High versus low dose cisplatin in epithelial ovarian cancer.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
C Williams
Publications and source records attributed to C Williams.
Inhibition of HIV infection by a novel CD4 domain 2-specific monoclonal antibody. Dissecting the basis for its inhibitory effect on HIV-induced cell fusion.
HIV use the CD4 molecule as their primary cellular receptor. Residues in the N-terminal domain (D1) of CD4 are crucial to HIV attachment through the gp120 envelope component. However, other regions of CD4 appear to be required subsequently for virus- and cell-cell fusion. Little is understood of the post-binding steps which may differ between HIV variants. We report a novel anti-CD4 mAb that does not block CD4/gp120 binding, but that does efficiently block both viral infection and cell-cell syncytia formation, and define its contact site as residues in CD4 D2 using both mouse/human CD4 chimeras and CD4 substitution mutants. We also investigated the basis for its antiviral effect. Using the CD4 D2 specific mAb, we identify another conserved step in HIV infection, as evidenced by its ability to neutralize a broad range of primary isolates and T cell-line passaged strains. Monovalent forms of the mAb were used to determine if its activity was due to masking of the D2 epitope, to steric inhibition, or bivalency. Our data indicate that both binding site and bivalency of the mAb underlie its potency. The need for bivalency is not simply explained by affinity, because monovalent forms can displace the intact mAb and reverse its protective effect. These results provide evidence that binding of the D2-specific mAb prevents structural alterations necessary for membrane fusion.
Animals↗
Lipoamide dehydrogenase from Azotobacter vinelandii: site-directed mutagenesis of the His450-Glu455 diad. Kinetics of wild-type and mutated enzymes.
Three amino acid residues in the active site of lipoamide dehydrogenase from Azotobacter vinelandii were replaced with other residues. His450, the active-site base, was replaced with Ser, Tyr or Phe. Pro451, from X-ray analysis found to be in cis conformation positioning the backbone carbonyl of His450 close to N3 of the flavin, was changed to Ala. Glu455, from X-ray analysis expected to be involved in modulating the pKa of the base (His450), was replaced with Asp and Gln. The general conclusion is that mutation of the His-Glu diad impairs intramolecular electron transfer between the disulfide/dithiol and the FADH-/FAD. The wild-type enzyme functions according to a ping-pong mechanism in the physiological reaction in which the formation of NADH is rate-limiting. Above pH 8.0 the enzyme is strongly inhibited by the product NADH. The pH dependence of the steady-state kinetics using the NAD+ analog 3-acetylpyridine adenine dinucleotide (AcPyAde+) reveals a pKa of 8.1 in the pKm AcPyAde+ plot indicating that this pKa is related to the deprotonation of His450 [Benen, J., Berkel van, W., Zak, Z., Visser, T., Veeger, C. & Kok de, A. (1991) Eur. J. Biochem. 202, 863-872] and to the inhibition by NADH. The mutations considerably affect turnover. Enzymes with the mutations Pro451----Ala, His450----Phe and His450----Tyr appear to be almost inactive in both directions. Enzyme His450----Ser is minimally active, V at the pH optimum being 0.5% of wild-type activity in the physiological reaction. Rapid reaction kinetics show that for the His450-mutated enzymes the reductive half reaction using reduced 6,8-thioctic acid amide [Lip(SH)2] is rate-limiting and extremely slow when compared using reduced 6,8-thioctic acid amide [Lip(SH)2] is rate-limiting and extremely slow when compared to the wild-type enzyme. For enzyme Pro451----Ala it is concluded that the loss of activity is due to over-reduction by Lip(SH)2 and NADH. The Glu455-mutated enzymes are catalytically competent but show strong inhibition by the product NADH (enzyme Glu455----Asp more than Glu455----Gln). The inhibition can largely be overcome by using AcPyAde+ instead of NAD+ in the physiological reaction. The rapid reaction kinetics obtained for enzymes Glu455----Asp and Glu455----Gln deviate from the wild-type enzyme. It is concluded that this difference is due to cooperativity between the active sites in this dimeric enzyme.(ABSTRACT TRUNCATED AT 400 WORDS)
Azotobacter vinelandii↗
Ovarian and cervical cancer.
Death rates from cervical cancer have already fallen this century and for patients with invasive cervical cancer five year survival rates are greater than for most solid tumours. Better screening for premalignant changes may further reduce the incidence of invasive cancer; indeed, it has been claimed that the reduction in mortality could be as high as 90%, though estimates of screening efficacy have varied greatly. For those with advanced invasive carcinoma neoadjuvant chemotherapy may reduce the risk of relapse and improve survival.
Combined Modality Therapy↗
Cloning of murine and rat vascular cell adhesion molecule-1.
Vascular cell adhesion molecule-1 (VCAM1) is a member of the immunoglobulin (Ig) superfamily which interacts with the integrin very late antigen 4 (VLA4). We have cloned the cDNAs for both murine and rat VCAM1 from endotoxin-treated lung libraries. Both sequences encode proteins with seven extracellular Ig-like domains, which show 75.9% and 76.9% identity, respectively, with human VCAM1. Both murine and human cell lines show VLA4-dependent binding to COS cells transiently expressing murine and rat VCAM1. Two mAbs, M-K/1 and M-K/2, which recognize an antigen on murine bone marrow stromal cell lines, bind to murine VCAM1 expressed in COS cells and block VCAM1-dependent adhesion, confirming that these mAbs recognize murine VCAM1.
Amino Acid Sequence↗
A role for IGF-1 in the rescue of CNS neurons following hypoxic-ischemic injury.
Three days after unilateral hypoxic-ischemic injury in infant rats insulin-like growth factor 1 (IGF-1) production by astrocytes was enhanced in the injured region. This was associated with increased expression of mRNA for IGF binding protein-3 but not for binding protein-1. In adult rats a single lateral cerebroventricular injection of IGF-1 two hours following a similar injury markedly reduced neuronal loss. It is suggested that endogenous IGF-1 is neurotrophic and that centrally administered IGF-1 may have therapeutic potential for brain injury.
Animals↗
Genotype analysis for delta F508, G551D and R553X mutations in children and young adults with cystic fibrosis with and without chronic liver disease.
Genetic factors have been implicated in the pathogenesis of liver disease in cystic fibrosis. To investigate whether liver disease is associated with particular mutations of the defective gene in cystic fibrosis, we have determined the frequencies of three mutations--delta F508, G551D and R553X--in 111 children and young adults with cystic fibrosis by analysis of genomic DNA segments amplified by the polymerase chain reaction. Twenty-nine patients had severe liver disease with portal hypertension, 19 had clinical and/or biochemical evidence of liver disease but no associated portal hypertension and 63 had no evidence of liver disease. No significant differences in the frequencies of the delta F508, G551D or R553X mutations in the three clinical subgroups were found, and we conclude that the development of liver disease in cystic fibrosis is unlikely to be associated with a specific mutation in the gene. However, because 27% of cystic fibrosis chromosomes do not have a defined mutation, this possibility cannot be ruled out. A familial concordance for clinical liver disease of 20% in this study, compared with a reported prevalence of 4.7%, suggests that genes outside the cystic fibrosis locus and/or environmental factors are involved in the pathogenesis of liver disease in cystic fibrosis.
Adolescent↗
Modelling bivariate relationships when repeated measurements are recorded on more than one subject.
This paper examines the problems of modelling bivariate relationships when repeated observations are recorded for each subject. The statistical methods required to test for a common group model were introduced using an example from exercise physiology, where the oxygen cost of running at four different speeds was recorded for a group of 30 recreationally active males. When data for each subject were studied individually, both the plots and correlations suggested the relationship to be linear. Hence, the homogeneity of the subjects' regression lines was compared using the appropriate ANOVA test. The analysis revealed a significant difference in the slopes and intercepts of the lines, thus precluding the use of a single linear model to represent the group. If the subjects were divided into two groups according to the median maximum oxygen consumption (VO2max), a multivariate analysis of variance of the slope and intercept parameters helped to explain some of this heterogeneity (P less than 0.05). However, for physiological rather than statistical reasons, it was necessary to re-analyse the data without the fourth running speed. The revised analysis suggested that the subjects' lines would be better modelled with a common slope but separate intercepts. As before, by dividing the subjects into two groups according to the median VO2max score, a simple t-test indicated that differences in the subjects' intercept parameters were not significant (P = 0.08). Notwithstanding the relatively homogeneous nature of the 30 subjects in terms of VO2max, the statistical methods showed that differences in running economy are, to some extent, dependent on VO2max.
Adolescent↗
Scaling physiological measurements for individuals of different body size.
This paper examines how selected physiological performance variables, such as maximal oxygen uptake, strength and power, might best be scaled for subject differences in body size. The apparent dilemma between using either ratio standards or a linear adjustment method to scale was investigated by considering how maximal oxygen uptake (l.min-1), peak and mean power output (W) might best be adjusted for differences in body mass (kg). A curvilinear power function model was shown to be theoretically, physiologically and empirically superior to the linear models. Based on the fitted power functions, the best method of scaling maximum oxygen uptake, peak and mean power output, required these variables to be divided by body mass, recorded in the units kg 2/3. Hence, the power function ratio standards (ml.kg-2/3.min-1) and (W.kg-2/3) were best able to describe a wide range of subjects in terms of their physiological capacity, i.e. their ability to utilise oxygen or record power maximally, independent of body size. The simple ratio standards (ml.kg-1.min-1) and (W.kg-1) were found to best describe the same subjects according to their performance capacities or ability to run which are highly dependent on body size. The appropriate model to explain the experimental design effects on such ratio standards was shown to be log-normal rather than normal. Simply by taking logarithms of the power function ratio standard, identical solutions for the design effects are obtained using either ANOVA or, by taking the unscaled physiological variable as the dependent variable and the body size variable as the covariate, ANCOVA methods.
Analysis of Variance↗
The effect of a high carbohydrate diet on running performance during a 30-km treadmill time trial.
The purpose of the present study was to examine the influence of a high carbohydrate diet on running performances during a 30-km treadmill time trial. Eighteen runners (12 men and 6 women) took part in this study and completed a 30-km time trial on a level treadmill without modifying their food intake (trial 1). The runners were then randomly assigned to a control or a carbohydrate (CHO) group. The CHO group supplemented their normal diets with additional carbohydrate in the form of confectionery products during the 7 days before trial 2; the control group matched the increased energy intake of the CHO group by consuming additional fat and protein. The mean (SEM) carbohydrate intake of both groups was 334 (22) g before trial 1, after which the CHO group consumed 566 (29) g.day-1 for the first 3 days and 452 (26) g.day-1 for the remaining 4 days of recovery. Although there was no overall difference between the performance times for the two groups during trial 2, the CHO group ran faster during the last 5 km of trial 2 than during trial 1 [3.64 (0.24) m.s-1 vs 3.44 (0.26) m.s-1; P less than 0.05]. Furthermore, the 6 men in the CHO group ran the 30 km faster after carbohydrate loading [131.0 (5.4) min vs 127.4 (4.9) min; P less than 0.05], whereas there was no such improvement in times of the men in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Words and actions: a study in nurse wastage.
This paper examines whether a group of nurses' stated intentions to leave were subsequently transformed into actual leaving actions. We argue that establishing the truth of relationships between words and actions is of fundamental importance in social science research. Nurses broadly did what they said they would do. Hence, definite intentions to leave were generally acted upon while less strong leaving intentions were not acted upon to any practically significant degree. We further investigate the link between the nurses' words and actions by reporting on a small interview study where nurses were asked why they did or did not do as they stated. The importance of these findings in terms of health authorities planning their labour force is discussed.
Attitude of Health Personnel↗
Hypoxia-ischemia induces transforming growth factor beta 1 mRNA in the infant rat brain.
Transforming growth factor beta 1 (TGF beta 1) mRNA expression was examined after hypoxia-ischemia in rat brains using in situ hybridization. Twenty-one-day-old Wistar rats had unilateral ligation of the right carotid artery followed by either 15 or 90 min inhalational hypoxia. Fifteen min of hypoxia resulted in moderate damage with selective neuronal loss in cortical layer 3 and in the hippocampus of the ligated hemisphere. Seventy-two hours after hypoxia TGF beta 1 expression was markedly increased above control levels in those sites. Levels were normal after 120 h. Ninety min of hypoxia led to an infarction of the lateral cerebral cortex and hippocampus of the ligated hemisphere. One hour after hypoxia TGF beta 1 mRNA was expressed in the hippocampus of the damaged side. Seventy-two and 120 h after hypoxia, expressing cells were found throughout the cerebral cortex, piriform cortex, striatum, thalamus and hippocampus of the infarcted side. These data show that TGF beta 1 mRNA expression is induced after a hypoxic-ischemic insult in the brain. TGF beta 1 may be involved in post-asphyxial repair mechanisms.
Animals↗
Accumulation of calcitonin-gene related peptide-like immunoreactivity after hypoxic-ischaemic brain injury in the infant rat.
Unilateral carotid ligation in immature rats, followed by either 15 min (moderate group) or 90 min (severe group) of hypoxia were used to assess the effects of hypoxia-ischaemia (HI) on the accumulation of the neuropeptide calcitonin-gene related peptide (CGRP). Severe, but not moderate, HI produced a massive time-dependent increase in CGRP-like immunoreactivity throughout the damaged regions of the brain (neocortex, caudate-putamen, hippocampus) beginning at 24 h and maximal at 3-5 days after HI. By 11 days after HI levels appeared to have returned to baseline. The increased immunoreactivity was largely localized to presumed axon terminals contacting neurons, blood vessels and non-nerve cells. Scattered neurons in the cingulate cortex, piriform cortex and striatum also showed increased immunoreactivity in their soma. These results raise the possibility that CGRP may be involved in neuronal repair after HI in the infant brain.
Animals↗
The diagnosis of Helicobacter pylori infection in uremic patients.
Two urease-based tests--the urease slide test and the radiolabeled urea breath test, are commonly used for the diagnosis of Helicobacter pylori infection of the stomach. The reliability of these tests in chronic uremia was compared with serological tests for H pylori antibodies, and with direct detection of the organism by microscopy or culture of gastric antral biopsies. Twenty-seven patients with chronic renal failure and dyspepsia underwent upper gastrointestinal endoscopy. Twelve of these patients (46%) were judged to be infected with H pylori on the basis of identification of the organism on microscopy or culture of antral biopsy. Both urease-based tests were able to determine H pylori status, despite the markedly increased concentrations of urea in the gastric juice found in chronic renal failure. The urease slide test performed on antral biopsies obtained at endoscopy proved reliable in determining H pylori status with no false-positive nor false-negative results after 20 minutes and 24 hours of incubation. The 14C-urea breath test also differentiated the infected from the uninfected patients. The 20-minute 14CO2 excretion (kg %dose/mmol CO2 x 100) ranged from 50 to 834 in the H pylori-infected patients, compared with 0.3 to 27 in the H pylori-noninfected patients (P < 0.0001); the 90-minute values ranged from 88 to 398 in the former, compared with 1 to 79 in the latter (P < 0.0001). The excretion of 14CO2 (derived from bacterial hydrolysis of ingested 14C-urea) was higher in all the uremic patients compared with nonuremic controls, and in half of the H pylori-noninfected uremic patients there was a late increase in 14CO2 excretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Computer simulation for teaching endoscopic procedures.
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Computer Graphics↗
Physiological and metabolic responses of men and women to a 5-km treadmill time trial.
Previous studies have reported strong correlations between 5-km performance times and maximal oxygen uptake (VO2 max) and also for running speeds equivalent to blood lactate concentrations of 4 mM. However, there is little information on the physiological responses of individuals during races over this distance. Therefore, the aim of the present study was to measure the physiological and metabolic responses of endurance trained male (n = 8) and female (n = 8) runners during a 5-km time trial using an instrumented treadmill. Performance times were 18.77 +/- 1.27 min for the men and 21.80 +/- 1.98 min for the women (P less than 0.01). The corresponding times on the athletics track were 17.68 +/- 0.39 min for the men (P less than 0.05) and 20.70 +/- 2.16 min for the women (N.S.). During the treadmill time trials, both the men and women were able to utilize approximately 90% VO2 max, 82% VE max, 98% HR max and produce similar concentrations of blood lactate. Although the physiological and metabolic responses of these endurance-trained men and women to 5-km treadmill running were similar, the faster running times recorded by the men in this study were the result of their higher VO2 max values.
Energy Metabolism↗
Production of human monoclonal antibodies specific for conformational and linear non-V3 epitopes of gp120.
Three IgG1 human monoclonal antibodies (MAbs) directed against conformational epitopes of the gp120 envelope protein of HIV-1 were produced, as was a single human MAb to a linear epitope spanning amino acids 487-509 in the C-terminal portion of gp120. All three conformation-dependent MAbs reacted optimally with recombinant gp120 (rgp120) captured on plastic via its carbohydrate moieties with Concanavalin A. These MAbs were able to block the interaction between recombinant CD4 (rCD4) and rgp120; they were also able to achieve 50% neutralization of HTLV-IIIB and MN strains of HIV-1 in a concentration range of 0.5-12.8 micrograms/mL. The MAb to the linear determinant is the first reported human MAb specific for the immunodominant portion of gp120; this MAb was most reactive with rgp120 when it was coated directly on plastic. It could neither inhibit rCD4-rgp120 binding nor neutralize either HTLV-IIIB or MN. The binding affinities of the four human MAbs for rgp120 in solution, reflected by their dissociation constants (Kd), ranged from 0.5 x 10(-8) to 7.5 x 10(-8) M.
Antibodies, Monoclonal↗
Steroid treatment in giant cell arteritis.
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Dose-Response Relationship, Drug↗