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Biomedical subjects

N Fisher

Publications and source records attributed to N Fisher.

At least 19 recordsLinked to original sources
PubMed2001

Effects of mutations in mitochondrial cytochrome b in yeast and man. Deficiency, compensation and disease.

The mitochondrial cytochrome bc(1) complex is a key protonmotive component of eukaryotic respiratory chains. The mitochondrially encoded cytochrome b forms, with cytochrome c(1) and the iron--sulfur protein, the catalytic core of this multimeric enzyme. Mutations of cytochrome b have been reported in association with human diseases. In the highly homologous yeast cytochrome b, several mutations that impair the respiratory function, and reversions that correct the defect, have been described. In this paper, we re-examine the mutations in the light of the atomic structure of the complex, and discuss the possible effect, at enzyme level, of the human cytochrome b mutations and the correcting effect of the reversions.

Cardiomyopathies↗
PubMed2001

The directional tuning of the barber-pole illusion.

In order to study the integration of local motion signals in the human visual system, we measured directional tuning curves for the barber-pole illusion by varying two crucial aspects of the stimulus layout independently across a wide a range in the same experiment. These were the orientation of the grating presented behind the rectangular aperture and the aspect ratio of the aperture, which in combination determine the relative contributions of local motion signals perpendicular to the gratings and parallel to the aperture borders, respectively. The strength of the illusion, ie the tendency to perceive motion along the major axis of the aperture, obviously depends on the spatial layout of the aperture, but also on grating orientation. Subjects were asked which direction they perceived and how compelling their motion percept was, revealing different strategies of the visual system to deal with the barber-pole stimulus. Some individuals respond strongly to the unambiguous motion information at the boundaries, leading to multistable percepts and multimodal distributions of responses. Others tend to report intermediate directions, apparently being less influenced by the actual boundaries. The general pattern of deviations from the motion direction perpendicular to grating orientation--a decrease with aspect ratio approaching unity (ie square-shaped apertures) and with gratings approaching parallel orientation to the shorter aperture boundary--is discussed in the context of simple phenomenological models of motion integration. The best fit between model predictions and experimental data is found for an interaction between two stimulus parameters: (i) cycle ratio, which is the sine-wave gratings equivalent of the terminator ratio for line gratings, describing the effects from the aperture boundaries, and (ii) the grating orientation, responsible for perpendicular motion components, which describes the influence of motion signals from inside the aperture. This suggests that the most simple cycle (terminator) ratio explanation cannot fully account for the quantitative properties of the barber-pole illusion.

Adult↗
PubMed2000

A motif for quinone binding sites in respiratory and photosynthetic systems.

Many of the membrane-bound protein complexes of respiratory and photosynthetic systems are reactive with quinones. To date, no clear structural relationship between sites that bind quinone has been defined, apart from that in the homologous family of "type II" photosynthetic reaction centres. We show here that a structural element containing a weak sequence motif is common to the Q(A) and Q(B) sites of bacterial reaction centres and the Q(i) site of the mitochondrial bc(1) complex. Analyses of sequence databases indicate that this element may also be present in the PsaA/B subunits of photosystem I, in the ND4 and ND5 subunits of complex I and, possibly, in the mitochondrial alternative quinol oxidase. This represents a first step in the structural classification of quinone binding sites.

Amino Acid Sequence↗
PubMed2000

Cardiac arrest outcomes at the Melbourne Cricket Ground and shrine of remembrance using a tiered response strategy-a forerunner to public access defibrillation.

The provision of medical, paramedical and first aid services at major public events is an important concern for pre-hospital emergency medical care providers. Patient outcomes of a cardiac arrest response strategy employed at the Melbourne Cricket Ground (MCG) and the Shrine of Remembrance by St John Ambulance Australia volunteers are reported. Twenty-eight consecutive events occurring between December 1989 and December 1997 have been analysed. Included are three cardiac arrests managed at ANZAC day parades utilising the same response strategy by the same unit. The incidence of cardiac arrest at the MCG was 1:500000 attendances. Of the 28 patients, 24 (86%) left the venue alive and 20 (71%) were discharged home from hospital. In all cases the initial rhythm was ventricular fibrillation (VF). All 26 patients (93%) who were defibrillated by St John teams had this intervention within 5 min from the documented time of collapse. One patient in VF spontaneously reverted during CPR. Of the eight fatalities, four died at the scene. At major public venues and events, a co-ordinated emergency life support provision strategy, tailor made for the venue, is necessary for the delivery of prompt CPR, timely defibrillation and advanced life support.

Adult↗
PubMed1999

Effects of mutation of the conserved glutamic acid-286 in subunit I of cytochrome c oxidase from Rhodobacter sphaeroides.

We have studied the effects of mutations, E286Q and E286D, of the conserved glutamate in subunit I of cytochrome c oxidase from Rhodobacter sphaeroides with a view to evaluating the role of this residue in redox-linked proton translocation. The mutation E286D did not have any dramatic effects on enzyme properties and retained 50% of wild-type catalytic activity. For E286Q a fraction of the binuclear center was trapped in an unreactive, spectrally distinct form which is most likely due to misfolded protein, but the majority of E286Q reacted normally with formate and cyanide in the oxidized state, and with carbon monoxide and cyanide in the dithionite-reduced form. The mutation also had little effect on the pH-dependent redox properties of haem a in the reactive fraction. However, formation of the P state from oxidized enzyme with hydrogen peroxide or by aerobic incubation with carbon monoxide was inhibited. In particular, only an F-type product was obtained, at less than 25% yield, in the reaction with hydrogen peroxide. The aerobic steady state in the presence of ferrous cytochrome c was characterized by essentially fully reduced haem a and ferric haem a3, suggesting that the mutation hinders electron transfer from haem a to the binuclear center. Under these conditions or after reoxidation, on a seconds time scale, of haem a3 following anaerobiosis, there was no indication of accumulation of significant amounts of P state. We propose that the glutamate is implicated in several steps in the catalytic cycle, O --> R, P --> F, and, possibly, F --> O. The results are discussed in relation to the "glutamate trap" model for proton translocation.

Aspartic Acid↗
PubMed1998

A randomized trial of solvent/detergent and standard fresh frozen plasma in the treatment of the coagulopathy seen during Orthotopic Liver Transplantation.

BACKGROUND: Viral transmission remains a residual risk in single unit blood component therapy. Virus inactivation of pooled fresh frozen plasma (FFP) by the solvent/detergent (SD) method can be used to reduce this risk but results in some loss of factor activity including factor VIII and (2-antiplasmin. This study was aimed at assessing the clinical effectiveness solvent/detergent treated pooled fresh frozen plasma (SDFFP) in the correction of the coagulopathy seen during Orthotopic Liver Transplantation (OLT) as compared with standard FFP. METHOD: Twenty eight patients with an underlying derangement of coagulation and who were due to undergo OLT were randomized to receive either FFP or SDFFP. They were assessed for side effects, correction of coagulopathy, and seroconversion for viral markers. RESULTS: Patients undergoing OLT showed equal correction of clotting factors and partial thromboplastin time (PTT) when treated with FFP or SDFFP. There was also a similar time course to return to baseline values in each group. There was no significant difference in correction of INR in either group. Usage of other blood components during the operation was identical in the two groups. No seroconversions were seen for HIV, HBC or HCV but only 12 patients were available for long term follow-up. CONCLUSION: SDFFP is an efficacious and safe source of coagulation factors for patients with liver disease undergoing Orthotopic Liver Transplantation. No adverse effects were seen during its administration. Further work is required to ascertain long term possibilities of seroconversion.

Adult↗
PubMed1997

Imaging 5-HT1A receptors with positron emission tomography: initial human studies with [11C]CPC-222.

The novel radioligand [11C]CPC-222 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)-2-bicyclo [2,2,2]octane carboxamide) was evaluated as an in vivo probe of the 5-HT1A receptors using positron emission tomography (PET). Three human volunteers were imaged with PET over a 90 min period following intravenous injection of the radioligand. There was a high accumulation of the radioligand in brain regions with a high density of 5-HT1A receptors. The peak cortical concentration was 1.0-2.5% of the injected dose per litre. The ratio of radioactivity in receptor-rich regions to that of the cerebellum reached a plateau of 2.5-4.0 by 45 min after injection. Analysis of the plasma revealed no detectable amount of the potential metabolite, radiolabelled WAY-100634. This new radioligand has suitable properties to study the 5-HT1A receptors in man with PET.

Adult↗
PubMed1996

Fibrillin-1 (FBN1) mutations in patients with thoracic aortic aneurysms.

BACKGROUND: Mutations in the FBN1 gene are the cause of the Marfan syndrome, an autosomal dominant disorder with skeletal, ocular, and cardiovascular complications. Aneurysms or dissections of the ascending thoracic aorta are the major cardiovascular complications of the disorder. We tested the hypothesis that FBN1 mutations cause thoracic aortic aneurysms or dissections in patients who do not have the Marfan syndrome. METHODS AND RESULTS: The FBN1 gene was screened for mutations by use of genomic DNA from two patients with thoracic aortic aneurysms who did not have the Marfan syndrome. Individual FBN1 exons were amplified with intron-based exon-specific primers; the DNA fragments were screened for mutations using single-stranded conformational polymorphism analysis; and aberrantly migrating bands were sequenced directly. We identified a missense mutation in one patient, D1155N in exon 27. Dermal fibroblasts from the affected individual were used to study the effect of the missense mutation D1155N on fibrillin-1 cellular processing. The mutation decreased the amount of fibrillin-1 deposited into the pericellular matrix. A second putative FBN1 mutation was identified in the second patient, P1837S in exon 44. Although this alteration was not observed in 234 chromosomes from unrelated individuals, the alteration may represent a rare polymorphism. CONCLUSIONS: Results of these studies support the hypothesis that FBN1 mutations cause thoracic aortic aneurysms in patients who do not have the Marfan syndrome. This information is important for understanding the pathogenesis of aortic aneurysms and identification of individuals at risk for developing thoracic aortic aneurysms or dissections.

Adult↗
PubMed1994

Estimating numbers of homeless and homeless mentally ill people in north east Westminster by using capture-recapture analysis.

OBJECTIVES: To use routinely collected data to provide a reliable estimate of the size and psychiatric morbidity of the homeless population of a given geographical area by using capture-recapture analysis. DESIGN: A multiple sample, log-linear capture-recapture method was applied to a defined area of central London during 6 months. The method calculates the total homeless population from the sum of the population actually observed and an estimate of the unobserved population. Data were collected from local agencies used by homeless people. SUBJECTS: Homeless people in north east Westminster residing in bed and breakfast accommodation and hotels or sleeping rough who had contacted statutory or voluntary agencies in the area. RESULTS: 2150 contacts by 1640 homeless people were recorded. The estimated unobserved population was 3293, giving a total homeless population for the period of around 5000 (SD 1250). Mental health problems were significantly less prominent in the unobserved compared with the observed population (23% (754) v 40% (627), P < 0.0001). For both groups the prevalence varied greatly with age and sex. CONCLUSIONS: Capture-recapture techniques can overcome problems of ascertainment in estimating populations of homeless and homeless mentally ill people. Prevalences of mental illness derived from surveys that do not correct for ascertainment are likely to be falsely inflated while at the same time underestimating the total size of the homeless mentally ill population. Population estimates derived from capture-recapture techniques may usefully provide a good basis for including homeless populations in capitation calculations for allocating funds within health services.

Adult↗