed in the presence of Na+ as well as Mg2+, Ca2+, Sr2+ and Ba2+ ions. The overall, ensemble average, hairpin conformation is therefore salt-dependent. Electrostatic considerations are thus involved in the balance between different hairpin conformers as well as the duplex-hairpin equilibrium. The data presented here demonstrate that 19F NMR is a powerful tool for the study of conformational heterogeneity in RNA, which is particularly important for probing the effects of metal ions on RNA structure. The thermodynamic characterisation of duplex-hairpin equilibria will also be valuable in the development of theoretical models of nucleic acid structure.

Fluorine↗
PubMed2000

Health insurance status and mood during pregnancy and following birth: a longitudinal study of multiparous women.

OBJECTIVE: The objective of this study was to investigate the relationship between health insurance status and mood during pregnancy and following childbirth. METHOD: 320 women were recruited in the early stage of pregnancy to participate in a longitudinal, prospective study of the psychological aspects of childbirth among multiparous women. Study volunteers were surveyed during each trimester of pregnancy and 2 and 8 months following childbirth. A range of self-administered psychometric tests were used to assess mood (Profile of Mood State), locus of control, defence style and partner support. Demographic information including health insurance status was noted at study entry. RESULTS: Public patients consistently had a more disturbed mood compared with private patients. This difference reached statistical significance during the second and third trimesters of pregnancy and 8 months after birth. Multivariate analysis was undertaken to identify predictors of mood during pregnancy and following birth. A better mood score was positively associated with private health insurance, a more caring partner and mature defence style, and negatively associated with external locus of control and immature defence style. A distinct mood pattern during pregnancy and following childbirth was observed and is described. CONCLUSIONS: Public patients have a more disturbed mood during pregnancy and following childbirth compared with private patients. This information is relevant when planning social, psychological and psychiatric services that target childbearing women.

Adult↗
PubMed2000

Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term?

BACKGROUND: It is postulated that some aspects of methotrexate toxicity may be related to its action as an anti-folate. Folic acid (FA) is often given as an adjunct to methotrexate therapy, but there is no conclusive proof that it decreases the toxicity of methotrexate and there is a theoretical risk that it may decrease the efficacy of methotrexate. OBJECTIVES: To look at the effect of stopping FA supplementation in UK rheumatoid arthritis (RA) patients established on methotrexate <20 mg weekly and FA 5 mg daily, to report all toxicity (including absolute changes in haematological and liver enzyme indices) and to report changes in the efficacy of methotrexate. METHODS: In a prospective, randomized, double-blind, placebo-controlled study, 75 patients who were established on methotrexate <20 mg weekly and FA 5 mg daily were asked to stop their FA and were randomized to one of two groups: placebo or FA 5 mg daily. Patients were evaluated for treatment toxicity and efficacy before entry and then at intervals of 3 months for 1 yr. RESULTS: Overall, 25 (33%) patients concluded the study early, eight (21%) in the group remaining on FA and 17 (46%) in the placebo group (P = 0.02). Two patients in the placebo group discontinued because of neutropenia. At 9 months there was an increased incidence of nausea in the placebo group (45 vs. 7%, P = 0.001). The placebo group had significantly lower disease activity on a few of the variables measured, but these were probably not of clinical significance. CONCLUSIONS: It is important to continue FA supplementation over the long term in patients on methotrexate and FA in order to prevent them discontinuing treatment because of mouth ulcers or nausea and vomiting. Our data suggest that FA supplementation is also helpful in preventing neutropenia, with very little loss of efficacy of methotrexate.

Aged↗