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Biomedical subjects

M Riley

Publications and source records attributed to M Riley.

At least 19 recordsLinked to original sources
PubMed2000

Crystal structure of native chicken fibrinogen at 5.5-A resolution.

The crystal structure of native chicken fibrinogen has been determined at a resolution of 5.5 A. The full-length molecule is 460 A in length and sigmoidally shaped. The structure includes the full sweep of the coiled coils that connect the central and terminal domains; the chain paths of the central domain confirm a predicted scheme of planar disulfide rings in apposition with each other. Electron density maps have revealed the outlines of disordered alphaC domains nestled within the confines of the sinuous coiled coils. The amino-terminal segments of the alpha- and beta-chains, including the fibrinopeptides A and B, are also disordered.

Animals↗
PubMed2000

Kinetics and mechanism of the citrate synthase from the thermophilic archaeon Thermoplasma acidophilum.

The kinetics and mechanism of the citrate synthase from a moderate thermophile, Thermoplasma acidophilum (TpCS), are compared with those of the citrate synthase from a mesophile, pig heart (PCS). All discrete steps in the mechanistic sequence of PCS can be identified in TpCS. The catalytic strategies identified in PCS, destabilization of the oxaloacetate substrate carbonyl and stabilization of the reactive species, acetyl-CoA enolate, are present in TpCS. Conformational changes, which allow the enzyme to efficiently catalyze both condensation of acetyl-CoA thioester and subsequently hydrolysis of citryl-CoA thioester within the same active site, occur in both enzymes. However, significant differences exist between the two enzymes. PCS is a characteristically efficient enzyme: no internal step is clearly rate-limiting and the condensation step is readily reversible. TpCS is a less efficient catalyst. Over a broad temperature range, inadequate stabilization of the transition state for citryl-CoA hydrolysis renders this step nearly rate-limiting for the forward reaction of TpCS. Further, excessive stabilization of the citryl-CoA intermediate renders the condensation step nearly irreversible. Values of substrate and solvent deuterium isotope effects are consistent with the kinetic model. Near its temperature optimum (70 degrees C), there is a modest increase in the reversibility of the condensation step for TpCS, but reversibility still falls short of that shown by PCS at 37 degrees C. The root cause of the catalytic inefficiency of TpCS may lie in the lack of protein flexibility imposed by the requirement for thermal stability of the protein itself or its temperature-labile substrate, oxaloacetate.

Acetyl Coenzyme A↗
PubMed2000

The EcoCyc and MetaCyc databases.

EcoCyc is an organism-specific Pathway/Genome Database that describes the metabolic and signal-transduction pathways of Escherichia coli, its enzymes, and-a new addition-its transport proteins. MetaCyc is a new metabolic-pathway database that describes pathways and enzymes of many different organisms, with a microbial focus. Both databases are queried using the Pathway Tools graphical user interface, which provides a wide variety of query operations and visualization tools. EcoCyc and MetaCyc are available at http://ecocyc.PangeaSystems.com/ecocyc/

Database Management Systems↗
PubMed2000

Breastfeeding in early life and bone mass in prepubertal children: a longitudinal study.

The aim of this study was to determine whether breastfeeding in early life is associated with bone mass in prepubertal children. We studied 330 8-year-old male and female children from Southern Tasmania representing 47% of those who originally took part in a birth cohort study of risk factors for Sudden Infant Death Syndrome in 1988. Breastfeeding intention and habit were assessed in both 1988 and 1996. Bone mineral density was measured by dual-energy X-ray densitometry. Children who were breastfed had higher bone mineral density at the femoral neck (+0.20 SD, p = 0.07), lumbar spine (+0.25 SD, p = 0.03) and total body (+0.29 SD, p = 0.006) compared with those who were bottle-fed. This association with breastfeeding was present in children born at term (femoral neck: +0.26 SD, p = 0.05; lumbar spine: +0.34 SD, p = 0.007; total body: +0.41 SD, p = 0.0008) but not those born preterm, and remained significant after adjustment for size, lifestyle factors and socioeconomic factors. Breastfeeding for less than 3 months was not associated with increased bone mass at any site. In conclusion, this study has demonstrated a beneficial association between breastfeeding in early life and bone mass in 8-year-old children born at term, particularly those breastfed for 3 months or longer, which appears biological. If this association is confirmed in other populations and persists until the attainment of peak bone mass then the implication would be that osteoporosis prevention programs need to start very early in the life cycle.

Analysis of Variance↗
PubMed1999

Eco Cyc: encyclopedia of Escherichia coli genes and metabolism.

The EcoCyc database describes the genome and gene products of Escherichia coli, its metabolic and signal-transduction pathways, and its tRNAs. The database describes 4391 genes of E.coli, 695 enzymes encoded by a subset of these genes, 904 metabolic reactions that occur in E.coli, and the organization of these reactions into 129 metabolic pathways. The EcoCyc graphical user interface allows scientists to query and explore the EcoCyc database using visualization tools such as genomic-map browsers and automatic layouts of metabolic pathways. EcoCyc has many references to the primary literature, and is a (qualitative) computational model of E. coli metabolism. EcoCyc is available at URL http://ecocyc. PangeaSystems.com/ecocyc/

Classification↗
PubMed1999

An epidemic of burkholderia cepacia transmitted between patients with and without cystic fibrosis.

Burkholderia cepacia is an important pathogen in cystic fibrosis (CF) and an infrequent cause of nosocomial infection in non-CF patients. This report describes a large hospital outbreak that appeared to involve both patient groups, a previously unrecognized phenomenon. Ribotype restriction fragment length polymorphism (RFLP) profiles and pulsed-field gel electrophoresis-resolved macrochromosomal RFLPs were analyzed, a ribotype-based phylogenic tree was constructed, and case-control and cohort studies were performed. A single dominant clone was found in both CF and non-CF groups. Phylogenic analysis suggests that it has evolved independently and that such highly transmissible strains can emerge rapidly and randomly. Acquisition risk in the CF patients was linked to hospitalization (odds ratio=5.47, P=.0158, confidence interval=1. 28-26.86) and was associated with significantly increased mortality rates. Infection control policies must now consider this threat of transmission between non-CF and CF patients.

Adolescent↗
PubMed1999

Water fluoridation, bone mass and fracture: a quantitative overview of the literature.

OBJECTIVE: To use the technique of meta-analysis to address the following research questions: Is water fluoridation associated with altered fracture risk at a population level and are the differences between studies consistent with confounding or chance variation between studies? METHOD: The data sources utilised were Medline 1966-97, reviews and bibliographies. The search terms were fluoridation, bone mass and/or fracture. We included all observational studies published in English relating water fluoridation to bone mass and/or fracture in the initial assessment. RESULTS: Water fluoridation had no evident effect on fracture risk (RR 1.02, 95% CI 0.96-1.09, n = 18 studies). There was marked heterogeneity between studies which could be explained, in part, by the combination of gender, urbanicity and study quality (R2 0.25, p = 0.05, weighted analysis). CONCLUSIONS: Water fluoridation both at levels aimed at preventing dental caries and, possibly, at higher naturally occurring levels appears to have little effect on fracture risk, either protective or deleterious, at a population level. The small effect on bone mass seen in studies performed at the individual level is consistent with this finding. Variation between studies is also likely to be due to differences in the distribution of other recognised fracture risk factors between different populations. Confirmation of these findings is required in large studies performed at the individual level.

Analysis of Variance↗
PubMed1999

Maternal smoking during pregnancy, growth, and bone mass in prepubertal children.

There have been no studies of smoking during pregnancy and bone mineralization in children. The objective of this population-based longitudinal study was to determine whether maternal smoking during pregnancy is associated with bone mass and other growth variables in prepubertal children. We studied 330 8-year-old male and female children representing 47% of those who originally took part in a study of risk factors for Sudden Infant Death Syndrome in 1988. The main outcome measures were bone mineral density measured by a Hologic QDR2000 densitometer: birth weight, placental weight, height, and weight. Maternal smoking during pregnancy was associated with deficits in growth with these children having lower height (-1.53 cm, 95% confidence interval [CI] -3.03 to -0.03) and a trend to lower weight (-1.35 kg, 95% CI -2.75 to 0.11) at age 8. Furthermore, there was a disproportionate deficit in bone mass such that those children whose mothers smoked during pregnancy had lower size adjusted bone mass at the lumbar spine (-0.019 g/cm2, 95% CI -0.033 to -0.005) and femoral neck (-0.018 g/cm2, 95%CI -0.034 to -0.002) but not total body (-0.005 g/cm2, 95% CI -0.015 to 0.005). This association was only present for children born at term. Mothers who smoked during pregnancy also had lower placental weight (- 56 g, 95% CI -95 to -17), and further adjustment for placental weight led to nonsignificant results for smoking with both growth and bone parameters, suggesting that these associations may be mediated through placental size and function. Maternal smoking habit in 1996 was not significantly associated with bone mass at any site. In conclusion, this study has demonstrated a long-term negative association between maternal smoking during pregnancy and both growth and bone mass in children born at term, and suggests that the timing of exposure rather than the dose or duration is critical. If these associations are present in other populations and they persist until the attainment of peak bone mass, then our findings suggest that osteoporosis prevention programs should start very early in the life cycle.

Birth Weight↗
PubMed1998

Risk for valvular heart disease among users of fenfluramine and dexfenfluramine who underwent echocardiography before use of medication.

BACKGROUND: Because uncontrolled echocardiographic surveys suggested that up to 30% to 38% of users of fenfluramine and dexfenfluramine had valvular disease, these drugs were withdrawn from the market. OBJECTIVE: To determine the risk for new or worsening valvular abnormalities among users of fenfluramine or dexfenfluramine who underwent echocardiography before they began to take these medications. DESIGN: Cohort study. SETTING: Academic primary care practices. PATIENTS: 46 patients who used fenfluramine or dexfenfluramine for 14 days or more and had echocardiograms obtained before therapy. MEASUREMENTS: Follow-up echocardiography. The primary outcome was new or worsening valvulopathy, defined as progression of either aortic or mitral regurgitation by at least one degree of severity and disease that met U.S. Food and Drug Administration criteria (at least mild aortic regurgitation or moderate mitral regurgitation). RESULTS: Two patients (4.3% [95% CI, 0.6% to 14.8%]) receiving fenfluramine-phentermine developed valvular heart disease. One had baseline bicuspid aortic valve and mild aortic regurgitation that progressed to moderate regurgitation. The second patient developed new moderate aortic insufficiency. CONCLUSION: Users of diet medications are at risk for valvular heart disease. However, the incidence may be lower than that reported previously.

Adult↗
PubMed1998

Effects of changes in three catalytic residues on the relative stabilities of some of the intermediates and transition states in the citrate synthase reaction.

This work reports the relative importance of the interactions provided by three catalytic residues to individual steps in the mechanism of citrate synthase. When the side chains of any of the residues (H320, D375, and H274) are mutated, the data indicate that they are involved in the stabilization of one or more of the transition/intermediate states in the multistep citrate synthase reaction. H320 forms a hydrogen bond with the carbonyl of oxaloacetate and the alcohols of the citryl-coenzyme A and citrate products. Enzymes substituted at H320 (Q, G, N, and R) have reaction profiles for which the condensation reaction is cleanly rate determining. None of these mutants can activate the carbonyl of oxaloacetate by polarization. All these mutants catalyze the necessary proton transfer from the methyl group of acetyl-coenzyme A only poorly, a process which occurs in a structurally separate site. Furthermore, all H320 mutants hydrolyze the citryl-coenzyme A intermediate significantly more slowly than does the wild-type. D375 is the base removing the proton of acetyl-coenzyme A. D375E and D375G have greatly diminished ability to catalyze proton transfer from acetyl-CoA. The D375 mutants polarize the oxaloacetate carbonyl as well as wild-type. For D375E, the hydrolysis of citryl-CoA is rate determining. D375G, having no side chain capable of acid-base chemistry in either the condensation or hydrolysis reactions is nearly completely devoid of activity in any of the reactions catalyzed by the wild-type. H274 hydrogen bonds to the carbonyl of acetyl-coenzyme A but also forms the back wall of the oxaloacetate-binding site. H274G cannot properly activate either oxaloacetate or acetyl-coenzyme A, and the condensation reaction is overwhelmingly rate determining. Nonetheless, hydrolysis of the intermediate is impaired. All the enzymes except H320R and H274G show kinetic cooperativity with CitCoA as substrate, indicating changes in the subunit interactions with these latter two mutants. The energetics of citrate synthase are surprisingly tightly coupled. All changes affect more than one step in the catalytic cycle. Within the condensation reaction, the intermediate of proton transfer must occupy a shallow well between transition states close in free energy so that perturbations of one have substantial effects on that of the other.

Acetyl Coenzyme A↗
PubMed1998

Crystal structure of fragment double-D from human fibrin with two different bound ligands.

Factor XIII-cross-linked fragment D (double-D) from human fibrin was crystallized in the presence of two different peptide ligands and the X-ray structure determined at 2.3 A. The peptide Gly-Pro-Arg-Pro-amide, which is an analogue of the knob exposed by the thrombin-catalyzed removal of fibrinopeptide A, was found to reside in the gamma-chain holes, and the peptide Gly-His-Arg-Pro-amide, which corresponds to the beta-chain knob, was found in the homologous beta-chain holes. The structure shows for the first time that the beta-chain knob does indeed bind to a homologous hole on the beta-chain. The gamma- and beta-chain holes are structurally very similar, and it is remarkable they are able to distinguish between these two peptides that differ by a single amino acid. Additionally, we have found that the beta-chain domain, like its gamma-chain counterpart, binds calcium.

Crystallography, X-Ray↗
PubMed1998

EcoCyc: Encyclopedia of Escherichia coli genes and metabolism.

The encyclopedia of Escherichia coli genes and metabolism (EcoCyc) is a database that combines information about the genome and the intermediary metabolism of E.coli. The database describes 3030 genes of E.coli , 695 enzymes encoded by a subset of these genes, 595 metabolic reactions that occur in E.coli, and the organization of these reactions into 123 metabolic pathways. The EcoCyc graphical user interface allows scientists to query and explore the EcoCyc database using visualization tools such as genomic-map browsers and automatic layouts of metabolic pathways. EcoCyc can be thought of as an electronic review article because of its copious references to the primary literature, and as a (qualitative) computational model of E.coli metabolism. EcoCyc is available at URL http://ecocyc.PangeaSystems.com/ecocyc/

Computer Graphics↗
PubMed1998

Genes and proteins of Escherichia coli K-12.

GenProtEC is a database of Escherichia coli genes and their gene products, classified by type of function and physiological role and with citations to the literature for each. Also present are data on sequence similarities among E.coli proteins, representing groups of paralogous genes, with PAM values, percent identity of amino acids, length of alignment and percent aligned. GenProtEC can be accessed at the URL http://www.mbl.edu/html/ecoli.html

Bacterial Proteins↗
PubMed1998

Systems for categorizing functions of gene products.

As the sequencing of the total DNA of many organisms continues, attention is turning next to the interpretation of the function of all of the genes and gene products, with the aim of learning the full meaning of the entire genetic blueprint of a sequenced organism in concrete terms. To set the stage for accomplishing this, systems need to be constructed for the expression of the functions of gene products in systematic yet rich ways. As much as possible, the same systems should be applicable to all organisms, so that when comparability exists among organisms the connections will become clear.

Animals↗
PubMed1998

Exercise tolerance in asymptomatic elderly men with fluoroscopically detected coronary artery calcification.

STUDY OBJECTIVE: The value of detecting coronary artery calcification (CAC), by cardiac imaging, for the diagnosis of coronary artery disease (CAD) in asymptomatic middle-aged men has been demonstrated. However, the incidence of CAC increases with age. The functional significance of CAC remains unknown in asymptomatic elderly men. The purpose of this study is to explore whether CAC in asymptomatic aging men signifies the presence of cardiovascular dysfunction during exercise. DESIGN: This study was designed to address whether elderly asymptomatic men, selected because they have CAC, have reduced exercise tolerance due to functionally significant CAD. PARTICIPANTS AND SETTING: Thirty-eight asymptomatic male volunteers (ages 50 to 75 years, mean [+/-SD] 64+/-7 years) with a normal resting ECG and at least one coronary risk factor, in a population study. Nineteen subjects had CAC detected by digital subtraction fluoroscopy in at least two major coronary arteries, and 19 subjects had no identifiable CAC. METHODS AND RESULTS: Each subject underwent a symptom-limited incremental exercise test with 12-lead ECG monitoring and respiratory gas analysis. Four indexes of exercise oxygen transport were evaluated: peak oxygen uptake (VO2), lactic acidosis threshold, peak VO2/heart rate ratio, and VO2 relative to a work rate increase. Eleven of 38 subjects (28%) were found to have reduced oxygen transport, which was defined as an abnormal reduction in more than two of the above four indexes of oxygen transport. Five of the 11 subjects with reduced oxygen transport had CAC, and 6 subjects did not (not significant). Only one subject with CAC had exercise ST depression. CONCLUSION: Significant CAC in asymptomatic men over age 50 does not signify exercise limitation due to CAD.

Aged↗
PubMed1997

Differences in HDL cholesterol concentrations in Japanese, American, and Australian children.

BACKGROUND: Mortality from coronary heart disease is relatively low in Japan compared with other developed countries and has remained low despite an increasing standard of living and an apparent increase in mean plasma cholesterol concentration in adults over the past three decades. Important differences in childhood plasma lipoprotein profile might contribute to some of the difference in coronary heart disease mortality seen between Japan and both Australia and North America. METHODS AND RESULTS: Plasma HDL cholesterol and total cholesterol were surveyed in representative populations of schoolchildren in Australia, Japan, and Bogalusa, La. The mean concentration of plasma HDL cholesterol (but not total cholesterol) was higher for Japanese schoolchildren than for Australian or US schoolchildren (P<.001). In addition, the difference in plasma HDL cholesterol between the ages of 8 to 10 years and 12 to 15 years was much greater for Australian (boys, 15.2%; girls, 2.6%) and US (boys, 9.1%; girls, 2.7%) children than for their Japanese counterparts (boys, 4.2%; girls, 1.9%). An examination of potential explanatory factors revealed little difference in body mass index between samples, higher physical activity levels for the Japanese compared with the Australians, and substantial differences in dietary intake between Japanese and Australian schoolchildren. CONCLUSIONS: The relatively high ratio of plasma HDL cholesterol to total cholesterol in Japanese schoolchildren and the relatively small negative difference of plasma HDL cholesterol with age may help to explain why the coronary heart disease mortality rate in Japan is low compared with that in other developed countries.

Adolescent↗
PubMed1997

Use of record linkage between a statewide genetics service and a Birth Defects/Congenital Malformations Register to determine use of genetic counselling services.

The Birth Defects/Congenital Malformations Register of the Victorian Department of Human Services contains detailed, confidential information on over 2,000 babies born with a birth defect each year in Victoria, Australia, representing approximately 3% of the annual number of births. For 1991 and 1993, the type of anomaly was categorised as warranting a high, moderate, or low need of referral for genetic counselling, depending on risk of recurrence and possible genetic cause. The Victorian Clinical Genetics Service at the Murdoch Institute, Melbourne, offers free, centralised genetic counselling services for the entire state. A comparison of case records between the two agencies has shown little difference in overall use of genetic counselling between 1991 (17%) and 1993 (16%). Rate of uptake in the "high need" category improved only slightly during that period, from 40% in 1991 to 43% in 1993. Utilization of genetic counselling services did not vary disproportionately with mother's country of birth, but was higher for older mothers. As was expected, rates were highest when a baby was born at the only hospital that provides on-site genetic counselling services. Even where a statewide genetic counselling service is in place, it is disappointing that over half of those judged at high need for genetic counselling are not making use of this service. This study will provide baseline information to which future studies can be compared. Using the same study methodology, it will be possible to examine whether the uptake rate increases in accordance with increased genetic services.

Congenital Abnormalities↗