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Biomedical subjects

J Fisher

Publications and source records attributed to J Fisher.

At least 145 records · Page 8Linked to original sources

Identification of amino acid residues critical for aggregation of human CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES. Characterization of active disaggregated chemokine variants.

Human CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES (regulated on activation normal T cell expressed) self-associate to form high-molecular mass aggregates. To explore the biological significance of chemokine aggregation, nonaggregating variants were sought. The phenotypes of 105 hMIP-1alpha variants generated by systematic mutagenesis and expression in yeast were determined. hMIP-1alpha residues Asp26 and Glu66 were critical to the self-association process. Substitution at either residue resulted in the formation of essentially homogenous tetramers at 0.5 mg/ml. Substitution of identical or analogous residues in homologous positions in both hMIP-1beta and RANTES demonstrated that they were also critical to aggregation. Our analysis suggests that a single charged residue at either position 26 or 66 is insufficient to support extensive aggregation and that two charged residues must be present. Solution of the three-dimensional NMR structure of hMIP-1alpha has enabled comparison of these residues in hMIP-1beta and RANTES. Aggregated and disaggregated forms of hMIP-1alpha, hMIP-1beta, and RANTES generally have equivalent G-protein-coupled receptor-mediated biological potencies. We have therefore generated novel reagents to evaluate the role of hMIP-1alpha, hMIP-1beta, and RANTES aggregation in vitro and in vivo. The disaggregated chemokines retained their human immunodeficiency virus (HIV) inhibitory activities. Surprisingly, high concentrations of RANTES, but not disaggregated RANTES variants, enhanced infection of cells by both M- and T-tropic HIV isolates/strains. This observation has important implications for potential therapeutic uses of chemokines implying that disaggregated forms may be necessary for safe clinical investigation.

Amino Acid Sequence↗

E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium.

Ovarian carcinomas are thought to arise in the ovarian surface epithelium (OSE). Although this tissue forms a simple epithelial covering on the ovarian surface, OSE cells exhibit some mesenchymal characteristics and contain little or no E-cadherin. However, E-cadherin is present in metaplastic OSE cells that resemble the more complex epithelia of the oviduct, endometrium and endocervix, and in primary epithelial ovarian carcinomas. To determine whether E-cadherin was a cause or consequence of OSE metaplasia, we expressed this cell-adhesion molecule in simian virus 40-immortalized OSE cells. In these cells the exogenous E-cadherin, all three catenins, and F-actin localized at sites of cell-cell contact, indicating the formation of functional adherens junctions. Unlike the parent OSE cell line, which had undergone a typical mesenchymal transformation in culture, E-cadherin-expressing cells contained cytokeratins and the tight-junction protein occludin. They also formed cobblestone monolayers in two-dimensional culture and simple epithelia in three-dimensional culture that produced CA125 and shed it into the culture medium. CA125 is a normal epithelial-differentiation product of the oviduct, endometrium, and endocervix, but not of normal OSE. It is also a tumor antigen that is produced by ovarian neoplasms and by metaplastic OSE. Thus, E-cadherin restored some normal characteristics of OSE, such as keratin, and it also induced epithelial-differentiation markers associated with weakly preneoplastic, metaplastic OSE and OSE-derived primary carcinomas. The results suggest an unexpected role for E-cadherin in ovarian neoplastic progression.

Actins↗

Phospholipase A2 (PLA2) activity in mini pigs after acute high dose i.v.-paraoxon (POX) intoxication.

The purpose of the present study was to establish in the mini pig model the effects of paraoxon (POX) on PLA2 activity. Six anesthetized and mechanically ventilated mini pigs were infused over 50 min with 0.3, 1, 3, 9, 27 and 81 mg POX kg(-1) BW(-1) dissolved in ethanol, respectively. The control animal received no POX but the ethanol amount corresponding to the highest POX dose. PLA2 activity measurements were carried out immediately after POX application. Data were analysed with the Mann Whitney-Wilcoxon rank order test. Statistical significance was assumed for P < or = 0.05. Exposure to POX inhibited PLA2 activity to 50.5 +/- 8.9% of baseline activity. The changes seen were not dose-dependent. The dose dependency previously demonstrated in vitro was not reproducible in vivo. This is most probably due to the massive endogenous catecholamine release leading to PLA2 activation. An additional masking effect is due to the (co)administration of drugs needed for anesthesia and cardiovascular support, especially Mg2+. These substances also influence the PLA2 activity.

Adrenal Glands↗

The effect of sizing on the in vitro hydrodynamic characteristics and leaflet motion of the Toronto SPV stentless valve.

OBJECTIVES: We established an in vitro model to investigate the effects of valve sizing on the hemodynamic characteristics and leaflet motion of the Toronto SPV valve (St Jude Medical, Inc, St Paul, Minn). METHODS: Nine valves were first implanted in fresh porcine aortic roots and then retested in glutaraldehyde-treated porcine aortic roots. Three valves were 1- to 2-mm oversized, 3 were 1- to 2-mm undersized, and there were 3 size-for-size implantations. The elasticities of the aortic roots and the composite roots were measured in the pressure range between 0 and 120 mm Hg, and the composite roots were then tested in a pulsatile flow simulator. The transvalvular gradient and regurgitation were measured and the effective orifice area and performance index were calculated for each root. Leaflet motion was recorded on videotape. RESULTS: The external diameter of the fresh root increased by 35% as the hydrostatic pressure rose from 0 to 120 mm Hg, as compared with 11% for the glutaraldehyde-treated root. Valve implantation in the fresh root reduced the distensibility to 22% but did not change distensibility in the glutaraldehyde-treated root. The effective orifice area was dependent on the valve size, with the transvalvular gradient decreasing as the valve size increased. For the same size of valve the hydrodynamic parameters were slightly better if the valve was undersized by 1 mm. A significant difference in favor of the undersized valves was found in open-leaflet bending deformation. CONCLUSION: Leaflet motion of the stentless porcine aortic valve in vitro is improved if the valve is slightly undersized, and this may be beneficial to the long-term durability of the prosthesis.

Animals↗

Analysis of retrieved alumina ceramic components from Mittelmeier total hip prostheses.

This study analyses explanted prostheses from a single surgeon's 16-yr series of Mittelmeier cementless total hip replacements. The patient group was young (patients aged 15-60, average 40) and active. Revision was related to various factors. All components were measured using a Kemco 3D coordinate measurement machine. Wear surfaces and linear wear penetrations of 11 retrieved Mittelmeier Autophor ceramic hip components (average implantation time 8.6 yr, range 1-13 yr) were analysed and the different types of wear identified. Surface analysis was then performed using Talysurf contacting profilometry and scanning electron microscopy. Three types of wear were identified: low wear (1 case), stripe wear (6 cases) and severe wear (4 cases). Stripe wear was characterised as a stripe of worn area on the head up to 150 microns deep whilst the rest of the head showed very low wear. The cups in the stripe wear cases were worn over about 40-50% of the surface. Severe wear cases had very large areas of heavy wear and visible volume loss on both heads and cups. The four cases of severe wear were associated with abnormal clinical histories.

Adolescent↗

A study of the wear resistance of three types of clinically applied UHMWPE for total replacement hip prostheses.

Ultra high molecular weight polyethylene (UHMWPE) is routinely used as one half of a bearing couple in clinical orthopaedic applications. This material is generally one of two grades, compression moulded GUR 1120, with a molecular weight of 4.4x 10(6) g mol(-1), or ram extruded GUR 4150HP with a molecular weight of 7.3x10(6) g mol(-1) although other grades are used as well. This study examines the effect of molecular weight and processing method by comparing the wear resistance of these two materials together with a non-standard extruded form of GUR 1120. Wear studies have been conducted against counterface surfaces which represent new and scratch-damaged femoral heads with bovine serum lubricant in a uniaxial reciprocating test configuration. No difference in the wear resistance was found between any material when tested against smooth cobalt chrome counterfaces. On rough cobalt chrome counterfaces, although no statistically significant difference (P>0.05) was found between the extruded and compression moulded GUR 1120, the extruded GUR 4150HP had a consistently better wear resistance. These results are discussed with reference to previous wear studies as well as the physical and mechanical properties of these materials.

Animals↗

The influence of size mismatch on the hemodynamic performance of the pulmonary autograft in vitro.

OBJECTIVES: We established an in vitro model to investigate the effect of size mismatch between the aortic and pulmonary root on the hydrodynamic performance and leaflet motion of the pulmonary autograft. METHODS: Ten fresh porcine pulmonary roots (annulus diameter: 19-25 mm) were tested in a pulsatile flow simulator. The autografts then were implanted in fresh porcine aortic roots (annulus diameter: 19-30 mm) and retested in the flow simulator. Three roots were oversized by 21-39%, three were undersized by 32-45% and there were four size for size implantations. The external diameter of the roots and autografts was measured at the sinotubular junction at hydrostatic pressures of 0 - 120 mmHg. The transvalvular gradient and regurgitation were also measured and the effective orifice area was calculated. The leaflet motion was recorded on video. RESULTS: The fresh pulmonary roots were more compliant than the fresh aortic roots (46 +/- 8.4% vs. 35 +/- 7.8% dilatation from 0 to 120 mmHg). The group of matching size autografts dilated by 43 +/- 4.9% in the same pressure range. The external diameter of the undersized autografts was 10 +/- 2.1% bigger than before implantation at 0 pressure and then the dilatation was 40 +/- 5.3% at 120 mmHg. The oversized implantation made the autografts 11 +/- 9.4% smaller in their relaxed state, but then they dilated by 65 +/- 11% as the pressure increased to 120 mmHg, resulting in a net dilatation of 54% over the original undilated state. The under or oversizing had little effect on the pressure gradient measured across the valves (5.6 +/- 2.57 mmHg before, 6.3 +/- 3.27 mmHg after implantation). Only the oversized valves showed significantly higher gradients than the native pulmonary valves. The effective orifice area of the undersized autografts was slightly bigger and the oversized autografts was slightly smaller after implantation, although the differences were not significant. The size mismatch did not cause regurgitation on the valves. The video images showed very low-open leaflet-bending deformation, both on the fresh pulmonary and the autograft valves. CONCLUSION: Under or oversizing the pulmonary autograft up to 40% of the annulus diameter did not affect the hydrodynamic parameters significantly. The compliance of the autograft root was able to compensate for the size mismatch without adversely influencing the valve performance.

Animals↗

An expedient and ethical alternative to xenotransplantation.

The current voluntary posthumous organ donation policy fails to provide sufficient organs to meet the demand. In these circumstances xenografts have been regarded as an expedient solution. The public perception seems to be that the only impediments to this technology are technical and biological. There are, however, important ethical issues raised by xenotransplantation that need to be considered as a matter of urgency. When the ethical issues raised by using non-human animals to provide replacement organs for human beings are considered in a wider context and the possible alternatives to xenotransplantation are taken into account, a new dimension is added to the debate. In this broader context it is argued that a less ethically problematic solution is to adopt a presumed consent or opt-out organ procurement policy to regulate posthumous organ harvesting from humans. If there are still too few organs available, then the whole question of transplantation must be reassessed.

Animals↗

Comparative wear under four different tribological conditions of acetylene enhanced cross-linked ultra high molecular weight polyethylene.

In this study, the wear of ultra high molecular weight polyethylene (UHMWPE) (Grade RCH 1000) crosslinked by gamma irradiation in acetylene was compared to virgin (non-irradiated) UHMWPE using four different wear configurations: (i) unidirectional motion with a smooth counterface, (ii) multidirectional motion with a smooth counterface, (iii) unidirectional motion with a rough counterface and (iv) multidirectional motion with a rough counterface.

Journal Article↗

Quantitative analysis of the wear and wear debris from low and high carbon content cobalt chrome alloys used in metal on metal total hip replacements.

The biological reactions to polyethylene wear debris have been shown to result in osteolysis and loosening of total hip arthroplasties. This has led to renewed interest in the use of metal on metal bearings in hip prostheses. This study employed uniaxial and biaxial multistation pin on plate reciprocators to assess how the carbon content of the cobalt chrome alloy and the types of motion affected the wear performance of the bearing surfaces and the morphology of the wear debris generated. The low carbon specimens demonstrated higher wear factors than both the mixed carbon pairings and the high carbon pairings. The biaxial motion decreased the wear rates of all specimens. Plate wear was significantly reduced by the biaxial motion, compared to pin wear. The metal wear particles isolated were an order of magnitude smaller than polyethylene particles, at 60-90 nm, and consequently, 100-fold more particles were produced per unit volume of wear compared to polyethylene. The low carbon specimens produced significantly larger particles than the other material combinations, although it is thought unlikely that the difference would be biologically significant in vivo. The volumetric wear rates were affected by the carbon content of the cobalt chrome alloy, the material combination used and type of motion applied. However, particle morphology was not affected by the carbon content of the alloy or the type of motion applied.

Journal Article↗

The use of digital cameras in a mobile retinal screening environment.

AIMS: To assess how successfully digital camera technology might be incorporated into a mobile screening environment. METHODS: One hundred and ninety-seven people had their fundi photographed using a Topcon/Imagenet digital system and 534 using a Canon CR5/Ris-Lite system in addition to concurrent 45 degrees CR4NM Polaroid photography. One hundred and eighteen randomly selected patients were also sent for 7 field stereo photography as a gold standard. An acceptability questionnaire was answered by a random sample of those photographed. RESULTS: For the detection of any retinopathy, digital pictures had a sensitivity of 0.74 (95% confidence interval (CI) 0.68-0.80) whilst Polaroid was 0.72 (95% CI 0.66-0.78) and for referable retinopathy digital pictures had a sensitivity of 0.85 (95% CI 0.80-0.90) and Polaroid was 0.90 (95% CI 0.86-0.94). A concurrent ophthalmoscopic evaluation improved the sensitivity to 0.92 (95% CI 0.86-0.98) for detection of any retinopathy whilst the sensitivity at the referral level was improved to 0.95 (95% CI 0.91-0.99). Twenty-nine of 176 respondents experienced flash discomfort with the Polaroid system with only four of 154 describing 'some' discomfort from the digital systems which have a lower flash power (10 W vs. 300 W) and a faster recovery time. CONCLUSIONS: This study indicates that digital systems are a feasible and acceptable alternative to Polaroid-based cameras for use in a mobile environment.

Adult↗

Public hospital pregnancy termination services: are we meeting demand?

OBJECTIVES: To identify the socio-demographic characteristics of women seeking termination of pregnancy through a public hospital service and explore issues of accessibility to the service. METHOD: An audit of the Pregnancy Advisory Service (PAS) at the Royal Women's Hospital in Melbourne from January to March 1996. Data were collected from 1,088 intake forms of women seeking an abortion. RESULTS: The women were of low socio-economic status, with 437 (40.2%) living on a government pension or benefit and 55.6% holding a Health Benefits Card. However, only 33.8% were given an appointment for an abortion in the public clinic, with most (63.7%) referred to private services. CONCLUSIONS: The demand for this public hospital abortion service exceeds its capacity and economically disadvantaged women are required to seek abortion in private services. IMPLICATIONS: There is a role for regional health authorities to ensure adequate distribution of public hospital pregnancy termination services.

Abortion, Induced↗

Initial clinical experience with a fully automatic in-hospital external cardioverter defibrillator.

Sudden cardiac death due to ventricular tachyarrhythmia remains a significant problem in the in-hospital setting. Although the probability of survival is closely correlated with the rapidity of a response by qualified personnel, response times can be prolonged, even in specialized care units. In an effort to decrease response time, a fully automatic external cardioverter defibrillator was recently devised. This device was evaluated in the in-hospital setting to assess safety and efficacy. A total of 79 patients were studied in a multicenter trial. Patients were monitored with fully functional devices in the electrophysiology laboratory (51 patients) and in the cardiac care unit (28 patients). Performance of the device was assessed by comparing automatic responses to any sustained change in cardiac rhythm, either spontaneous or induced, to a retrospective review of stored ECG data and programmed parameters. During a total duration of 964 hours of monitoring, there were 99 episodes of sustained tachycardia. Therapy was appropriately delivered or advised in all episodes. Therapy was advised in one episode of supraventricular tachycardia. There were no episodes of inappropriate therapy delivery. There were no complications or adverse events. The device performed with a sensitivity of 100% and specificity of 98.8% with an average response time of 22 seconds. In conclusion, this automatic external defibrillator was safe, effective, and functioned as designed. Significant improvement in response time to life-threatening ventricular tachyarrhythmia in the in-hospital setting would be expected if this technology was widely adopted.

Adult↗

Re-examining death: against a higher brain criterion.

While there is increasing pressure on scarce health care resources, advances in medical science have blurred the boundary between life and death. Individuals can survive for decades without consciousness and individuals whose whole brains are dead can be supported for extended periods. One suggested response is to redefine death, justifying a higher brain criterion for death. This argument fails because it conflates two distinct notions about the demise of human beings--the one, biological and the other, ontological. Death is a biological phenomenon. This view entails the rejection of a higher brain criterion of death. Moreover, I claim that the justification of the whole brain (or brain stem) criterion of death is also cast into doubt by these advances in medical science. I proceed to argue that there is no need to redefine death in order to identify which treatments ought to be provided for the permanently and irreversibly unconscious. There are already clear treatment guidelines.

Attitude to Death↗

The influence of lubricant on the morphology of ultra-high molecular weight polyethylene wear debris generated in laboratory tests.

Since the implication of polyethylene wear debris as a major cause of osteolysis in total joint replacements, there has been much interest in polyethylene wear studies and in cell culture studies using ultra-high molecular weight polyethylene (UHMWPE) wear debris. Studies have shown that particles in the 0.1-10 microns size range are particularly important in causing adverse cellular reactions resulting in osteolysis. The morphology, the mass and size distributions, and the number of wear particles produced at the joint surfaces are influenced by the tribological conditions at the joint. Laboratory wear tests are used to investigate the wear properties of prosthetic joint materials and different research groups have used different lubricants in these tests. This paper shows that the volumetric wear and morphology of UHMWPE particles generated in vitro are influenced by the type of lubricant used. This study compared, quantitatively, UHMWPE wear debris generated in deionized water to debris that was generated in a system lubricated by bovine serum which was diluted to 25 per cent. The wear factors of UHMWPE in water and serum lubricants were significantly different (p < 0.05). UHMWPE wore 14 times more in water than in serum. Quantitative analysis of the wear particles showed that the debris that was generated in serum was morphologically different from debris that was produced in a water-lubricated system. Furthermore, the particles produced in serum showed a closer similarity to those found in retrieved acetabular tissues.

Blood↗