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Biomedical subjects

N Willis

Publications and source records attributed to N Willis.

At least 19 recordsLinked to original sources
PubMed2002

Transforming growth factor-beta 1 does not relate to hypertension in pre-eclampsia.

1. Pre-eclampsia is a human disease of pregnancy characterized by high blood pressure, proteinuria and end-organ damage, if severe. Pre-eclampsia is thought to be related to changes in early placental development, with the formation of a shallower than normal placental bed. 2. Transforming growth factor (TGF)-beta1 is a multifunctional fibrogenic growth factor involved in immune regulation that is elevated in some populations with a high risk of hypertensive end-organ disease related to increases in endothelin release. Transforming growth factor-beta1 is also an important factor in placental implantation. Alterations in TGF-beta1 may be related to abnormal placental development in early pregnancy and, thus, are a candidate for the development of hypertension in pre-eclampsia. 3. The aim of the present study was to examine the placental distribution and serum concentration of TGF-beta1 in patients with pre-eclampsia compared with normal pregnancy. 4. Patients with pre-eclampsia (n = 12) were compared with patients with normal pregnancy (n = 14). Transforming growth factor-beta1 was determined by TGF-beta1 Max ELISA (Promega, Madsion, WI, USA) after serum dilution (1/150) and acid activation. Placental distribution was determined by immunostaining with TGF-beta1 (Santa Cruz, Santa Cruz, CA, USA; 20 ng/mL) and the villi and decidual trophoblast were scored for intensity and extent of staining. 5. Patients with pre-eclampsia had a mean gestational age of 36 weeks, whereas those with a normal pregnancy had a mean gestational age of 39.0 +/- 0.4 weeks. There was no difference in TGF-beta1 concentration between the two groups (mean (+/-SEM) 27.1 +/- 1.0 vs 26.4 +/- 0.7 pg/mL for normal pregnancy and pre-eclampsia, respectively; P = 0.73, Mann-Whitney U-test). There was no correlation between systolic or diastolic blood pressure and TGF-beta1 concentration (regression analysis P = 0.4 and 0.2). Immunostaining was absent in the villous trophoblast cells and endovascular and extravillous trophoblast of term placentas. 6. Although TGF-beta1 is present in trophoblast cells in early pregnancy during placental development, TGF-beta1 concentrations were not increased in the placenta at term in pre-eclampsia and there was no correlation between blood pressure and serum TGF-beta1, suggesting that TGF-beta1 does not play a role in the development of late gestation pre-eclampsia and hypertension.

Adult↗
PubMed2001

Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras.

Adenocarcinoma of the lung is the most common form of lung cancer, but the cell of origin and the stages of progression of this tumor type are not well understood. We have developed a new model of lung adenocarcinoma in mice harboring a conditionally activatable allele of oncogenic K-ras. Here we show that the use of a recombinant adenovirus expressing Cre recombinase (AdenoCre) to induce K-ras G12D expression in the lungs of mice allows control of the timing and multiplicity of tumor initiation. Through the ability to synchronize tumor initiation in these mice, we have been able to characterize the stages of tumor progression. Of particular significance, this system has led to the identification of a new cell type contributing to the development of pulmonary adenocarcinoma.

Adenocarcinoma↗
PubMed2001

Non-corticosteroid treatment for nephrotic syndrome in children.

BACKGROUND: Eighty to ninety per cent children with steroid sensitive nephrotic syndrome (SSNS) have one or more relapses. About half of these children relapse frequently and are at risk of the adverse effects of corticosteroids. Non-corticosteroid immunosuppressive agents are used to prolong periods of remission in children, who relapse frequently. However these non-corticosteroid agents also have significant potential adverse effects. Currently there is no consensus as to the most appropriate second line agent in children who are steroid sensitive, but who continue to relapse. In this systematic review of randomised controlled trials (RCTs), the benefits and harms of these immunosuppressive agents are evaluated. OBJECTIVES: To evaluate the benefits and harms of non-corticosteroid immunosuppressive agents in relapsing SSNS in children. SEARCH STRATEGY: Published and unpublished randomised controlled trials were identified from the Cochrane Controlled Trials Register, MEDLINE, EMBASE, reference lists of articles, abstracts from proceedings and contact with known investigators in the area. SELECTION CRITERIA: Randomised or quasi-randomised trials were included if they were carried out in children (aged three months to 18 years) with relapsing SSNS, if they compared non-corticosteroid agents with placebo, prednisone or no treatment, different doses and/ or durations of the same non-corticosteroid agent, different non-corticosteroid agents and if they had outcome data at six months or more. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed all eligible studies for inclusion, assessed study quality and extracted data. The principle outcome measure was the number of children with and without relapse after six and 12 to 24 months. Secondary outcomes sought were the mean time to next relapse, the mean number of relapses per year and adverse events. A random effects model was used to estimate summary effect measures after testing for heterogeneity. Examination of possible between-study differences due to study quality, different interventions and different populations was attempted by subgroup analysis. MAIN RESULTS: Eighteen trials involving 828 children were identified. Cyclophosphamide (three trials; relative risk (RR) 0.44; 95% confidence intervals (95% CI) 0.26 to 0.73) and chlorambucil (two trials; RR 0.13; 95% CI 0.03 to 0.57) significantly reduced the relapse risk at six to twelve months compared with prednisone alone. In the single chlorambucil versus cyclophosphamide trial, there was no observed difference in relapse risk at two years (RR 1.31; 95% CI 0.80 to 2.13). Cyclosporin was as effective as cyclophosphamide (one trial, RR 1.07; 95% CI 0.48 to 2.35) and chlorambucil (one trial, RR 0.82; 95% CI 0.44 to 1.53) but the effect was not sustained when cyclosporin was ceased. During treatment levamisole (three trials, RR 0.60; 95% CI 0.45 to 0.79) was more effective than steroids alone but the effect was not sustained. Mizoribine (one trial) and azathioprine (two trials) were no more effective than placebo or prednisone alone in maintaining remission. REVIEWER'S CONCLUSIONS: Eight weeks courses of cyclophosphamide or chorambucil and prolonged courses of cyclosporin and levamisole reduce the risk of relapse in children with relapsing SSNS compared with corticosteroids alone. Clinically important differences in efficacy among these agents are possible and further comparative trials are still needed. Meanwhile choice between these agents depends on physician and patient preferences related to therapy duration and the type and frequency of complications.

Adolescent↗
PubMed2000

The coxsackie-adenovirus receptor (CAR) is used by reference strains and clinical isolates representing all six serotypes of coxsackievirus group B and by swine vesicular disease virus.

Group B coxsackieviruses are etiologically linked to many human diseases, and cell surface receptors are postulated to play an important role in mediating their pathogenesis. The coxsackievirus adenovirus receptor (CAR) has been shown to function as a receptor for selected strains of coxsackievirus group B (CVB) serotypes 3, 4, and 5 and is postulated to serve as a receptor for all six serotypes. In this study, we demonstrate that CAR can serve as a receptor for laboratory reference strains and clinical isolates of all six CVB serotypes. Infection of CHO cells expressing human CAR results in a 1000-fold increase in CVB progeny virus titer compared to mock transfected cells. CAR was shown to be a functional receptor for swine vesicular disease virus (SVDV), as CHO-CAR cells but not CHO mock transfected controls were susceptible to SVDV infection, produced progeny SVDV, and developed cytopathic effects. Moreover, SVDV infection could be specifically blocked by monoclonal antibody to CAR (RmcB). SVDV infection of HeLa cells was also inhibited by an anti-CD55 MAb, suggesting that this virus, like some CVB, may interact with CD55 (decay accelerating factor) in addition to CAR. Finally, pretreatment of CVB or SVDV with soluble CAR effectively blocks virus infection of HeLa cell monolayers.

Animals↗
PubMed1999

Blood volume determination by the carbon monoxide method using a new delivery system: accuracy in critically ill humans and precision in an animal model.

OBJECTIVE: To evaluate accuracy and repeatability of blood volume determinations made by the carbon monoxide method, using a ventilator-driven administration system. DESIGN: Prospective within-patient comparison, using simultaneous measurements by two methods to determine accuracy. Prospective laboratory investigation in animals to estimate repeatability. SUBJECTS: For accuracy: Nineteen ventilated critically ill patients in a university hospital intensive care unit. For repeatability: Six anesthetized, mechanically ventilated normovolemic pigs because this is impossible to perform in humans. INTERVENTIONS: In the accuracy study, a small mass of carbon monoxide was administered via a closed breathing system and arterial blood samples were taken from existing cannulas. In the repeatability study, an intramuscular sedative was given, followed by an inhalational anesthetic induction and mechanical ventilation via a tracheal tube. Left axillary artery and external jugular vein cannulas were sited. Anesthesia was maintained using an intravenous infusion. Five sequential circulating hemoglobin and blood volume estimations were made using the carbon monoxide method. MEASUREMENTS AND MAIN RESULTS: The small carboxyhemoglobin increase produced by uptake of a small, known mass of carbon monoxide was used to estimate the circulating blood volume. Simultaneous measurement, using 51Cr-labeled red blood cells, was performed. Twenty measurements were made in 19 patients. The bias (mean difference between blood volume measurements by the two methods) was 397 mL (5.53 mL x kg(-1)) +/-415 mL (+/-5.95 mL x kg(-1)); the limits of agreement (mean difference +/-2 SD) were -433 mL and 1227 mL (-6.36 mL x kg(-1) and 17.42 mL x kg(-1)). Therefore, 95% of expected differences will lie between these limits. The mean blood volume was 75.8 mL x kg(-1) in the animals. The coefficient of variation of repeated estimates was 9.49%. Mean circulating hemoglobin mass was 7.31 mmol with a coefficient of variation of 10.18%. The mean hemoglobin concentration, by co-oximetry, was 5.014 mmol x L(-1), coefficient of variation, 2.99%. CONCLUSION: This arrangement is a potential bedside method of estimating blood volume and circulating hemoglobin mass. We have rendered the technique more acceptable clinically by creating a ventilator-driven administration system.

Administration, Inhalation↗
PubMed1998

Double-blind placebo controlled trial of dextrose tablets and nicotine patch in smoking cessation.

In a placebo-controlled double-blind trial 308 smokers were individually randomly allocated to one of four groups: 1) 3 g dextrose tablets and 15 mg nicotine transdermal patch; 2) dextrose and placebo patch; 3) placebo tablets and nicotine patch; 4) placebo tablets and placebo patch. Patients were scheduled to attend weekly smokers clinic sessions starting 1 week before the quit date and continue for 4 weeks after that date. The primary outcome variable was biochemically verified abstinence at the final session, four weeks after the scheduled quit date. The proportion of smokers abstinent in the four groups was as follows: 49% - dextrose plus active patch; 44% - dextrose plus placebo patch; 36% - placebo tablet plus active patch; 30% - placebo tablet plus placebo patch. The difference between the dextrose and placebo tablets (13%) was statistically significant (P < 0.01, one-tailed); the difference between the active and placebo patches (6%) was not. There was no significant difference between the effect of the dextrose when accompanied by active versus placebo patches. There was no significant effect of dextrose on weight. The results suggest that dextrose supplementation to the diet may be a cheap and simple aid to giving up smoking. Further research is now needed to establish its long-term efficacy.

Adolescent↗
PubMed1998

Acute volume expansion and salt-loading studies in rats. The role of atrial natriuretic peptide and catecholamines.

Differences have been postulated for the mechanism of natriuresis due to atrial natriuretic peptide (ANP), salt loading with high salt diet (HS) and acute volume expansion (AcVE), in particular between AcVE and ANP based on the observed synergism between the two. Therefore the effects of and the interaction between the three were investigated in rats. ANP and AcVE produced the same natriuresis in HS as in normal salt (NS) rats and, in both, the actions of ANP and AcVe were significantly additive showing similarity in mechanisms. Synergism [(AcVE + ANP) - AcVE] was, however, present only in the NS rats. Proximal tubular sodium transport was the same with AcVE and ANP+AcVE suggesting that synergism is a property of more distal nephron segments. In conscious HS rats, plasma ANP was significantly less but natriuresis was higher than in NS rats. ANP therefore probably has some causative role in the natriuresis of AcVE but none in that of HS loading. Urinary dopamine was significantly increased by HS and further increased by AcVE in both NS and HS rats, the relationship between dopamine and natriuresis being significantly positive (r2 = 0.328) reaching equivalent levels in both NS and HS rats. Systemic benserazide prevented the increase in urinary dopamine but only attenuated the natriuresis of AcVE. We conclude that HS does not potentiate the natriuresis of AcVE or ANP, synergism between AcVE and ANP is not a proximal tubule event and dopamine accounts for significant natriuresis of VE in addition to other natriuretic factors.

Animals↗
PubMed1996

Cyclical changes in the renin-angiotensin-aldosterone system during the menstrual cycle of the baboon (Papio hamadryas).

This study characterizes the renin-angiotensin-aldosterone system during the normal menstrual cycle in the baboon. Ten animals received a daily dose of an ACE inhibitor or placebo in a randomized blind cross-over design. Data were obtained during the mid-follicular and early luteal phases of normal non-pregnant menstrual cycles. All examinations and blood collections were performed with ketamine sedation: 7-kg by im injection. Blood pressure was recorded by sphygmomanometer. Serum ACE activity was measured by spectrophotometry. Aldosterone (ALDO), angiotensin I (AI), and angiotensin II (AII) were measured by radioimmunoassay. Plasma renin activity (PRA) was measured by AI generation. The renin-angiotensin-aldosterone system was found to be activated in the follicular phase and suppressed during the luteal phase of the normal non-pregnant menstrual cycle in the baboon.

Aldosterone↗
PubMed1995

Non-invasive estimation of venous admixture: validation of a new formula.

We have developed a computer program that estimates venous admixture (intra-pulmonary shunt) from four measurements: haemoglobin concentration, end-tidal carbon dioxide tension (PE'CO2), fractional inspired oxygen concentration (FIO2) and pulse oximetry (SpO2). The formula was tested on patients in an intensive therapy unit by using it to estimate shunt while it was measured simultaneously by a standard, invasive method. A total of 101 measurements were made in 29 patients. After correcting the systematic errors in the assumed differences between PE'CO2 and arterial PCO2, and between SpO2 and co-oximetrically measured SaO2, and correcting for a trend in the arteriovenous oxygen concentration difference (C(a-v))2) with shunt, the bias of the non-invasive minus invasive shunt differences was negligible, with no significant dependence on shunt. The limits of agreement were then +/- 16% shunt overall (+/- 13% within patients). When SaO2 was used instead of SpO2, the limits were +/- 11% (+/- 8% within patients).

Carbon Dioxide↗
PubMed1995

Indicators of histohypoxia.

Cellular tissue damage due to inadequate oxygen supply is frequently encountered in the critically ill patient and can be the end result of a number of conditions. The eventual disruption to the normal processes required for the cell to survive can be due either to the hypoxic state per se or by damage caused during reperfusion of the tissue. Blood gas analysis is commonly used as a macro indicator of oxygen supply, state of art blood gas analysers provide information for oxygen tension (pO2), haemoglobin oxygen saturation (SO2) and concentration (THb), ideally, in arterial and mixed venous blood. The concurrent measurement of carbon dioxide tension (pCO2) and pH will allow the calculation of variables which assist in differentiating between respiratory and non-respiratory conditions. Measurement of cardiac output and clinical assessment of the patients' oxygen requirements will complete the macro picture of supply and demand and although computed indicators of hypoxia have been improved in recent years (1, 2) the definitive diagnosis of histohypoxia requires the measurement of the cellular and subcellular products of metabolic processes that are present when an inappropriate concentration of oxygen has been experienced. However, increases, for example, in blood lactate concentration can occur when an ischaemic area is reperfused and it is argued conversely, that the absence of hyperlactataemia in conditions such as acute respiratory distress syndrome does not necessarily preclude delivery dependence of oxygen consumption with the attendant potential for tissue hypoxia (3). Nevertheless there is general agreement that blood lactate levels can serve as a reliable clinical guide to therapy (4). The laboratory measurement of the metabolic products that accumulate when cellular oxygen supply is limited has become far less labour intensive and with the development of increasingly sophisticated instrumentation, these analytes can be available in small to medium hospital laboratories as well as the larger units. The relatively rapid and accurate analysis of metabolites that accumulate in hypoxic states has allowed us to measure concentrations of blood lactate, pyruvate, beta-hydroxybutyrate and acetoacetate and calculate the lactate/pyruvate ratio and beta-hydroxybutyrate/acetoacetate ratio. These measurements and ratios can then be compared with the non invasive macro blood gas indicators in order to determine their effectiveness as additional "routine" investigations and to indicate how each of the variables contributes to the eventual diagnosis. The parameters used in this study are as follows: Oxygen tension-pO2, Haemoglobin oxygen saturation-SaO2, Haemoglobin concentration-THb, Hydrogen ion concentration as-pH, Concentration of extractable oxygen-Cx, Oxygen extraction tension-px, Conditional extraction at an assumed pvO2 = 30 mmHg-C(a-30)O2, Lactate and pyruvate, beta-hydroxybutyrate and acetoacetate.

3-Hydroxybutyric Acid↗
PubMed1994

Estimation of effective and total erythropoiesis in myelodysplasia using serum transferrin receptor and erythropoietin concentrations, with automated reticulocyte parameters.

The erythroid abnormality in patients with myelodysplasia (MDS) is multifactorial, with ineffective erythropoiesis and poor in vitro progenitor response to erythropoietin (EPO). Serum EPO concentration is variable among patients for a given haemoglobin concentration. We studied 19 non-transfusion-dependent patients with MDS, and 13 healthy elderly control subjects in an attempt to define the factors governing variability in serum EPO and to further characterise the anaemia of MDS. Serum EPO concentration was appropriate for the degree of anaemia in 15/19 MDS patients, and was positively related to mean cell volume (MCV), mean cell haemoglobin (MCH), and percentage highly fluorescent reticulocytes (% HFR), but not to absolute or percentage reticulocyte count. Although the observed/predicted ratio for serum transferrin receptor (TfR) concentration was low in 12 of 19 MDS subjects, no relationship to haemoglobin concentration, reticulocytes or serum EPO was seen. Serum TfR was positively correlated with WBC and platelet counts. Serum TfR was higher in patients with sideroblastic anaemia than refractory anaemia. Standardized in vivo p50 was positively correlated to red cell 2,3 diphosphoglycerate concentration, although this was not the only factor influencing the oxygen dissociation curve. We conclude that effective erythroid output responsive to endogenous EPO drive in MDS is positively related to MCV, MCH and % HFR. Serum TfR may not represent effective output as precisely as % HFR, but may be proportional to total marrow erythropoietic activity.

Adult↗
PubMed1993

Effects of the correction of renal anaemia by erythropoietin on physiological changes during exercise.

The effects of treating the anaemia of end-stage renal failure with erythropoietin were studied in nine dialysis patients. The increase in haemoglobin concentration (by 59% from 7.0 +/- 1.2 to 11.1 +/- 1.1 g dl-1) was associated with increases in exercise duration (by 41%) and maximum oxygen consumption (by 34%). Treatment reduced resting heart rate but did not significantly alter heart rate at maximum exercise, nor resting or exercise blood pressure. Resting arterial potassium concentrations were slightly increased after treatment, but they increased similarly in relation to minute ventilation during exercise. Lactic acidaemia developed during exercise at both levels of haemoglobin, and was accompanied by similar reductions in arterial pH and bicarbonate levels but constant PaO2 and PaCO2. Ventilation was coupled to the metabolic rate of carbon dioxide production, ventilatory dead-space and arterial PCO2 before and after treatment of anaemia, the ventilatory requirement for carbon dioxide elimination being unchanged. Treatment of anaemia did not alter resting arterial lactate concentration; the concentration of lactate at maximum exercise was increased slightly following treatment but this increase did not reach statistical significance. The rate of increase in arterial lactate concentration as a function of oxygen consumption, assessed both with respect to the 'lactate threshold' and 'lactate slope index', was significantly delayed by treatment. Treatment of anaemia also delayed the 'anaerobic threshold', and there was good correlation between lactate and anaerobic thresholds. Treatment of renal anaemia by erythropoietin thus results in improved tissue oxygen supply during exercise, reflected by delay in the onset of lactic acidaemia.

Adolescent↗
PubMed1992

The ventilatory cost of exercise compared in chronic heart failure and chronic renal anaemia.

The cardiorespiratory responses to maximal treadmill exercise were compared in matched groups of patients with chronic renal anaemia or treated chronic heart failure, and in normal controls. Exercise capacity was similarly reduced in both patient groups compared to normal controls, the raised respiratory exchange ratio at peak exercise implying anaerobic metabolism due to limited oxygen delivery in heart failure and limited oxygen carrying capacity in anaemia. Minute ventilation (VE) was related linearly to minute CO2 production (VCO2) in all subjects (each r > 0.92) from all three groups. The slope of the VE/VCO2 relationship was normal in anaemia but steeper in heart failure, reflecting ventilation/perfusion mismatching in chronic heart failure.

Adolescent↗
PubMed1991

Syndrome X and hyperventilation.

The cardiorespiratory responses to exercise and forced hyperventilation were measured in 17 unselected patients with syndrome X (angina, positive exercise test, normal coronary arteriogram, no other cardiovascular disease) and compared with those in 15 healthy subjects. Forced hyperventilation produced hypocapnia and metabolic alkalosis but no chest pain or electrocardiographic change. Patients with syndrome X showed reduced maximum oxygen consumption with an increased respiratory exchange ratio at peak exercise, confirming that exercise was limited by skeletal muscle perfusion--and thus that the increase in cardiac output with exercise is limited in syndrome X as in heart failure. Arterial carbon dioxide tension (PCO2) homoeostasis during exercise was normal but the ventilatory cost of carbon dioxide excretion was increased in syndrome X (as in heart failure). End tidal PCO2 measurements correlated only poorly with arterial PCO2 in individual patients with syndrome X, providing a possible explanation for previous reports, based on end tidal PCO2 of inappropriate hyperventilation. Patients with syndrome X did not show inappropriate hyperventilation but they did show hyperventilation that was appropriate to maintain normal arterial PCO2 in the face of reduced cardiac reserve.

Adult↗