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Biomedical subjects

E Wallace

Publications and source records attributed to E Wallace.

At least 19 recordsLinked to original sources
PubMed2004

A cross-sectional survey to estimate the prevalence of family history of colorectal, breast and ovarian cancer in a Scottish general practice population.

A cross-sectional survey of all patients aged 30-65 in four general practices within one Local Health Care Co-operative in Fife, Scotland was undertaken to measure the prevalence of family history of colorectal, breast and ovarian cancer. A total of 7619 patients aged 30-65 responded to a postal questionnaire (response rate 59%). In all, 17% of respondents (1324, 95% Cl 16-18%) reported a relative affected by colorectal, breast or ovarian cancer. Of those, 6% (78, 95% CI 5-7%) met the Scottish guidelines for referral for genetics counselling. In all, 2% (24, 95% CI 1-3%) of all individuals with an affected relative had received genetic counselling and risk assessment. Of these, 25% (6, 95% CI 8-42%) met the moderate- or high-risk criteria for developing a cancer. In conclusion, the number of patients who are at a significantly increased risk of cancer on the basis of a family history is small (approximately 10 per General Practitioner (GP) list). It is therefore unrealistic to expect GPs to develop expertise in genetic risk estimation. A simple family history chart or pedigree is one way that a GP can, within the constraints of a GP consultation, determine which patients should be reassured and which referred to the local cancer genetic clinic.

Adult↗
PubMed2003

IL-11 and IL-11Ralpha immunolocalisation at primate implantation sites supports a role for IL-11 in placentation and fetal development.

Embryo implantation, endometrial stromal cell decidualization and formation of a functional placenta are critical processes in the establishment and maintenance of pregnancy. Interleukin (IL)-11 signalling is essential for adequate decidualization in the mouse uterus and IL-11 promotes decidualization in the human. IL-11 action is mediated via binding to the specific IL-11 receptor alpha (IL-11Ralpha). The present study examined immunoreactive IL-11 and IL-11Ralpha in cycling rhesus monkey endometrium, at implantation sites in cynomolgus and rhesus monkeys and in human first trimester decidua and defined distinct spatial and temporal patterns. In cycling rhesus monkey endometrium, IL-11 and IL-11Ralpha increased in both basalis and functionalis regions during the secretory compared with the proliferative phase, with changing cellular locations in luminal and glandular epithelium and stroma. The patterns were similar overall to those previously described in human endometrium. Differences were seen in immunostaining during implantation in cynomologus and rhesus monkey. In the cynomolgus, very little staining for IL-11 or IL-11Ralpha was seen in syncytio- and cyto-trophoblast cells in the villi between days 12 and 150 of pregnancy although there was moderate staining in cytotrophoblast in the shell between days 12 and 17 and in subpopulations of cytotrophoblast cells invading the arteries at day 17. By contrast in the rhesus monkey between days 24 and 35 of pregnancy and in human first trimester placenta, cyto- and syncytio-trophoblast in the villi but not cytotrophoblast in the shell were positively stained. The most intense staining for both IL-11 and IL-11Ralpha was present within the decidua in the maternal component of implantation sites in all three primates but moderate staining was also present in maternal vascular smooth muscle and glands perivascular cells and epithelial plaques. These results are consistent with a role for IL-11 both during decidualization and placentation in primates.

Animals↗
PubMed2001

Diaminoindanes as microsomal triglyceride transfer protein inhibitors.

The synthesis and biological activities of biarylamide-substituted diaminoindanes as microsomal triglyceride transfer protein (MTP) inhibitors are described. One of the more potent compounds, 8aR, inhibited both the secretion of apoB from Hep G2 cells and the MTP-mediated transfer of triglycerides between synthetic acceptor and donor liposomes with IC(50) values of 0.7 and 70 nM, respectively. In normolipidemic rats and dogs, oral administration of 8aR dose-dependently reduced both plasma triglycerides and total cholesterol. Moreover, in rats and dogs, 8aR also prevented the postprandial rise in plasma triglycerides following a bolus administration of a fat load. Because MTP inhibitors decrease very low density lipoprotein assembly in the liver, the potential for hepatic lipid accumulation was evaluated. In normolipidemic rats, hepatic cholesterol and triglyceride contents were dose-dependently increased by 8aR. However, hepatic lipid accumulation resulted in negligible change in total liver weight and was reversible after withdrawal of the compound.

Animals↗
PubMed2001

Physiological and regulatory roles of activin A in late pregnancy.

Unexplained fetal death in utero in late pregnancy represents an increasing proportion of perinatal deaths. It has been assumed that critical hypoxia is the likely mechanism underlying these losses, but the lack of a physiological marker has hampered both confirmation and prediction which could lead to timely intervention. In this paper, we report studies on hypoxia that we have performed in chronically cannulated late pregnant sheep, complemented by parallel investigations undertaken in human pregnancies. Our initial studies were directed towards determining activin secretion in the fetus and mother during late gestation, and immediately after fetal surgery using a sheep model. This led us to propose that there may be a relationship between hypoxia and activin A, follistatin and prostaglandin (PG) release from the feto-placental unit. Subsequent studies have been directed towards examining this potential relationship in sheep and in humans with compromised pregnancies. As a result of these studies, we have identified a potential mechanism by which activin A may be involved in regulating the response of the fetus to hypoxic insult. Activin A and follistatin concentrations increased in late gestation in ovine maternal plasma and in fetal fluids. Feto-placental hypoxemia or maternal isocapnic hypoxemia, leading to fetal hypoxia, were specific triggers for an acute increase in fetal activin A and follistatin concentrations during late gestation. The source and secretion of activin A, follistatin, and the associated release of PGE(2,) from within the feto-placental unit varied according to the site of the insult. The concomitant secretion of activin A and PGE(2) into the fetal circulation and amniotic fluid during reduced uterine blood flow provides an insight into the physiological regulatory mechanisms that might be involved. Changes observed in maternal activin A concentrations in mid and late gestation in the human may also be associated with fetal compromise. In human pregnancies, elevated activin A concentrations were observed in maternal plasma in mid and late gestation, in association with severe pre-eclampsia and with severe fetal growth restriction, compared to those observed in pregnancies with constitutionally small, healthy fetuses. Activin A was also elevated in maternal and arterial cord plasma in women at term during labour and immediately prior to undergoing emergency Caesarean section for failure to progress. These findings offer exciting new possibilities to gain insights into the mechanisms that underlie the maintenance of fetal wellbeing and provide a rationale for the potential that activin A may prove to be a useful clinical marker of fetal distress.

Activins↗
PubMed2001

A streamlined process to phenotypically profile heterologous cDNAs in parallel using yeast cell-based assays.

To meet the demands of developing lead drugs for the profusion of human genes being sequenced as part of the human genome project, we developed a high-throughput assay construction method in yeast. A set of optimized techniques allows us to rapidly transfer large numbers of heterologous cDNAs from nonyeast plasmids into yeast expression vectors. These high- or low-copy yeast expression plasmids are then converted quickly into integration-competent vectors for phenotypic profiling of the heterologous gene products. The process was validated first by testing proteins of diverse function, such as p38, poly(ADP-ribose) polymerase-1, and PI 3-kinase, by making active-site mutations and using existing small molecule inhibitors of these proteins. For less well-characterized genes, a novel random mutagenesis scheme was developed that allows a combination selection/screen for mutations that retain full-length expression and yet reverse a growth phenotype in yeast. A broad range of proteins in different functional classes has been profiled, with an average yield for growth interference phenotypes of approximately 30%. The ease of manipulation of the yeast genome affords us the opportunity to approach drug discovery and exploratory biology on a genomic scale and shortens assay development time significantly.

Amino Acid Sequence↗
PubMed2001

Feto-placental hypoxemia regulates the release of fetal activin A and prostaglandin E(2).

The evaluation of the role of critical hypoxia in unexplained fetal death in utero has been hampered by the lack of a physiological marker. Here we report the novel observation that feto-placental hypoxemia is an acute trigger for increased activin secretion from the feto-placental unit in late pregnancy. Hypoxemia was induced in chronically cannulated late pregnant fetal sheep by restricting blood flow through the maternal uterine arteries. Using maternal and fetal blood samples and amniotic fluid obtained via chronically implanted catheters, fetal blood gas parameters, plasma and amniotic fluid concentrations of activin A, prostaglandin (PG) E(2) and PGFM, the circulating metabolite of PGF(2alpha), were determined before, during and after a ten hour period of fetal hypoxemia. Hypoxemia acutely increased activin A and PGE(2) levels in both amniotic fluid and the fetal circulation with values rapidly returning to baseline with normoxemia. PGFM also increased in both compartments with a relatively delayed time frame compared to that of activin A and PGE(2). The increase in activin A and PGE(2) induced by hypoxemia may be a mechanism to regulate feto-placental blood flow during fetal compromise and also offers the possibility that activin A represents a useful marker of feto-placental hypoxemia.

Activins↗
PubMed2001

Changes in molecular weight forms of inhibin A and pro-alpha C in maternal serum during human pregnancy.

Maternal serum pools obtained from healthy women throughout normal pregnancy were fractionated by a combined immunoaffinity chromatography, preparative PAGE, and electroelution procedure. Inhibin A and the pro-alpha C region of the inhibin alpha-subunit were determined in the eluted fractions by specific ELISAs, and the profiles of immunoactivity characterized in terms of molecular weight and percent recovery. The molecular weight patterns of inhibin A and pro-alpha C in serum during early pregnancy (<19 wk gestation) showed peaks between 25-40K and approximately 60K, consistent with the presence of known mature and larger precursor inhibin forms. However, during late pregnancy (>19 wk gestation), an increase in the proportion of smaller molecular weight forms (from 2% to approximately 25%) of inhibin A and pro-alpha C of unknown structure were observed in the less than 30K and less than 25K regions, respectively. To assess whether this change in molecular weight distribution in late pregnancy was related to the method of serum collection, serum and plasma from women during early and late pregnancy were collected and snap-frozen. Three pools [one from early pregnancy (12-15 wk), two from late pregnancy (28-39 wk)] of serum and plasma were then fractionated as described above. No differences in molecular weight patterns of inhibin A and pro-alpha C were observed between serum and plasma pools obtained in early pregnancy. However, in late pregnancy there was a reduction in the proportion of low molecular weight forms between serum (25% inhibin A, 35% pro-alpha C) and plasma (12% and 17%, respectively), but not to the low levels seen in early pregnancy. Incubation of iodinated 30K human inhibin A with serum or plasma obtained from early or late pregnancy showed no evidence of cleavage, suggesting that 30K inhibin A is not the cleavage precursor. It is speculated that the formation of small molecular weight forms of both inhibin A and pro-alpha C is attributed to proteolytic changes, in part induced in the circulation during late gestation and in part by the placenta before secretion. It is concluded that inhibin A and pro-alpha C are processed in late pregnancy by more than one mechanism to form low molecular weight circulating forms of unknown structure.

Chemical Fractionation↗
PubMed2000

Reliability, repeatability, and sensitivity of the modified shuttle test in adult cystic fibrosis.

STUDY OBJECTIVES: The purpose of this study was to investigate the test-retest reliability, repeatability, and sensitivity of the modified shuttle test (MST) in adult patients with cystic fibrosis (CF). DESIGN: : Prospective study. SETTING: Adult CF Unit, Belfast City Hospital. PATIENTS: : Adult patients with CF. INTERVENTIONS: Test-retest reliability-none; sensitivity-inpatient IV antibiotic therapy for an acute exacerbation of respiratory disease. MEASUREMENTS: The test-retest reliability and repeatability of the MST was assessed by comparing performance on two consecutive MSTs performed in 12 patients with CF and stable disease. The sensitivity of the MST was assessed by measuring the change in MST performance after 2 weeks of IV antibiotic therapy in 24 patients admitted to hospital with acute exacerbations of their respiratory disease. RESULTS: In the assessment of test-retest reliability and repeatability (n = 12), there was a significant and strong correlation between trials for distance completed (Pearson's r = 0. 99; p < 0.01), peak heart rate (Pearson's r = 0.99; p < 0.01), peak arterial oxygen saturation (SaO(2); Pearson's r = 0.99; p < 0.01), and peak Borg rating of perceived breathlessness (Pearson's r = 0. 99; p < 0.01). The coefficients of repeatability for these variables were small (coefficient of repeatability: distance completed, 4 shuttles; peak heart rate, 6 beats/min; peak SaO(2), 4%; and peak Borg rating of perceived breathlessness, 0.9). In the assessment of sensitivity (n = 24), the standardized response mean (SRM) for distance completed on MST (SRM = 1.18) was the SRMs for spirometric measures of lung function (FEV(1), SRM = 0.96; FEV(1) percent predicted, SRM = 0.88). CONCLUSIONS: This study demonstrates that the MST is a reliable, repeatable, and sensitive measure of exercise capacity in adult CF. The MST may be of value in determining prognosis, evaluation for lung transplantation, exercise prescription, and establishing the impact of new treatments on the disability associated with CF.

Adolescent↗
PubMed1999

The adaptations of a quality of life questionnaire for routine use in clinical practice: the Chronic Respiratory Disease Questionnaire in cystic fibrosis.

The assessment of quality of life (QoL) is necessary to monitor the course of disease and to assess the effect of new and existing interventions in clinical practice. This will only be achieved if QoL can be measured accurately and routinely. The aim of this study was to demonstrate the methodology involved in the adaptation and shortening of the Chronic Respiratory Disease Questionnaire (CRDQ) in a population of adults with cystic fibrosis (CF). A single interviewer administered the CRDQ to a sample of 45 adult patients (32 males) with CF prior to assessment of spirometric measures of lung function. Those patients whose lung function was stable at the time of study and who could attend for a retest within 14 days were asked to complete the questionnaire at a subsequent visit (n = 10). The mean interval between visits was 7 days (range 5-14 days). Correlations between spirometry and CRDQ dimensions ranged from -0.003 to 0.426. The fatigue, emotion and mastery dimensions showed high internal consistency and adequate construct validity. In the small number of patients suitable for retest, the results indicated that the dimensions exhibited adequate test-retest reliability. In contrast, low internal consistency was demonstrated for the dyspnoea dimension. The fatigue, emotion and mastery dimensions could be reduced, in terms of their number of items, without a substantial loss in explanatory power. This study suggests that QoL measurement can be made convenient and, thus, more easily accessible for routine clinical assessment.

Activities of Daily Living↗
PubMed1999

Validity of a modified shuttle test in adult cystic fibrosis.

BACKGROUND: The purpose of this study was to provide some evidence of the validity of a modified shuttle test (MST) by comparing performance on the MST with peak oxygen consumption (VO2peak) measured during a treadmill test in a group of adult patients with cystic fibrosis. METHOD: Twenty patients with stable cystic fibrosis performed a ramped maximal treadmill test (STEEP protocol) and the MST using a randomised balanced design. RESULTS: The relationship between the distance achieved on the MST and VO2peak was strong (r = 0.95, p<0.01) with 90% of the variance in VO2peak explained by the variance in MST distance. The relationship was represented by the regression equation (with 95% confidence intervals) VO2peak = 6.83 (2.85 to 10.80) + 0.028 (0.019 to 0.024) x MST distance. CONCLUSION: This study provides evidence of the construct validity of the MST as an objective measure of exercise capacity in adults with cystic fibrosis.

Adult↗
PubMed1998

Value of C-reactive protein measurements in exacerbations of chronic obstructive pulmonary disease.

C-reactive protein (CRP) has been shown to be a useful and sensitive indicator of pyogenic infections in many clinical situations, including acute pneumonia and infective pulmonary exacerbations in cystic fibrosis patients. Exacerbations of COPD are often, but not always, associated with demonstrable infection. The value of CRP measurement in this situation has not been assessed. We have evaluated CRP measurement in 50 patients [age 71 +/- 8 (SD) years] who were admitted to hospital with clinical evidence of exacerbation [PaO2 = 7.3 +/- 1.3 (SD) kPa, baseline FEV1 = 0.8 +/- 0.4 (SD) l]. These patients all had serial measurement of CRP [polarizing immunofluorescence (Abbot, TDx)], peripheral white cell count (WCC), body temperature, peak expiratory flow rate, Karnofsky performance status and chest X-ray, in addition to serial sputum bacteriological analysis carried out in a specialized laboratory. CRP was elevated (> 10 mg l-1) in all patients (n = 29) with proven infection [103 +/- 98 (SD) mg l-1]. Levels were markedly elevated in patients infected with Streptococcus pneumoniae (mean 156 mg l-1); there was also a rapid fall in the CRP with therapy. WCC fell with therapy, giving a correlation with CRP level (r = 0.44, P < 0.01). Since CRP elevation was observed in patients having exacerbation with proven infections and also in those where infection was not proven, it is possible that, while it is a marker for COPD exacerbation, it is not necessarily a marker of bacterial infection per se. However, it is evident from our study that it is of value in the assessment of exacerbations of COPD, where routine bacterial culture of sputum is often unreliable, and thus the measurement of serum CRP may provide an additional objective indicator of infection.

Acute Disease↗
PubMed1997

The philosophy of psychiatry: who needs it?

Many a psychiatrist has said that he did not want to burden himself with a philosophy and that this science had nothing to do with philosophy. But the exclusion of philosophy would nevertheless be disastrous for psychiatry: firstly, if we are not clearly conscious of our philosophy we shall mix it up with our scientific thinking quite unawares and bring about a scientific and philosophic confusion. Secondly, since in psychopathology in particular the scientific knowledge is not all of one kind, we have to distinguish the different modes of knowing and clarify our methods, the meaning and validity of our statements and the criteria of tests- and all this calls for philosophic logic ... To sum up: If anyone thinks he can exclude philosophy and leave it aside as useless, he will be eventually defeated by it in some obscure form or another.

Culture↗
PubMed1996

Reproducibility of iodine-123-beta-CIT SPECT brain measurement of dopamine transporters.

UNLABELLED: Iodine-123-beta-CIT has been used as a probe of monoamine transporters in human and nonhuman primates utilizing SPECT. To assess the utility of this tracer for measurement of striatal dopamine (DA) transporters in human disease, we studied the test/retest variability and reliability of SPECT measures obtained after bolus injection of [123I]beta-CIT 0-7 hr (Day 1) and 18-24 hr (Day 2) after administration. METHODS: For the Day 2 study, seven healthy humans (4 men, 3 women; aged 19-74 yr) participated in two [123I]beta-CIT SPECT scans separated by 7-14 days. Subjects were imaged at 18, 21 and 24 hr postinjection of 370 MBq (10 mCi) [123I]beta-CIT. Two outcome measures were evaluated: (a) the ratio of specific striatal (activity associated with DA transporter binding) to nondisplaceable uptake, also designated V"3 and (b) the total, specific striatal uptake (%SSU) expressed as a percentage of injected radiotracer dose. Test/retest variability associated with V"3 and total specific striatal uptakes were compared for scans acquired at 18, 21 and 24 hr with 24 hr only postinjection scans. For the Day 1 study, three of the subjects participated in two kinetic studies of [123I]beta-CIT uptake. A three-compartment model was used for determination of konBmax and binding potential (BP = Bmax/Kd) and the reproducibility of the measures assessed. RESULTS: In the Day 2 study, both outcome measures demonstrated excellent test/retest reproducibility with variability of V"3 = 6.8 +/- 6.8% and percent striatal uptake = 6.6 +/- 4.3% using data acquired from all time points. There were no significant differences in variability for the two outcome measures obtained. The intraclass correlation coefficient rho was 0.96 and 0.98 for V"3 and %SSU, respectively. Considering the 24 hr postinjection scans only, there was a nonsignificant trend toward lower test/retest variability for %SSU compared to V"3 (6.6 +/- 4.2% and 12.8 +/- 9.0%, respectively). The test/retest variability for the Day 1 kinetic modeling data showed marked differences depending on the fitting strategy and assumptions about the reversibility of [123I]beta-CIT in striatum. Using a model that assumed a low, fixed value for reversible striatal binding (k4) produced low variability (12 +/- 9%). CONCLUSION: These data suggest that SPECT imaging performed at either 0-7 hr or 18-24 hr after [123I]beta-CIT injection permits calculation of reliable and reproducible measures of dopamine transporters and supports the feasibility of using [123I]beta-CIT in serial evaluation of human neuropsychiatric disease.

Adult↗
PubMed1995

Pamidronate treatment of the neurologic sequelae of pagetic spinal stenosis.

Spinal stenosis is a serious complication of Paget's disease of bone. Surgical decompression has a high complication rate and is not always effective. Medical therapy with bisphosphonates is established treatment in other forms of Paget's disease. To our knowledge, this is the first report of the use of intravenous pamidronate disodium as the sole treatment of lower limb weakness attributable to pagetic spinal stenosis. Our patient has been restored to independent living and has maintained his remission, with repeated treatment, for more than 5 years.

Aged↗