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Biomedical subjects

P England

Publications and source records attributed to P England.

At least 19 recordsLinked to original sources
PubMed2001

Plateau 'pop-up' in the great 1897 Assam earthquake.

The great Assam earthquake of 12 June 1897 reduced to rubble all masonry buildings within a region of northeastern India roughly the size of England, and was felt over an area exceeding that of the great 1755 Lisbon earthquake. Hitherto it was believed that rupture occurred on a north-dipping Himalayan thrust fault propagating south of Bhutan. But here we show that the northern edge of the Shillong plateau rose violently by at least 11 m during the Assam earthquake, and that this was due to the rupture of a buried reverse fault approximately 110 km in length and dipping steeply away from the Himalaya. The stress drop implied by the rupture geometry and the prodigious fault slip of 18 +/- 7 m explains epicentral accelerations observed to exceed 1g vertically and surface velocities exceeding 3 m s-1 (ref. 1). This quantitative observation of active deformation of a 'pop-up' structure confirms that faults bounding such structures can penetrate the whole crust. Plateau uplift in the past 2-5 million years has caused the Indian plate to contract locally by 4 +/- 2 mm yr-1, reducing seismic risk in Bhutan but increasing the risk in northern Bangladesh.

Journal Article↗
PubMed2000

Neutralizing human anti crotoxin scFv isolated from a nonimmunized phage library.

Combinatorial phage display technology offers a new possibility for making human antibodies which could be used in immune therapy. We explored the use of this technology to make human scFvs specific for crotoxin, the main toxic component of the venom of the South-American rattlesnake Crotalus durissus terrificus. Crotoxin, a phospholipase A2 neurotoxin constituted by the association of two subunits, exerts its lethal action by blocking neuromuscular transmission. This is the first report of human anticrotoxin scFvs (scFv 1, scFv 6 and scFv 8) isolated from a naive library of more than 1010 scFv clones with in vivo neutralizing activity. Nevertheless, differences are observed at the level of biological and immunological effects. Only scFv 8 is able to reduce the myotoxicity induced by crotoxin and scFv 1 is capable of altering the in vitro enzymatic activity of this toxin. All three scFvs recognize a region of one subunit located at the junction with the other one. Moreover these scFvs share strong amino acid homologies at the level of either the heavy or the light chain. Taken together, our results suggest that the use of human anticrotoxin scFvs may lead to a new and less aggressive passive immune therapy against poisoning by the venom of Crotalus durissus terrificus.

Amino Acid Sequence↗
PubMed2000

A prospective management study of slow-release aspirin in the palliation of uteroplacental insufficiency predicted by uterine artery Doppler at 20 weeks.

OBJECTIVE: To investigate the effect of low-dose, slow-release aspirin in reducing the incidence and/or severity of pregnancy complications in women identified as high risk of developing problems associated with uteroplacental insufficiency, namely pre-eclampsia or delivering a small-for-gestational age (SGA) baby. DESIGN: A prospective, randomized management study. One thousand and twenty-two women of mixed parity underwent color flow/pulsed Doppler (CFPD) imaging of the uterine arteries at the time of the 17-23 week (mean 19.9) anomaly scan. Women who were screen positive were randomized to a control or treatment group. The treatment group was given 100-mg slow-release aspirin (Disprin CV) daily and followed up at regular intervals. Women in the routine group received routine antenatal care. Main outcome measures were pre-eclampsia and SGA < 3rd centile. Secondary outcome measures were: SGA < 10th centile, pre-eclampsia requiring delivery before 34 weeks, placental abruption, an Apgar score < 7 at 5 min, admission to neonatal intensive care unit or a pregnancy that resulted in a stillbirth or neonatal death. Odds ratios (OR) with 95% confidence intervals (CI) were calculated for severe and any complications. RESULTS: Two hundred and sixteen women were screen positive according to the defined criteria. One hundred and three women were assigned to the treatment group and 113 to the control group. The difference in the incidence of pre-eclampsia and SGA < 3rd centile between the control and treatment groups did not reach statistical significance. There was a statistically significant reduction in any (OR 0.41 (CI 0.35-0.45), P < 0.01) and severe pregnancy complications (OR 0.43 (CI 0.21-0.84), P < 0.05) in the treatment group compared with the controls. CONCLUSIONS: The administration of slow-release aspirin to women identified as high risk, using color Doppler imaging of the uterine arteries at 20 weeks' gestation, did not significantly alter the incidence of pre-eclampsia or delivery of a SGA baby. It did, however, improve the outcome by reducing the overall incidence of complications associated with uteroplacental insufficiency.

Adult↗
PubMed2000

A new visual identity for the National Health Service.

The following article gives a brief overview of the new visual identity being adopted by the National Health Service in England. It looks at the thinking behind the identity, the identity's component parts and provides sources for obtaining further information on the identity's application. It is compiled from a presentation by Stephanie Hood from the corporate identity team of the NHS Executive communications unit given on 22nd October 1999 at the National Designers in Health Network seminar, Time-out '99, Sheffield. Supporting information was obtained from the NHS Communications website http:¿nww.doh.nhsweb.uk/commsnet.

Guidelines as Topic↗
PubMed1999

Fluid flow in chondritic parent bodies: deciphering the compositions of planetesimals

Alteration of the Allende meteorite caused shifts in oxygen isotope ratios along a single mass fractionation line. If alteration was caused by aqueous fluid, the pattern of oxygen isotope fractionation can be explained only by flow of reactive water down a temperature gradient. Down-temperature flow of aqueous fluid within planetesimals is sufficient to explain the mineralogical and oxygen isotopic diversity among CV, CM, and CI carbonaceous chondrites and displacement of the terrestrial planets from the primordial slope 1. 00 line on the oxygen three-isotope plot.

Journal Article↗
PubMed1999

Functional characterization of the somatic hypermutation process leading to antibody D1.3, a high affinity antibody directed against lysozyme.

The impact of somatic hypermutation on the affinity of Abs directed against protein Ags remains poorly understood. We chose as a model the secondary response Ab D1.3 directed against hen egg lysozyme. During the maturation process leading to this Ab, five replacement somatic mutations occurred. After reconstituting the germline Ab from which D1.3 originated, we assessed the energetic and kinetic importance of each of the somatic mutations, individually or combined, using the BIAcore apparatus. We found that the mutations induced an overall 60-fold improvement of affinity, principally due to a decrease in the kinetic rate of dissociation. We showed that their effects were additive and context independent; therefore, in the case of D1.3, the order in which somatic mutations were introduced and selected is unimportant. Interestingly, most of the affinity improvement was due to a single somatic mutation (Asn50-->Tyr in VL), involving a residue that belongs to the functional interface between Ab D1.3 and lysozyme. This replacement could either establish new Van der Waals contacts between the Ab and the Ag or help stabilize the conformation of a closely situated crucial residue of the Ab paratope. The four other mutations played only a marginal part in affinity maturation; potential reasons for which these mutations were nevertheless selected are discussed.

Animals↗
PubMed1999

Miniaturized FRET assays and microfluidics: key components for ultra-high-throughput screening.

Assay miniaturization applicable across a wide range of target classes, along with automation and process integration, are well-recognized goals for ultra-high-throughput screening on an industrial scale. This report summarizes the implementation of fluorescence resonance energy transfer (FRET)-based biochemical and cell-based assays in 3456-well NanoWelltrade mark assay plates using key components of Aurora's ultra-high-throughput screening system.

Journal Article↗
PubMed1998

The rate of dissociation between antibody and antigen determines the efficiency of antibody-mediated antigen presentation to T cells.

We analyzed the role of Ab affinity on Ab-mediated Ag uptake and presentation to T cells. Hen egg white lysozyme (HEL) was captured by bifunctional hybrid proteins (Fv-MalE) in which the variable fragment (Fv) of the anti-HEL mAb D1.3 was covalently linked to the Escherichia coli MalE protein. These complexes were targeted via two anti-MalE mAbs to an APC expressing a receptor for the Ab constant region. The combination of Fv-MalE and anti-MalE mAbs increased, specifically, HEL presentation. With this experimental system, we evaluated the impact of six different mutations, affecting the Fv-MalE complementarity determining regions, on the increase of HEL presentation by the corresponding hybrids. These mutations increase the dissociation rate constant (k(off)), and, thus, the dissociation constant of the HEL/Fv-MalE interaction, up to 650-fold, as compared with the wt Fv-MalE. Increasing the k(off) from 7 x 10(-4) s(-1) up to 300 x 10(-4) s(-1) did not interfere with the enhancement of HEL presentation. A mutant with a k(off) of 600 x 10(-4) s(-1) had a reduced enhancement ability, and mutants with k(off) higher than 5700 x 10(-4) s(-1) did not enhance HEL presentation at all. These results show that affinity determines the efficiency of Ab-mediated Ag presentation to T cells. One consequence is that affinity maturation in specific B lymphocytes can drastically enhance their ability to collaborate with T cells in an MHC-restricted way. This may contribute to the selection of high affinity B cell clones.

ATP-Binding Cassette Transporters↗
PubMed1998

The role of color Doppler imaging of the uterine arteries at 20 weeks' gestation in stratifying antenatal care.

OBJECTIVE: To determine the value of one-stop color Doppler imaging of the uterine arteries at the time of the 20-week anomaly scan, to select women at risk of developing pre-eclampsia and intrauterine growth restriction (IUGR). PATIENTS AND METHODS: A total of 1022 unselected women had color Doppler imaging of both uterine arteries at the time of their dating/anomaly scan (19-21 weeks' gestation). The presence or absence of notching of the flow velocity waveform (FVW) was noted, and the resistance index (RI) was measured. The main outcome measures were pre-eclampsia, birth weight, placental abruption and stillbirth. RESULTS: The outcome in 946 women (92.6%) was available for analysis. Of these, 216 (23%) had abnormal uterine artery Doppler studies, 117 (12.4%) with bilateral (right and left FVW) notches; 21 (2.2%) women developed pre-eclampsia, and 57 (6.0%) neonates were small for gestational age (SGA; < 5th centile), at birth. For women with bilateral notches the odds ratio (OR) for developing pre-eclampsia was 12.8 (95% confidence interval (CI) 5.3-30.8), and 52.6 (95% CI 6.4-430.1) for pre-eclampsia requiring delivery before 37 weeks' gestation. If the uterine artery Doppler studies were normal, the odds ratio for developing pre-eclampsia was 0.11 (95% CI 0.04-0.28), and 0.3 (95% CI 0.17-0.51) for the delivery of an SGA baby less than the 5th centile. In women with bilateral notches with mean RI greater than 0.55, the positive predictive value for the main outcome measures was 46%. CONCLUSION: Women with normal uterine artery color/pulsed Doppler studies at 20 weeks' gestation constitute a group that have a low risk of developing obstetric complications related to uteroplacental insufficiency. Women with high resistance in both uterine arteries (bilateral notches) have an increased risk of the subsequent development of such complications, in particular those requiring delivery before term. The addition of color Doppler imaging of the uterine arteries at the time of the routine 20-week dating/anomaly scan may be of use in determining the type and level of antenatal care that is offered to women.

Arteries↗
PubMed1997

Energetic and kinetic contributions of contact residues of antibody D1.3 in the interaction with lysozyme.

Fully functional variable fragments (Fv) of D1.3, a mouse antibody directed against the hen egg lysozyme, were readily produced as hybrids (Fv-MalE) with the maltose-binding protein of Escherichia coli and purified independently of their antigen-binding properties. We used site-directed mutations of residues in the complementarity-determining regions (CDRs) of D1.3 as local conformational probes, and compared their effects on the binding of Fv and Fv-MalE to lysozyme. We found that the MalE moiety did not significantly interfere with the interaction between the antigen and the antibody Fv fragment. We then determined the contribution of several potential contact residues of D1.3 in the interaction with lysozyme, by assaying the effect of site-directed mutations on the kinetics of association and dissociation of the complex between Fv-MalE and immobilized lysozyme, using the BIAcore apparatus. While the k(on) values were virtually unaffected by the mutations, the k(off) values varied by more than three orders of magnitude. Both charged (aspartate and arginine) and aromatic (tyrosine and tryptophan) residues in the CDR3 regions of the heavy and light chains of D1.3, which form the center of its antigen-combining site, played a preponderant part in the binding of lysozyme. Our results also showed that indirect hydrogen bonds, bridged by water molecules, contributed significantly to the interaction between D1.3 and lysozyme, and that their energy could be estimated at 1 to 2 kcal.mol-1.

ATP-Binding Cassette Transporters↗
PubMed1996

Antibiotic prophylaxis for patients undergoing transurethral resection of the prostate.

OBJECTIVES: To evaluate the prevention of urinary tract infections (UTIs) after transurethral resection of the prostate (TURP) in a prospective randomized study using a quinolone antibiotic (fleroxacin) to compare the efficacy of: (1) a single oral dose, (2) a single intravenous (IV) dose, and (3) an extended regimen consisting of an initial IV dose followed by oral therapy until removal of the urinary catheter, but for less than 6 days. METHODS: We excluded from study patients who received antimicrobial agents within 48 hours of surgery. Single-dose prophylaxis consisted of 400 mg of fleroxacin given either orally or intravenously. The extended regimen consisted of an initial 400 mg IV dose followed by 400 mg oral each day (patients older than 75 years, or with a creatinine clearance less than 40 mL/min, received 200 mg/day). UTI was defined as clinical evidence of infection plus the presence of more than 10 white blood cells (WBC)/mm3 in any urine specimen plus the presence of more than 10(4) cfu/mL in midstream urine specimens or more than 10(2) cfu/mL in catheter specimens. RESULTS: Prior to TURP, 30% (25/84) of the patients had a urethral catheter in situ and 12% (3/25) of these patients had bacteriuria. Only 1 patient developed a UTI and that was 22 days after a TURP (intergroup comparisons, Fisher's exact test greater than 0.05). There were no instances of urosepsis. CONCLUSIONS: A single oral dose of a fluoroquinolone agent provided optimum prophylaxis for patients undergoing TURP.

Administration, Oral↗
PubMed1996

The effect of the sex composition of jobs on starting wages in an organization: findings from the NLSY.

We show that individuals in a job with a higher percentage of females earn lower starting wages with an employing organization. This holds true with controls for individuals' human capital, job demands for skill or difficult working conditions, and detailed industry. We use a measure of sex composition that applies to detailed jobs: cells in a three-digit census occupation by three-digit census industry matrix. We use pooled panel data from the 1979-1987 waves of the National Longitudinal Survey of Youth. The unit of analysis is the spell-the time in which a person worked for one organization. The dependent variable is the first wage in the spell. We use models with fixed-effects to control for unmeasured, unchanging individual characteristics; we also show results from OLS and weighted models for comparison. The negative effect on wages of the percentage female in one's job is robust across procedures for black women, white women, and white men. For black men the sign is always negative but the coefficient is often nonsignificant.

Adult↗
PubMed1994

Apparent cooperativity for carbamoylphosphate in Escherichia coli aspartate transcarbamoylase only reflects cooperativity for aspartate.

The reaction catalyzed by Escherichia coli aspartate transcarbamoylase (ATCase) proceeds through an ordered mechanism, in which carbamoylphosphate binds first, followed by aspartate; upon binding of this second substrate, the enzyme undergoes a concerted transition from a low-affinity T state to a high-affinity R state. In various studies, conflicting results were obtained concerning the existence of positive cooperativity for the first substrate, carbamoylphosphate. It is shown here that cooperativity for this substrate is only apparent. Indeed, saturation curves for carbamoylphosphate display sigmoidicity only if the aspartate concentration used is high enough to shift ATCase into the R state. Furthermore, it is shown that succinate, an unreactive aspartate analogue which is able to promote the T-->R conformational transition, also induces the appearance of cooperativity for carbamoylphosphate. Similar results were obtained in the course of continuous-flow-dialysis experiments, which show that the binding of carbamoylphosphate is apparently cooperative only in the presence of a concentration of succinate high enough to shift the enzyme into the R state. Taken together, these data show that the apparent cooperativity for carbamoylphosphate is not an intrinsic property of ATCase, as it only reflects the cooperativity for the second substrate, aspartate, as a consequence of the process of ordered substrate binding.

Aspartate Carbamoyltransferase↗
PubMed1994

Involvement of the gamma-phosphate of UTP in the synergistic inhibition of Escherichia coli aspartate transcarbamylase by CTP and UTP.

The allosteric control of Escherichia coli aspartate transcarbamylase (ATCase) involves synergistic feedback inhibition by CTP and UTP. Previously reported results [England, P., & Hervé, G. (1992) Biochemistry 31, 9725-9732] suggest that this phenomenon relies entirely on interactions between the two neighboring allosteric sites, which belong to the same regulatory dimer. Furthermore, it has been demonstrated that UTP alone binds to the enzyme, but that it is only in the presence of CTP that this binding inhibits the catalytic activity. The properties of mutants in which the synergistic inhibition is totally abolished suggested that the terminal gamma-phosphate of the pyrimidine triphosphate nucleotides may play a crucial role in promoting site-site interactions within the regulatory dimer. In the present work, kinetic studies and binding experiments by continuous-flow dialysis were performed, using combinations of diphosphate and triphosphate nucleotides. The results obtained show that the gamma-phosphate lf UTP is indeed essential for synergistic inhibition to occur, as UDP is unable to inhibit ATCase activity, whether alone or in combination with CTP. On the contrary, the gamma-phosphate of CTP can be suppressed without modifying the inhibitory properties of this nucleotide and its synergy of action with UTP. These results indicate that the mutual effects of CTP and UTP on their respective binding are not symmetrical and that the signals emitted upon binding of the two triphosphate pyrimidine nucleotides to the regulatory sites do not follow the same pathway and involve different mechanisms.

Aspartate Carbamoyltransferase↗
PubMed1992

Synergistic inhibition of Escherichia coli aspartate transcarbamylase by CTP and UTP: binding studies using continuous-flow dialysis.

The allosteric control of Escherichia coli aspartate transcarbamylase (ATCase) involves feedback inhibition by both CTP and UTP, although it is only in the presence of CTP that UTP appears to inhibit the activity of the enzyme. In order to better understand the parts played by both pyrimidine nucleotides in this synergistic inhibition, binding studies were performed by continuous-flow dialysis and ultracentrifugation methods. The results obtained show that UTP binds to ATCase in the absence of CTP. Nevertheless, this binding does not induce any inhibition unless CTP is present. The mutual influence of CTP and UTP on their respective binding constants suggests that they bind to the same regulatory sites. However, the results obtained cannot be satisfactorily explained by a simple competition between the nucleotides, and it is shown that reciprocal affinity enhancements play a fundamental role. CTP enhances the affinity of UTP for the regulatory sites 80-fold, and conversely, UTP enhances the affinity of CTP 5-fold. Interestingly, the isolated regulatory subunits bind the two pyrimidine nucleotides following the same pattern as the entire enzyme. These observations indicate that the synergistic inhibition mechanism relies entirely on interactions between the two adjacent allosteric sites which belong to the same regulatory dimer.

Allosteric Regulation↗
PubMed1992

Testifying in criminal court: emotional effects on child sexual assault victims.

Child victims must cope not only with the emotional consequences of criminal acts but also with the potentially traumatizing effects of legal involvement. Dramatic increases in the reporting of child sexual abuse are bringing greater numbers of children into contact with the criminal justice system, raising fears that child victims of sex crimes will be further harmed by the courts. In the present study, the effects of criminal court testimony on child sexual assault victims were examined in a sample of 218 children. From this sample, the behavioral disturbance of a group of "testifiers" was compared to that of a matched control group of "nontestifiers" at three points following testimony: 3 months, 7 months, and after prosecution ended. At 7 months, testifiers evinced greater behavioral disturbance than nontestifiers, especially if the testifiers took the stand multiple times, were deprived of maternal support, and lacked corroboration of their claims. Once prosecution ended, adverse effects of testifying diminished. In courthouse interviews before and after testifying, the main fear expressed by children concerned having to face the defendant. Children who appeared more frightened of the defendant while testifying were less able to answer the prosecutors' questions; and later, after the cases were closed, they were more likely to say that testifying had affected them adversely. The two most pervasive predictors of children's experiences in the courtroom, however, were age and severity of abuse. Despite relevant laws, few innovative techniques were used to help the children testify. The results are discussed in relation to children's ability to cope with stressful situations, the interaction of the legal system with the child/family system, and debates about the need to protect child victims who testify in criminal court.

Adaptation, Psychological↗