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J Kay

Publications and source records attributed to J Kay.

At least 19 recordsLinked to original sources
PubMed2004

The new materials processing beamline at the SRS Daresbury, MPW6.2.

A new beamline (MPW6.2) has been designed and built for the study of materials during processing where three synchrotron techniques, SAXS, WAXS and XAS, are available simultaneously. It has been demonstrated that Rietveld refinable data can be collected from silicon SRM 640b over a 60 degrees range in a time scale of 1 s. The data have been refined to a chi(2) of 2.4, the peaks fitting best to a Pearson VII function or with fundamental parameters. The peak halfwidths have been found to be approximately constant at 0.06 degrees over a 120 degrees angular range indicating that the instrumental resolution function has matched its design specification. A quantitative comparison of data sets collected on the same isotactic polypropylene system on MPW6.2 and DUBBLE at the ESRF shows a 17% improvement in angular resolution and a 1.8 improvement in peak-to-background ratio with the RAPID2 system; the ESRF data vary more smoothly across detector channels. The time-dependent wide-angle XRD was tested by comparing a hydration reaction of gypsum-bassanite-anhydrite with energy-dispersive data collected on the same system on the same time scale. Three sample data sets from the reaction were selected for analysis and gave an average chi(2) of 3.8. The Rietveld-refined lattice parameters are a good match with published values and the corresponding errors show a mean value of 3.3 x 10(-4). The data have also been analysed by the Pawley decomposition phase-modelling technique demonstrating the ability of the station to quickly and accurately identify new phases. The combined SAXS/WAXS capability of the station was tested with the crystallization and spinodal decomposition of a very dilute polymer system. Our measurements show that the crystallization of a high-density co-polymer (E76B38) as low as 0.5% by weight can be observed in solution in hexane. The WAXS and SAXS data sets were collected on the same time scale. The SAXS detector was calibrated using a collagen sample that gave 30 orders of diffraction in 1 s of data collection. The combined XRD and XAS measurement capability of the station was tested by observing the collapse and re-crystallization of zinc-exchanged zeolite A (zeolite Zn/Na-A). Previous studies of this material on station 9.3 at the SRS were compared with those from the new station. A time improvement of 38 was observed with better quality counting statistics. The improved angular resolution from the WAXS detector enabled new peaks to be identified.

Equipment Design↗
PubMed2004

The role of interleukin-1 in the pathogenesis of rheumatoid arthritis.

A significant body of experimental evidence has implicated the proinflammatory cytokine IL-1 in the pathogenesis of RA. For example, IL-1beta overexpression in rabbit knee joints causes arthritis with clinical and histological features characteristic of RA, whereas IL-1 deficiency is associated with reduced joint damage. In experimental models, IL-1 blockers, including IL-1 receptor antagonist (IL-1Ra), significantly reduce clinical and histological disease parameters. In RA patients, plasma and synovial fluid concentrations of IL-1 are elevated, and these correlate with various parameters of disease activity. The production of endogenous IL-1Ra, however, appears to be insufficient to balance these higher IL-1 levels. The efficacy of blocking IL-1 in patients with active RA has been established in controlled clinical trials of anakinra, a recombinant human IL-1Ra (r-metHuIL-1ra). When used alone or in combination with methotrexate, anakinra significantly reduces the clinical signs and symptoms of RA compared with placebo. Taken together, these results indicate that IL-1 plays an important role in the pathogenesis of RA.

Animals↗
PubMed2003

Hepatic control of perfusate homeostasis during normothermic extrocorporeal preservation.

BACKGROUND: We investigated the ability of the isolated porcine liver to maintain acid-base homeostasis in the perfusate and the impact of ischemia-reperfusion injury without or with extracorporeal perfusion. METHODS: Harvested livers were either stored for 24 hours in cold University of Wisconsin solution or preserved by continuous, normothermic, oxygenated sanguineous perfusion with supplemental nutrition, prostacyclin, and bile salts. After a further 24-hour period of reperfusion of both groups on an extracorporeal circuit, the perfusate was assessed for both biochemical indices of synthetic and metabolic liver function as well as hepatocellular injury and blood gas analysis. RESULTS: Livers injured by cold ischemia during preservation displayed inferior synthetic and metabolic functions. Perfused livers, which displayed minimal ischemic injury, produced more bicarbonate than the cold-stored organs, suggesting autoregulation of pH homeostasis in perfused livers in contrast to progressively worsening acidosis in cold-stored organs. CONCLUSIONS: Given proper physiologic substrate the porcine liver has the ability to maintain acid-base homeostasis, provided there is not a significant ischemia-reperfusion injury.

Adenosine↗
PubMed2001

Exploring the relationship between proper name anomia and word retrieval: a single case study.

We report the results of an investigation of the spoken word retrieval abilities of a patient, BG, with proper name anomia. Our investigations reveal that she is impaired in retrieving common nouns as well as proper names. Common noun retrieval was influenced by age-of-acquisition, word familiarity and name agreement. Cued retrieval of proper names was influenced by age-of-acquisition, although effects of other linguistic variables were not excluded. It is claimed that an explanation in terms of a 'continuum of word retrieval difficulty' rather than of proper names as 'pure referring expressions' can best account for the findings. However, this proposal is unlikely to be able to explain all cases of proper name anomia. Nonetheless, it is suggested that similar findings may be observed in other people with proper name anomia, and that it is necessary for future studies to investigate not only proper name but also common noun retrieval. We also provide evidence that Plausible Phonology and Specificity hypotheses of proper name anomia cannot account for BG's naming abilities.

Aged↗
PubMed2001

Aspartic proteases of Plasmodium falciparum and other parasitic protozoa as drug targets.

All parasitic protozoa contain multiple proteases, some of which are attracting attention as drug targets. Aspartic proteases are already the targets of some clinically useful drugs (e.g. chemotherapy of HIV infection) and a variety of factors make these enzymes appealing to those seeking novel antiparasite therapies. This review provides a critical analysis of the current knowledge on Plasmodium aspartic proteases termed plasmepsins, proposes a definitive nomenclature for this group of enzymes, and compares these enzymes with aspartic proteases of humans and other parasitic protozoa. The present status of attempts to obtain specific inhibitors of the parasite enzymes that will be useful as drugs is outlined and suggestions for future research priorities are proposed.

Amino Acid Sequence↗
PubMed2001

Regulation of human and mouse procathepsin E gene expression.

Cathepsin E is an intracellular aspartic proteinase that is considered to have a number of physiological roles including antigen processing. Quantitation of procathepsin E mRNA by LightCyclertrade mark technology indicated that the gene was transcribed in lung but not in kidney of both human and mouse origin. In contrast, the transcript was present in mouse spleen and alveolar macrophages but not in the counterpart tissue/cells from humans. Regulation of human and mouse procathepsin E gene expression was shown not to be influenced by the extent of CpG methylation but depended on the recognition of potential binding motifs in each promoter region by transcription factors such as GATA1, PU1 and YY1, as revealed by functional analysis using a series of promoter/luciferase reporter gene fusion constructs. Thus the extent to which the procathepsin E gene is expressed in a particular cell type may depend on the balance between the effects produced by positive-acting, cell-specific transcription factors such as GATA1 and PU1 and the negative influence of the ubiquitous YY1 factor. In this way, the relative abundance and influence of general and cell-specific transcription factors can govern the production of cathepsin E and thereby account for the sporadic cell and tissue distribution of this enzyme in different species.

Animals↗
PubMed2001

beta(2)-Microglobulin modified with advanced glycation end products delays monocyte apoptosis.

BACKGROUND: A local inflammatory reaction to beta(2)-microglobulin (beta(2)m) amyloid deposits by monocytes/macrophages is a characteristic histologic feature of dialysis-related amyloidosis (DRA). Since beta(2)m modified with advanced glycation end products (AGE-beta(2)m) is a major constituent of amyloid in DRA, we tested the hypothesis that AGE-beta(2)m affects apoptosis and phenotype of human monocytes. METHODS: Human peripheral blood monocytes were incubated with or without in vitro-derived AGE-beta(2)m, and their viability, extent of apoptosis, morphology, and function examined over the subsequent four days. RESULTS: AGE-modified but not unmodified beta(2)m significantly delayed spontaneous apoptosis of human peripheral blood monocytes in adherent and nonadherent cultures. The effect of AGE-beta(2)m on monocytes apoptosis was time- and dose-dependent and was attenuated by a blocking antibody directed against the human AGE receptor (RAGE). There was no difference in effect between AGE-beta(2)m and that of AGE-modified human serum albumin. Culture of monocytes with AGE-beta(2)m did not alter membrane expression of Fas or Fas ligand. Monocytes cultured with AGE-beta(2)m underwent substantial changes in morphology similar to those observed when monocytes differentiate into macrophages. The cultured cells increased in size and vacuolization, and their content of beta-glucuronidase and acid phosphatase increased by 5- to 10-fold at day 4. Expression of the monocyte--macrophage membrane antigens HLA-DR, CD11b, and CD11c also increased at day 4. Although exhibiting phenotypic characteristics of macrophages, monocytes cultured with AGE-beta(2)m functioned differently than macrophages cultured with serum. Superoxide production in response to phorbol myristic acetate was maintained in monocytes cultured with AGE-beta(2)m, but declined with time in cells cultured with serum. Constitutive synthesis of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and prostaglandin E2 (PGE2) increased in monocytes cultured for four to six days with AGE-beta(2)m. CONCLUSIONS: These findings support a novel role for AGE-modified proteins such as AGE-beta(2)m that may contribute to the development of a local inflammatory response, with predominant accumulation of monocytes/macrophages, in DRA.

Antibodies↗
PubMed2001

The fate of integrated treatment: whatever happened to the biopsychosocial psychiatrist?

OBJECTIVE: The authors suggest that pharmacotherapy and psychotherapy, the major treatment modalities in psychiatry, have become fragmented from one another, creating an artificial separation of the psychosocial and biological domains in psychiatry. METHOD: After a brief discussion of the economic factors influencing this trend, the authors provide a selective overview of recent research. In the absence of systematic empirical data regarding which patients and which conditions might benefit from integrated treatment by one psychiatrist, the authors propose specific clinical situations that call for such integration and also discuss concerns about cost-effectiveness. RESULTS: Recent research suggests that combining psychotherapy and pharmacotherapy may have advantages over either treatment alone in certain clinical situations involving specific disorders. While few of the studies on combined treatment have tested whether a one-person or two-person model of treatment provision is more effective, there are a number of advantages to the one-person treatment model in which a psychiatrist conducts the psychotherapy and prescribes medication for the same patient. CONCLUSIONS: The authors suggest that further research is needed to clarify the optimal situations for the one-person model of integrated treatment and also propose systematic teaching of integrated treatment in all residency training programs.

Biological Psychiatry↗
PubMed2001

Geochemistry of acid mine contamination-aquifer interactions.

The Pinal Creek Basin near Globe, Arizona, is an example of a groundwater/surface water system contaminated by wastes from historic metal mining practices. Acidic mining wastes that have leached into the regional aquifer have come in contact with alluvial sediments, dissolving manganese oxides and precipitating iron sulfato-hydroxides. Manganese is reoxidized in sediments of a perennial stream (Pinal Creek) formed as the aquifer thins and groundwater is forced to land surface. Iron and manganese in the system are inextricably linked through redox couples. These interactions, which produce reaction rates varying by orders of magnitude and non-stoichiometric release of manganese, are poorly understood. We have designed a flow-through reaction cell to obtain in situ real time X-ray adsorption spectroscopy (XAS) data during geochemical reactions. By coupling solution chemistry data with spectroscopic measurements, we were able to show that the spinel mineral, jacobsite, forms as a metastable intermediate phase during the reductive dissolution of manganese oxide (MnO2) by ferrous iron (Fe(II)). The production of Fe(III) followed by the precipitation of ferric hydroxides and the formation of the jacobsite phase, were responsible for reducing the rate of the reaction as time progressed. Laboratory studies have determined that Mn-oxidation in stream sediments increases Co, Ni, and Zn loading through a variety of processes, including oxidation, co-precipitation, solid solution formation, structural exchange, and/or sorption. This information provides a more complete picture of the controls on metal transport and attenuation in the Pinal Creek Basin.

Acids↗
PubMed2000

The potency and specificity of the interaction between the IA3 inhibitor and its target aspartic proteinase from Saccharomyces cerevisiae.

The yeast IA3 polypeptide consists of only 68 residues, and the free inhibitor has little intrinsic secondary structure. IA3 showed subnanomolar potency toward its target, proteinase A from Saccharomyces cerevisiae, and did not inhibit any of a large number of aspartic proteinases with similar sequences/structures from a wide variety of other species. Systematic truncation and mutagenesis of the IA3 polypeptide revealed that the inhibitory activity is located in the N-terminal half of the sequence. Crystal structures of different forms of IA3 complexed with proteinase A showed that residues in the N-terminal half of the IA3 sequence became ordered and formed an almost perfect alpha-helix in the active site of the enzyme. This potent, specific interaction was directed primarily by hydrophobic interactions made by three key features in the inhibitory sequence. Whereas IA3 was cut as a substrate by the nontarget aspartic proteinases, it was not cleaved by proteinase A. The random coil IA3 polypeptide escapes cleavage by being stabilized in a helical conformation upon interaction with the active site of proteinase A. This results, paradoxically, in potent selective inhibition of the target enzyme.

Amino Acid Sequence↗
PubMed2000

The aspartic proteinase from Saccharomyces cerevisiae folds its own inhibitor into a helix.

Aspartic proteinase A from yeast is specifically and potently inhibited by a small protein called IA3 from Saccharomyces cerevisiae. Although this inhibitor consists of 68 residues, we show that the inhibitory activity resides within the N-terminal half of the molecule. Structures solved at 2.2 and 1.8 A, respectively, for complexes of proteinase A with full-length IA3 and with a truncated form consisting only of residues 2-34, reveal an unprecedented mode of inhibitor-enzyme interactions. Neither form of the free inhibitor has detectable intrinsic secondary structure in solution. However, upon contact with the enzyme, residues 2-32 become ordered and adopt a near-perfect alpha-helical conformation. Thus, the proteinase acts as a folding template, stabilizing the helical conformation in the inhibitor, which results in the potent and specific blockage of the proteolytic activity.

Amino Acid Sequence↗
PubMed2000

Molecular organization, expression and chromosomal localization of the mouse pronapsin gene.

Napsins have been identified only very recently as new aspartic proteinases of the pepsin family. Isolation, sequencing and functional analysis of the mouse genomic locus indicates that the organization of the pronapsin gene into nine exons is identical to that of other mammalian aspartic proteinase precursors, including pepsinogen. However, the additional C-terminal residues, which are a distinguishing feature of napsins, are encoded within exon 9 and not within an additional exon. Quantitation of pronapsin mRNA using RT-PCR indicates that the gene is transcribed in lung, kidney and spleen but not in heart. Regulation of gene expression was not influenced by the extent of CpG methylation but depended on the recognition of potential binding motifs in the promoter region by specific transcription factors such as YY-1. The single copy of the mouse pronapsin gene was located on chromosome 7. In humans, there are two pronapsin genes and, based on the mouse information, preliminary structures were deduced for these from sequences in the human genome databases. They appear to be located together on chromosome 19.

Amino Acid Sequence↗
PubMed2000

Comparison of orbital colour Doppler findings with computed tomography angiography.

Colour Doppler imaging (CDI) of orbital vessels is noninvasive but may be fallacious, while computed tomography (CT) angiography displays a visual outline of orbital vessels. We compared clinical findings of the two methods in 33 patients with a wide variety of clinical conditions. It was not possible to visualize the central retinal arteries with CT angiography, but it was possible to show the intracranial carotid, which CDI could not. Changes in the ophthalmic arteries on CDI usually showed changes in calibre on CT angiography. Patients with unexplained or gross visual loss often showed marked abnormalities on CT scanning, not entirely consistent with the clinical picture. Several patients showed marked ectasia of the intracranial carotid along with variable clinical findings. Findings on CT angiography complement and augment those on CDI, and are likely to be more clinically valuable in the future.

Adult↗
PubMed2000

Osteoarticular disorders of renal origin: disease-related and iatrogenic.

Osteoarticular disorders significantly limit the quality of long-term survival with chronic renal failure. beta 2M amyloidosis is a complication of chronic renal failure that has been recognized mostly in patients receiving long-term haemodialysis. Patients with beta 2M amyloidosis typically present with the triad of shoulder periarthritis, carpal tunnel syndrome, and flexor tenosynovitis of the hands. Other musculoskeletal manifestations of beta 2M amyloidosis include destructive spondyloarthropathy, cervico-occipital pseudotumours, bone cysts, and pathological fractures. At present, only renal transplantation may slow or halt the progession of beta 2M amyloidosis. Crystal-induced arthropathy, most commonly caused by basic calcium phosphate crystals, is an important cause of acute joint inflammation in the patient with renal failure. The incidence of bone and joint infection is increased in patients undergoing dialysis. Haemodialysis and peritoneal dialysis are also associated with an erosive or destructive arthropathy of finger joints, which is not explained by local amyloid deposition.

Amyloidosis↗
PubMed2000

Effect of posture and isoproterenol on beat-to-beat heart rate and QT variability.

RATIONALE: Recent literature emphasizes the utility of QT variability to study ventricular electrophysiologic function. In this investigation, we sought to test the hypothesis that beat-to-beat fluctuations in QT intervals are mediated by sympathetic activity in normal subjects using postural challenge and isoproterenol infusions. SUBJECTS AND METHODS: We obtained ECG in the supine and standing postures during spontaneous breathing, at 12, 15 and 20 per minute controlled breathing (n = 19), and before and after infusions of isoproterenol, a beta-adrenergic agent, in the supine posture during spontaneous breathing (n = 11) using lead II configuration in healthy human adult subjects. Heart rate (HR) and QT time series data were analyzed by spectral analysis of 256 s of real-time data. Beat-to-beat QT intervals were measured by automated analysis of ECG. A QT variability index (QT(vi)) was calculated for each subject as the logarithm of the ratio of normalized QT variance to normalized HR variance. We also calculated fractal dimensions of QT time series during spontaneous breathing. RESULTS: QT(vi) was significantly higher in the standing than in the supine posture (-1. 93 +/- 0.27 vs. -1.47 +/- 0.41; p = 0.0001), and also during isoproterenol infusions in the supine posture (-1.83 +/- 0.39 vs. -1. 27 +/- 0.43; p = 0.0001). Fractal dimensions of QT time series were also significantly higher during standing (p = 0.00001) and isoproterenol infusions (p = 0.0002). Respiratory rate or tidal volume did not account for the increased QT variability seen in the standing posture. CONCLUSIONS: A change from the supine to the standing posture as well as infusion of isoproterenol significantly increased the absolute as well as normalized QT variability, which appears to be due to an increase in sympathetic activity associated with these conditions.

Adult↗
PubMed1999

Naturally-occurring and recombinant forms of the aspartic proteinases plasmepsins I and II from the human malaria parasite Plasmodium falciparum.

Comparable kinetic parameters were derived for the hydrolysis of peptide substrates and the interaction of synthetic inhibitors with recombinant and naturally-occurring forms of plasmepsin II. In contrast, recombinant plasmepsin I was extended by 12 residues at its N-terminus relative to its naturally-occurring counterpart and a 3-10-fold diminution in the k(cat) values was measured for substrate hydrolysis by the recombinant protein. However, comparable Ki values were derived for the interaction of two distinct inhibitors with both forms of plasmepsin I, thereby validating the use of recombinant material for drug screening. The value of plasmepsin I inhibitors was determined by assessing their selectivity using human aspartic proteinases.

Amino Acid Sequence↗