Showing papers by "King's College London published in 1992"

The United Nations Framework Convention on Climate Change

Abstract: In accordance with decision 9/2 of the Intergovernmental Negotiating Committee of the Framework Convention on Climate Change (INC/FCCC) and endorsed by the Conference of the Parties in its decision, 3/CP.1 (FCCC/CP/1995/7/Add.1), the secretariat is to make available, in the official languages of the United Nations, the executive summaries of the national communications submitted by Annex I Parties.

Oxidative stress as a cause of nigral cell death in Parkinson's disease and incidental lewy body disease

Abstract: We examine the evidence for free radical involvement and oxidative stress in the pathological process underlying Parkinson's disease, from postmortem brain tissue. The concept of free radical involvement is supported by enhanced basal lipid peroxidation in substantia nigra in patients with Parkinson's disease, demonstrated by increased levels of malondialdehyde and lipid hydroperoxides. The activity of many of the protective mechanisms against oxidative stress does not seem to be significantly altered in the nigra in Parkinson's disease. Thus, activities of catalase and glutathione peroxidase are more or less unchanged, as are concentrations of vitamin C and vitamin E. The activity of mitochondrial superoxide dismutase and the levels of the antioxidant ion zinc are, however, increased, which may reflect oxidative stress in substantia nigra. Levels of reduced glutathione are decreased in nigra in Parkinson's disease; this decrease does not occur in other brain areas or in other neurodegenerative illnesses affecting this brain region (i.e., multiple system atrophy, progressive supranuclear palsy). Altered glutathione metabolism may prevent inactivation of hydrogen peroxide and enhance formation of toxic hydroxyl radicals. In brain material from patients with incidental Lewy body disease (presymptomatic Parkinson's disease), there is no evidence for alterations in iron metabolism and no significant change in mitochondrial complex I function. The levels of reduced glutathione in substantia nigra, however, are reduced to the same extent as in advanced Parkinson's disease. These data suggest that changes in glutathione function are an early component of the pathological process of Parkinson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulation of lipid peroxidation and hydroxyl-radical generation by the contents of human atherosclerotic lesions.

Abstract: Lipid peroxidation within human arterial lesions is thought to play an important role in the development of atherosclerosis. Peroxidation can be accelerated by the presence of 'catalytic' iron or copper ions. Gruel samples from advanced atherosclerotic lesions in the abdominal aortae of human cadavers were tested for pro-oxidant properties. All samples contained bleomycin-detectable iron and phenanthroline-detectable copper. Almost all gruel samples stimulated peroxidation of rat liver microsomes, and this was usually inhibited by the iron-ion chelator desferrioxamine. Some samples stimulated formation of hydroxyl radicals from H2O2 in the presence of ascorbate, a reaction again inhibited by desferrioxamine. We conclude that the interior of human advanced atherosclerotic lesions is a highly pro-oxidant environment, and that the use of copper or iron ions to promote peroxidation of low-density lipoproteins in vitro may be a valid model for events in the arterial wall.

The Electron-Transport Proteins of Hydroxylating Bacterial Dioxygenases

Abstract: The degradation of aromatic compounds by aerobic bacteria frequently begins with the dihydroxylation of the substrate by nonheme iron-containing dioxygenases. These enzymes consist of two or three soluble proteins that interact to form an electron-transport chain that transfers electrons from reduced nucleotides (NADH) via flavin and [2Fe-2S] redox centers to a terminal dioxygenase. The dioxygenases may be classified in terms of the number of constituent components and the nature of the redox centers. Class I consists of two-component enzymes in which the first protein is a reductase containing both a flavin and a [2Fe-2S] redox center and the second component is the oxygenase; Class II consists of three-component enzymes in which the flavin and [2Fe-2S] redox centers of the reductase are on a separate flavoprotein and ferredoxin, respectively; and Class III consists of three-component enzymes in which the reductase contains both a flavin and [2Fe-2S] redox center but also requires a second [2Fe-2S] center on a ferredoxin for electron transfer to the terminal oxygenase. Further subdivision is based on the the type of flavin (FMN or FAD) in the reductase, the coordination of the [2Fe-2S] center in the ferredoxin, and the number of terminal oxygenase subunits. From the deduced amino acid sequence of several dioxygenases the ligands involved in the coordination of the nucleotides, iron-sulfur centers, and mononuclear nonheme iron active site are proposed. On the basis of their spectroscopic properties and unusually high redox potentials, the [2Fe-2S] clusters of the ferredoxins and terminal oxygenases have been assigned to the class of Rieske-type iron-sulfur proteins. The iron atoms in the Rieske iron-sulfur cluster are coordinated to the protein by two histidine nitrogens and two cysteine sulfurs.

Plasma endothelin immunoreactivity in liver disease and the hepatorenal syndrome.

Abstract: Background. Severe renal vasoconstriction is central to the pathogenesis of renal failure in the hepatorenal syndrome. Endothelin-1 and endothelin-3 are potent, long-acting vasoconstrictors, and endothelin-1 has selective potency as a renal vasoconstrictor. These properties suggest a role for endothelins in the hepatorenal syndrome. Methods. We measured plasma endothelin-1 and endothelin-3 concentrations using specific radioimmunoassays in subjects with the hepatorenal syndrome, liver disease but normal renal function, chronic renal failure, acute renal failure, liver dysfunction and renal impairment, or normal liver and kidney function. Results. The patients with the hepatorenal syndrome had markedly elevated mean (±SE) plasma concentrations of endothelin-1 (36±5 ng per liter [14.5±1.8 pmol per liter]) and endothelin-3 (43±3 ng per liter [16.3±1.0 pmol per liter]) as compared with the normal subjects (endothelin-1, 4±1 ng per liter [1.7±0.2 pmol per liter]; and endothelin-3, 18±1 ng per liter [6...

Vacancy-related centers in diamond

Abstract: It is established that vacancies in diamond migrate, during annealing, primarily in their neutral charge state, with an activation energy of 2.3\ifmmode\pm\else\textpm\fi{}0.3 eV. Negative vacancies are destroyed by first converting to neutral centers in a reversible charge transfer process. In relatively pure diamonds (type IIa) and in diamonds (type I) containing large concentrations of nitrogen, effectively all the vacancies in the samples after irradiation can be accounted for in their neutral (${\mathit{V}}^{0}$) and negative (${\mathit{V}}^{\mathrm{\ensuremath{-}}}$) charge states. In nitrogen-rich diamonds, the vacancies are predominantly trapped during annealing at the nitrogen. From the annealing data we derive the relative oscillator strengths of the main absorption bands of ${\mathit{V}}^{0}$, ${\mathit{V}}^{\mathrm{\ensuremath{-}}}$, and of one vacancy combined either with a single N atom, a pair of N atoms, or the larger ``B'' aggregate of nitrogen. In the absence of the intrinsic nonradiative decay channels of luminescence from ${\mathit{V}}^{0}$, we show that the radiative decay time would be 35\ifmmode\pm\else\textpm\fi{}7 ns. In common natural (``type IaA'') diamonds, variations of absorption linewidths during annealing imply that about 40% of the vacancies are created within a few atomic sites of the nitrogen impurity, and direct observation confirms that vacancy production is enhanced in these diamonds. About half the vacancies, including those created near the nitrogen, anneal at each temperature about 12 times faster than those vacancies whose creation is not correlated with the nitrogen.

New insights into the cause of Parkinson's disease

Abstract: Current concepts as to the cause of Parkinson's disease (PD) suggest an inherited predisposition to environmental or endogenous toxic agents. Study of the substantia nigra after death in PD has highlighted three major changes: (1) evidence of oxidative stress and depletion of reduced glutathione; (2) high levels of total iron, with reduced ferritin buffering; and (3) mitochondrial complex I deficiency. Which of these is the primary event, generating a secondary cascade of changes culminating in nigral cell death, is unknown. In presymptomatic Lewy body-positive control brains, the nigra shows depletion of reduced glutathione content and, possibly, a reduction of complex I activity. Whatever the significance of these various abnormalities, be they causal or secondary, they provide novel targets for the development of new strategies to treat the cause of PD.

Developing Flanagan's critical incident technique to elicit indicators of high and low quality nursing care from patients and their nurses.

Abstract: This paper discusses a development of Flanagan's critical incident technique (CIT) to elicit indicators of high and low quality nursing from patients and their nurses on medical, surgical and elderly care wards. Stages in undertaking the CIT are identified and presuppositions held by most researchers about the nature of the technique are identified. The paper describes how the authors moved to a different set of presuppositions during the course of the study. Preliminary analysis of interview transcripts revealed that critical incidents need not always be demarcated scenes with a clear beginning and end, but may arise from respondents summarizing their overall experience within their description of one incident. Characteristically respondents were unable to give a detailed account of such incidents but validity may be established by the fact that respondents appear to recount what actually happened as they saw it, and what they said was clearly important to them. The researchers found that the most appropriate basic unit of analysis was not the incident itself but 'happenings' revealed by incidents that are 'critical' by virtue of being important to respondents with respect to the quality of nursing care. The importance of CIT researchers achieving an understanding of the 'meaning' of critical happenings to respondents is emphasized. Analysis of the interview transcripts is facilitated by the use of INGRES, a relational database computer program which should enable a 'personal theory' of quality nursing for each respondent, both patients and nurses, to be described. The study suggests that the CIT is a flexible technique which may be adapted to meet the demands of nursing research. If carefully applied, the CIT seems capable of capitalizing on respondents' own stories and avoids the loss of information which occurs when complex narratives are reduced to simple descriptive categories. Patients and nurses have unique perspectives on nursing and their views are of primary importance in understanding what quality means with respect to the interpersonal processes that are integral to nursing care. This paper discusses the identification of indicators of quality nursing from interviews with patients and nurses using the authors' development of Flanagan's critical incident technique.

Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia

Abstract: Previously we have shown that cell death in the substantia nigra (SN) in Parkinson's disease (PD) is associated with an increase in iron content but a decrease in the level of the iron-binding protein ferritin. Alterations in other metal ion levels were also observed; copper levels were reduced, whereas zinc levels were increased. The importance of these changes in iron, ferritin, and other metal ions in the pathophysiology of PD depends on whether they are specific to the illness. We measured levels of iron, copper, zinc, manganese, and ferritin in postmortem tissue from patients with progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) (which shows pathology in the SN and striatum) and Huntington's disease (HD) (which shows pathological changes in the striatum, compared with control subjects). Total iron levels were elevated in areas of the basal ganglia showing pathological changes in these disorders. In particular, total iron content was increased in SN in PD, PSP, and MSA, but not in HD. Total iron levels in the striatum (caudate nucleus and/or putamen) were increased in PSP, MSA, and HD, but not in PD. There were no consistent alterations in manganese levels in the basal ganglia in any of the diseases studied. Copper levels were decreased in the SN in PD and in the cerebellum in PSP, and were elevated in the putamen and possibly the SN in HD. Zinc levels were only increased in PD in the SN, the caudate nucleus, and the putamen.(ABSTRACT TRUNCATED AT 250 WORDS)

Iron−sulfur clusters in enzymes: themes and variations

Abstract: Publisher Summary This chapter discusses the diversity of iron–sulfur proteins. From consideration of the primary and tertiary structure of the iron–sulfur proteins determined so far, it is possible to discern a number of distinct structural themes. Most of the complex proteins are constructed from domains, some of which are related to the ferredoxin-like sequences and Rieske iron–sulfur proteins. Differences are exhibited at several levels: (1) in the different types of iron–sulfur clusters, which have been identified by structure determination and by spectroscopy, (2) in the proteins that bind these clusters (the same type of cluster may be coordinated to protein domains of different sequences and structure), (3) in the other prosthetic groups that are present, and (4) in the different catalytic activities of the clusters. From studies of the ferredoxins and other small iron–sulfur proteins, it is known that there is a variety of iron–sulfur cluster types. These clusters are usually, but not invariably, coordinated to cysteine residues of the protein in conserved arrangements.

Cities and Administration in Roman Egypt

Abstract: These two inscriptions come from the precinct of the temple of Hathor at Denderah (Tentyra), capital of the Tentyrite nome, just north of Thebes in Upper Egypt. The impressive remains of the complex are mostly late Ptolemaic and Roman (re)constructions, but they look Pharaonic and suggest social and cultural continuity across the centuries. The inscriptions, however, illustrate the radical changes in communal organization and administration which the Romans introduced. These changes form the subject of this paper. The first inscription dates to 12 B.C., but is almost entirely in the pre-Roman tradition. It is a trilingual dedication with the primary version in demotic (i.e. Egyptian). Augustus is god, implicitly Pharaoh, and lacks his Roman titles. The strategos (governor of the nome) Ptolemaios gives himself obsolete court titles and a string of local priesthoods. Ptolemaios came from a family which had hereditarily held local priesthoods (and probably continued to hold them after him), and his father Panas had preceded him as strategos of the Tentyrite nome, retaining office through the Roman annexation. On this occasion Ptolemaios' dedication was personal, but other dedications show him acting, like his father, as the head of local cult associations. Ptolemaios is last attested as strategos in 5 B.C. Five years later, our second inscription, which dates to 23 September A.D. I, reveals a very different situation. The dedication was made on Augustus' birthday, and was finely inscribed in Greek only. The strategos Tryphon, whose name suggests an Alexandrian sent up to the Tentyrite nome, figures only as an element of the official dating clause standard throughout Roman Egypt; he is just a cog in the Roman administrative machine. The dedication was made corporately by the local community, structured, as we will see, on the new Roman model.

Myosin head movements are synchronous with the elementary force-generating process in muscle.

Abstract: Motor proteins such as myosin, dynein and kinesin use the free energy of ATP hydrolysis to produce force or motion, but despite recent progress their molecular mechanism is unknown. The best characterized system is the myosin motor which moves actin filaments in muscle. When an active muscle fibre is rapidly shortened the force first decreases, then partially recovers over the next few milliseconds. This elementary force-generating process is thought to be due to a structural 'working stroke' in the myosin head domain, although structural studies have not provided definitive support for this. X-ray diffraction has shown that shortening steps produce a large decrease in the intensity of the 14.5 nm reflection arising from the axial repeat of the myosin heads along the filaments. This was interpreted as a structural change at the end of the working stroke, but the techniques then available did not allow temporal resolution of the elementary force-generating process itself. Using improved measurement techniques, we show here that myosin heads move by about 10 nm with the same time course as the elementary force-generating process.

Retinoic acid and development of the central nervous system.

Abstract: We consider the evidence that RA, the vitamin A metabolite, is involved in three fundamental aspects of the development of the CNS: 1) the stimulation of axon outgrowth in particular neuronal sub-types; 2) the migration of the neural crest; and 3) the specification of rostrocaudal position in the developing CNS (forebrain, midbrain, hindbrain, spinal cord). The evidence we discuss involves RA-induction of neurites in cell cultures and explants of neural tissue; the teratological effects of RA on the embryo's nervous system; the observation that RA can be detected endogenously in the spinal cord; and the fact that the receptors and binding proteins for RA are expressed in precise domains and neuronal cell types within the nervous system.

The role of NAG (N-acetyl-beta-D-glucosaminidase) in the diagnosis of kidney disease including the monitoring of nephrotoxicity.

Abstract: The assay of urinary N-acetyl-beta-D-glucosaminidase (NAG) provides an early indication of tubular dysfunction resulting from renal disease or nephrotoxic damage. False positives are rare and its activity remains high during active disease or a sustained toxic insult but falls to normal levels on recovery or removal of the toxin. Urinary NAG activity can be used in conjunction with other tests to assess disease activity and prognosis. The assay of NAG isoenzymes increases the diagnostic potential of this test while the availability of dipsticks and simple assay kits will allow its use outside the laboratory.

Astrocyte-endothelial interaction: physiology and pathology

Abstract: The blood-brain barrier of higher vertebrates is formed by the layer of endothelial cells lining the brain microvessels. The close anatomical association between endothelial cells and per vascular astrocytic end feet suggests cooperation between these cell types in forming and maintaining the blood-brain barrier. This review considers evidence from grafting experiments, developmental studies and culture models of the brain endothelium, concerning the inductive influences acting on the endothelium, and from endothelial cells acting on perivascular astrocytes. Examples from pathology and neurotoxicology which may involve breakdown of induction are also considered.

Further characterization of the [Fe]-hydrogenase from Desulfovibrio desulfuricans ATCC 7757.

Abstract: The properties of the periplasmic hydrogenase from Desulfovibrio desulfuricans ATCC 7757, previously reported to be a single-subunit protein [Glick, B. R., Martin, W. G., and Martin, S. M. (1980) Can. J. Microbiol. 26, 1214-1223] were reinvestigated. The pure enzyme exhibited a molecular mass of 53.5 kDa as measured by analytical ultracentrifugation and was found to comprise two different subunits of 42.5 kDa and 11 kDa, with serine and alanine as N-terminal residues, respectively. The N-terminal amino acid sequences of its large and small subunits, determined up to 25 residues, were identical to those of the Desulfovibrio vulgaris Hildenborough [Fe]-hydrogenase. D. desulfuricans ATCC 7757 hydrogenase was free of nickel and contained 14.0 atoms of iron and 14.4 atoms of acid-labile sulfur/molecule and had E400, 52.5 mM-1.cm-1. The purified hydrogenase showed a specific activity of 62 kU/mg of protein in the H2-uptake assay, and the H2-uptake activity was higher than H2-evolution activity. The enzyme isolated under aerobic conditions required incubation under reducing conditions to express its maximum activity both in the H2-uptake and 2H2/1H2 exchange reaction. The ratio of the activity of activated to as-isolated hydrogenase was approximately 3. EPR studies allowed the identification of two ferredoxin-type [4Fe-4S]1+ clusters in hydrogenase samples reduced by hydrogen. In addition, an atypical cluster exhibiting a rhombic signal (g values 2.10, 2.038, 1.994) assigned to the H2-activating site in other [Fe]-hydrogenases was detected in partially reduced samples. Molecular properties, EPR spectroscopy, catalytic activities with different substrates and sensitivity to hydrogenase inhibitors indicated that D. desulfuricans ATCC 7757 periplasmic hydrogenase is a [Fe]-hydrogenase, similar in most respects to the well characterized [Fe]-hydrogenase from D. vulgaris Hildenborough.

Measurement of N-acetyl-beta-glucosaminidase and its isoenzymes in urine methods and clinical applications.

Abstract: 1. N-Acetyl-beta-glucosaminidase is the most widely used urinary enzyme assay for the assessment of renal disease and the detection of nephrotoxicity. 2. An increase in N-acetyl-beta-glucosaminidase activity in urine is a sensitive test for renal tubular damage, since its relative molecular mass (M(r) > 130,000) precludes its filtration by the glomerulus and it is the most active of the glycosidases found in the lysosomes in the proximal tubule. 3. The analytical methods available for the determination of urinary N-acetyl-beta-glucosaminidase include fluorometric, colorimetric, spectrophotometric and a dipstick test. 4. The isoenzyme profile of N-acetyl-beta-glucosaminidase in urine varies at different stages of renal disease and damage. In particular there are increases in the B and I2 forms which may reflect perturbation of the cellular biosynthetic processes. 5. The value of N-acetyl-beta-glucosaminidase assays in various areas of medicine is briefly discussed and attention paid to its future role.