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Biomedical subjects

G Webb

Publications and source records attributed to G Webb.

At least 19 recordsLinked to original sources
PubMed2003

Insulinoma presenting with hyperandrogenism: a case report and a literature review.

An 18-year-old woman presented with a 6-month history of amenorrhoea and hyperandrogenism. Three months later she developed several episodes of fasting hypoglycaemia and was subsequently diagnosed with an insulinoma. Hyperinsulinaemia was observed in association with an elevated serum testosterone level. Surgical removal of the insulinoma resulted in resolution of the clinical and biochemical features of the polycystic ovarian syndrome (PCOS). Polycystic ovarian syndrome is unusual in a patient having an insulinoma. The rarity of this association may be the result of the late age of onset of this type of tumour, intermittent secretion of excessive insulin by the tumour, the degree of hyperinsulinism or other factors extrinsic to the insulin receptor that may facilitate insulin activity. However, we could not discover how our patient differs in having had PCOS from the majority of women with insulinoma who do not. If other patients with insulinoma are subsequently found to have hyperandrogenism, then this tumour might be added to the differential diagnosis of causes of anovulatory cycles and hyperandrogenaemia, although rare the association would be uncommon.

Adolescent↗
PubMed2003

Exercise systolic blood pressures are of questionable value in the assessment of the adult with a previous coarctation repair.

BACKGROUND: The role of exercise testing in the follow up of adults with a coarctation repair is unclear. Exercise induced systolic hypertension has been advocated as an indication for further investigation; however, the value of exercise testing in this role has been questioned, especially in paediatric populations. OBJECTIVE: To assess the value of resting and exercise blood pressure measurements in a cohort of adults with repaired coarctation. SETTING: Tertiary referral centre for adult congenital cardiac disease. PATIENTS: 56 patients (33 male, 23 female) with a previous coarctation repair, and 33 age matched controls. MAIN OUTCOME MEASURES: Resting and exercise blood pressures, including arm-leg systolic blood pressure gradients; standard echocardiographic measurements of left ventricular mass, aortic root diameter, and repair site gradient. RESULTS: The coarctation cohort had higher resting upper limb blood pressures than the controls (systolic: 129.7 v 120.7 mm Hg, p = 0.014; diastolic: 76.8 v 72.2 mm Hg, p = 0.02). Mean resting arm-leg systolic blood pressure gradient was also higher, at 3.6 v -2.2 mm Hg, p = 0.027. However, there were no differences between the peak exercise systolic blood pressures of the two groups. Peak exercise systolic blood pressure did not correlate with resting arm-leg blood pressure gradient (r = 0.24, p = 0.13) or with repair site gradient (r = 0.14, p = 0.39). Resting upper limb systolic blood pressure and resting arm-leg systolic blood pressure gradient were related to repair site gradient (r = 0.33, p = 0.03, and r = 0.47, p = 0.002). CONCLUSIONS: Measurements of upper limb blood pressure during exercise are of limited value in the assessment of the post-repair coarctation patient. If routine exercise testing is to be advocated in this population it must be for another indication.

Adult↗
PubMed2003

Abrogation of protein convertase 2 activity results in delayed islet cell differentiation and maturation, increased alpha-cell proliferation, and islet neogenesis.

To date, the role of pancreatic hormones in pancreatic islet growth and differentiation is poorly understood. To address this issue, we examined mice with a disruption in the gene encoding prohormone convertase 2 (PC2). These mice are unable to process proglucagon, prosomatostatin, and other neuroendocrine precursors into mature hormones. Initiation of insulin (IN) expression during development was delayed in PC2 mutant mice. Cells containing IN were first detected in knockout embryos on d 15 of development, 5 d later than in wild-type littermates. However, the IN(+) cells of d 15 PC2 mutant mice coexpressed glucagon, as did the first appearing beta-cells of controls. In addition, lack of PC2 perturbed the pattern of expression of transcription factors presumed to be involved in the determination of the mature alpha-cell phenotype. Thus, in contrast to controls, alpha-cells of mutant mice had protracted expression of Nkx 6.1 and Pdx-1, but did not express Brn-4. Islets of adult mutant mice also contained cells coexpressing insulin and somatostatin, an immature cell type found only in islets of the wild-type strain during development. In addition to the effects on islet cell differentiation, the absence of PC2 activity resulted in a 3-fold increase in the rate of proliferation of proglucagon cells during the perinatal period. This increase contributed to the development of alpha-cell hyperplasia during postnatal life. Furthermore, the total beta-cell volume was increased 2-fold in adult mutants compared with controls. This increase was due to islet neogenesis, as the number of islets per section was significantly higher in knockout mice compared with wild-type mice, whereas both strains had similar rates of IN cell proliferation. These results indicate that hormones processed by PC2 affected processes that regulate islet cell differentiation and maturation in embryos and adults.

Age Factors↗
PubMed2002

Toll-like receptors 2 and 4 are up-regulated during intestinal inflammation.

BACKGROUND & AIMS: Bacterial wall products play an important role in the activation of immune and nonimmune cells of the intestinal mucosa. Toll-like receptors (TLRs) TLR2 and TLR4 have been identified as signaling receptors activated by bacterial wall components. METHODS: Expression of TLRs in human intestinal mucosa obtained by endoscopy and surgery was analyzed by immunohistochemistry. Intestinal macrophages were isolated by immunomagnetic beads armed with a CD33 antibody. Reverse-transcription polymerase chain reaction was performed for TLR1-5. Results were confirmed by Northern blot and flow cytometry. Interleukin-1beta messenger RNA (mRNA) was quantified by a polymerase chain reaction-enzyme-linked immunosorbent assay-kit. RESULTS: Immunohistochemistry revealed a significant increase in the TLR2 and TLR4 antigen expression on submucosal cells in inflamed intestinal mucosa compared with non-inflamed mucosa. TLR expression was localized in intestinal macrophages by double-labeling techniques. No TLR-polymerase chain reaction product could be obtained with mRNA from CD33-positive macrophages from normal mucosa. We observed an induction of mRNA for TLR2, TLR4, and TLR5 in inflammation-associated macrophages. TLR1 and TLR3 were only detectable in blood monocytes. Monocytes reacted to lipopolysaccharide stimulation with a 3-fold and in vitro differentiated macrophages with a 16-fold increase of cellular interleukin-1beta mRNA. Macrophages from normal mucosa did not respond to lipopolysaccharide showing the functional relevance of TLR expression. CONCLUSIONS: This study shows the inflammation-dependent induction of TLR2 and TLR4 expression in intestinal macrophages. The absence of TLRs abolishes the reactivity of mucosal macrophages to bacterial wall products. Presence of TLRs may thereby contribute to the inflammatory process.

Blood Cells↗
PubMed2002

Mannitol in cardioplegia as an oxygen free radical scavenger measured by malondialdehyde.

Oxygen free radicals (OFRs) are associated with ischaemia-reperfusion injury involving many organs, including the heart, which can lead to depressed cardiac function and abnormalities in the cardiac ultrastructure. This is seen upon the release of the aortic crossclamp when the ischaemic myocardium is reperfused in patients undergoing cardiopulmonary bypass (CPB). Various studies have shown that by adding OFR scavenging agents or antioxidants to the CPB prime or cardioplegia, cardiac performance improves. Mannitol is an osmotic diuretic with free radical scavenging properties, which has been shown to reduce the extent of ischaemic injury and improve the function of the myocardium. This study evaluated how effective mannitol is as an OFR scavenger by administering different concentrations of cardioplegia antegrade into the aortic root, thus maximising its effects directly upon the myocardium rather than being diluted in the CPB prime. Thirty-three patients undergoing primary coronary artery bypass grafting (CABG) were, by double blind random selection, allocated into one of three groups: group 1, a control group (consisting of 11 patients) receiving no mannitol; group 2 (11 patients), receiving a concentration of 4 g/l; and group 3 (11 patients), receiving 8 g/l. Three blood samples were taken directly from the coronary sinus during bypass: the first sample at the start of bypass, just prior to the crossclamp being applied; the second sample just after removal of the crossclamp; and the third sample just prior to termination of bypass. All samples were then centrifuged and the plasma analysed for malondialdehyde (MDA) using high-performance liquid chromatography (HPLC). MDA, an endproduct of lipid peroxidation, causes cellular damage and disruption of cell membranes when tissue antioxidants are exhausted. The more MDA produced, the greater the depletion of tissue antioxidants secondary to OR formation during reperfusion when the aortic crossclamp is removed. HPLC is a useful biochemical study; however, it is not a direct indicator of depressed myocardial function, such as an invasive test would be, and this should be borne in mind. Statistically, the results do not show a significant difference among the three groups or among the three samples. However, a trend can be seen, which shows lower levels of MDA in the two groups receiving mannitol and there is an indication of a rise in MDA levels upon the start of reperfusion in the two groups receiving mannitol, but not the control group. It is concluded that further samples would be needed to find a significant difference in MDA concentrations.

Adult↗
PubMed2001

Impact of pulmonary valve replacement on arrhythmia propensity late after repair of tetralogy of Fallot.

BACKGROUND: Chronic pulmonary regurgitation after repair of tetralogy of Fallot (TOF) may lead to right ventricular dilatation, which may be accompanied by ventricular tachycardia and sudden death. We aimed to examine the effects of pulmonary valve replacement (PVR) on (1) certain electrocardiographic markers predictive of monomorphic ventricular arrhythmia and sudden death and (2) sustained atrial flutter/fibrillation and monomorphic ventricular tachycardia. METHODS AND RESULTS: We studied 70 patients who underwent PVR for pulmonary regurgitation and/or right ventricular outflow tract obstruction late after repair of TOF. Maximum QRS duration and QT dispersion were measured from standard ECGs before PVR and at the latest follow-up. Arrhythmia was defined as sustained atrial flutter/fibrillation or sustained monomorphic ventricular tachycardia. Concomitant intraoperative electrophysiological mapping and/or cryoablation were performed in 9 patients (60%) with preexisting ventricular tachycardia and 6 patients (50%) with preexisting atrial flutter. QRS duration remained unchanged in the study group (P=0.46), but it was significantly prolonged (P<0.001) in a comparable group of patients with repaired TOF who did not undergo PVR. At a mean follow-up of 4.7 years, the incidence of ventricular tachycardia diminished from 22% to 9% (P<0.001), and atrial flutter/fibrillation decreased from 17% to 12% (P=0.32). Intraoperative ablation prevented recurrence of preexisting tachyarrhythmia (0 of 15 patients). CONCLUSIONS: PVR in patients with previous TOF repair and chronic pulmonary regurgitation leads to stabilization of QRS duration and, in conjunction with intraoperative cryoablation, to a decrease in the incidence of preexisting atrial and ventricular tachyarrhythmia. When applicable, this combined approach should be used in patients late after repair of TOF.

Adolescent↗
PubMed2001

Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice.

Mice homozygous for a deletion in the gene encoding prohormone convertase 2 (PC2) are generally healthy but have mild hypoglycemia and flat glucose-tolerance curves. Their islets show marked alpha (A)-cell hyperplasia, suggesting a possible defect in glucagon processing (Furuta, M., Yano, H., Zhou, A., Rouille, Y., Holst, J., Carroll, R., Ravazzola, M., Orci, L., Furuta, H., and Steiner, D. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 6646-6651). In this report we have examined the biosynthesis and processing of proglucagon in isolated islets from these mice via pulse-chase labeling and find that proglucagon undergoes essentially no processing in chase periods up to 8 h in duration. Only a small percent of cleavage at the sensitive interdomain site (residues 71 and 72) appears to occur. These observations thus conclusively demonstrate the essentiality of PC2 for the production of glucagon in the islet A-cells. Ultrastructural and immunocytochemical studies indicate the presence of large amounts of proglucagon in atypical appearing secretory granules in the hyperplastic and hypertrophic A-cells, along with morphological evidence of high rates of proglucagon secretion in PC2 null islets. These findings provide strong evidence that active glucagon is required to maintain normal blood glucose levels, counterbalancing the action of insulin at all times.

Animals↗
PubMed2001

Aerobic capacity in adults with various congenital heart diseases.

As an increasing number of patients with congenital heart disease reach adulthood, more information is needed regarding outcomes. The first signs of impaired heart function may appear during exercise testing. The aim of the present study was to establish mean values for maximal oxygen uptake in adults with various congenital heart diseases. Patients from 6 major diagnostic groups were identified, including patients with atrial septal defect (ASD, n = 93), transposition of the great arteries corrected with the Mustard procedure (n = 84), congenitally corrected transposition of the great arteries (CCTGA, n = 41), Tetralogy of Fallot (n = 168), Ebstein's anomaly (n = 37), and Modified Fontan procedure (n = 52). Diminished maximal oxygen uptake was found in all diagnostic groups across age compared with healthy subjects. A significant decrease in maximal oxygen uptake with aging was found in those with ASD (p <0.0001), CCTGA (p = 0.01), and Tetralogy of Fallot (p <0.0001). There was no significant decline, however, in Ebstein's anomaly (p = 0.270), Fontan procedure (p = 0.182), and in the Mustard patients (p = 0.188). All patients achieved significantly lower heart rates than predicted (mean for all groups, p <0.0001). Forced vital capacity values (3.51 L, mean SD +/- 1.02) were lower than predicted values (4.10 L, mean SD +/- 0.90, p <0.0001) for all patients groups except those with ASD. Mean values, however, were within the accepted 20% range of variance. This study showed diminished aerobic capacity in all diagnostic groups when compared with a healthy population. The maximal oxygen uptake values across age groups can be used as reference values in patients with similar diagnoses and as the basis for further research.

Adolescent↗
PubMed2001

Cardiopulmonary exercise performance in adult survivors of the Mustard procedure.

Most patients with the Mustard procedure are now adults. To date, however, there have been few reports on resting and exercise hemodynamics in a large population of adults with this circulation. The aim of this study is to describe such parameters in one of the largest and oldest populations of adults with the Mustard procedure. The database of the University of Toronto Congenital Cardiac Centre for Adults was examined to identify 84 adults with the Mustard procedure who have undergone cardiopulmonary exercise tests. Magnetic resonance imaging and echocardiography studies were obtained in order to assess right ventricular size, function and baseline hemodynamics. Patients achieved lower maximum uptake of oxygen, maximal heart rate, forced vital capacity, forced expiratory volume in 1 second, and oxygen saturations at maximal exercise compared to a healthy population. Magnetic resonance imaging showed significantly different right ventricular ejection fractions between patients and controls. There were no effects of operative variables or preoperative hemodynamics on current exercise capacity. Patients after the Mustard procedure have subnormal exercise capacities. Factors such as chronotropic incompetence, peripheral deconditioning, and impaired lung function may be responsible for these results.

Adolescent↗
PubMed2001

Results of aortic valve-sparing operations.

OBJECTIVE: To review the late results of valve-sparing operations in patients with aortic root aneurysm and in those with ascending aortic aneurysm and aortic insufficiency. METHODS: From May 1988 to June 2000, 120 patients with aortic root aneurysm and 68 with ascending aortic aneurysm and aortic insufficiency underwent aortic valve-sparing operations. Patients with aortic root aneurysm were younger, were predominantly male, and had less severe aortic insufficiency than patients with ascending aortic aneurysm, who were older and often had aneurysm of the transverse arch. Forty-eight patients with aortic root aneurysm had the Marfan syndrome. The prevalence of aortic dissection was similar in both groups. Reconstruction of the aortic root was performed by reimplanation of the aortic valve in 64 patients and by remodeling of the aortic root in 56. Patients with ascending aortic aneurysm and aortic insufficiency were treated by replacement of the ascending aorta with reduction in the diameter of the sinotubular junction. Approximately two thirds of the latter patients also required replacement of the transverse aortic arch. The mean follow-up was 35 +/- 31 months for patients with aortic root aneurysm and 26 +/- 23 months for those with ascending aortic aneurysm. RESULTS: There were 2 operative and 5 late deaths in patients with aortic root aneurysm and 1 operative and 9 late deaths in patients with ascending aortic aneurysm. The 5-year survival for patients with aortic root aneurysm was 88% +/- 4% and for patients with ascending aortic aneurysm, 68% +/- 12% (P =.01). Severe aortic insufficiency developed in 2 patients, and they required aortic valve reoperation. The 5-year freedom from aortic valve reoperation was 99% +/- 1% for patients with aortic root aneurysm and 97% +/- 4% for those with ascending aortic aneurysm. Seven patients had moderate aortic insufficiency at the latest echocardiographic study. The 5-year freedom from severe or moderate aortic insufficiency was 90% +/- 4% in patients who had aortic root aneurysm and 98% +/- 2% in those who had ascending aortic aneurysm. CONCLUSIONS: Aortic valve-sparing operations have provided excellent clinical outcomes and few valve-related complications. The function of the reconstructed aortic root remains unchanged in most patients during the first 5 years of follow-up.

Adult↗
PubMed2001

Exercise capacity in adult patients with congenitally corrected transposition of the great arteries.

OBJECTIVE: To examine cardiopulmonary values, static lung function, and ejection fraction in adult patients with congenitally corrected transposition of the great arteries (CCTGA). PATIENTS AND METHODS: 41 patients who had undergone static lung function testing and cardiopulmonary exercise tests with measurements of ejection fraction were identified at the Toronto Congenital Cardiac Centre for Adults. RESULTS: Aerobic capacity in patients with CCTGA was severely diminished, varying from 30-50% of the results achieved by healthy subjects. Normal values of right ventricular and left ventricular ejection fraction were found. However, the systemic right ventricular ejection fraction increased by 2% from rest to exercise, as opposed to the expected > 5% increase in a healthy population. The pulmonary left ventricular ejection fraction decreased by 2% at peak exercise. CONCLUSION: Diminished values of heart rate, forced expiratory volume in one second (FEV(1)), forced vital capacity, and systolic blood pressure compared to the predicted values may contribute to the reduced maximal oxygen uptake (VO(2)max) found in patients with CCTGA. In addition, a limited increase in systolic right ventricular ejection fraction and a decrease in pulmonary left ventricle contractility suggest a dysfunction of both ventricles.

Adult↗
PubMed2001

Lung function and aerobic capacity in adult patients following modified Fontan procedure.

OBJECTIVE: To examine cardiopulmonary performance in 52 adult patients with a Fontan circulation. DESIGN: Retrospective cohort study. Values of maximum oxygen uptake (VO(2)max), maximum heart rate (HRmax), forced vital capacity (FVC), and forced expiratory volume in one second (FEV(1)) were compared with predictive values for different age groups. Patients were further subdivided into those with a pulmonary artery connection (RA-PA) or right atrium to right ventricle conduit (RA-RV). RESULTS: At late follow up (median 10 years, range 1 to 26 years), patients with Fontan circulation had greatly diminished VO(2)max, HRmax, FVC, and FEV(1) compared with predicted values. Early age at surgery had a positive impact on aerobic capacity. The FEV(1):FVC ratio indicated restrictive lung function. No differences were found with respect to any variable between patients with RA-PA connections and those with RA-RV connections. CONCLUSIONS: Patients with a Fontan circulation have greatly diminished values of aerobic capacity and a restrictive pattern of lung function. Patients with an early surgical procedure obtained higher values of VO(2)max. The theoretical benefits of including the right ventricle in a Fontan circulation were not apparent.

Adult↗