Biomedical subjects
Publications and source records attributed to L O'Toole.
Assessment of late effects in a cohort of female Hodgkin's lymphoma patients treated with mantle radiotherapy, identified from the DoH breast cancer screening recall showed high mortality and frequent undiagnosed abnormalities in tissues affected by radiotherapy. With increasing age, this patient group may suffer premature cardiac and respiratory morbidity.
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The production of the capsular polysaccharide, polyribosylribitolphosphate, from Haemophilus influenzae type b is important for the production of effective conjugate vaccines. Factors limiting the production of this polysaccharide from H. influenzae type b in liquid culture were investigated. A fed-batch fermentation was developed that increased cell density and PRP titer approximately four fold when compared to the batch fermentation. This fed-batch process was successfully scaled from the 1.5 l development scale to the 500 l manufacturing scale. The maximum cell density in the 500 l fermentation was 6 g dry cell weight per liter and the PRP concentration was 1.3 g l(-1).
We sought to compare bladder emptying function in normal women during the proliferative and secretory phases of the menstrual cycle and to evaluate whether urethral catheterization affected uroflowmetry parameters. Forty-nine normal volunteers (ages 19-42 years) were recruited and underwent uroflowmetry in the proliferative and secretory phases of the menstrual cycle. A serum progesterone level of <3.0 ng/mL defined the proliferative phase. During the proliferative phase, volunteers underwent uroflowmetry analysis when a sensation of fullness was appreciated. A post-void residual volume was determined, and the bladder was filled with 400 mL of normal saline. Repeat uroflowmetry analysis was then performed. This two-step procedure was repeated at a separate visit during the secretory phase. Voided volume, residual volume, maximum and average flow rates, time-to-maximum flow, and duration of flow were recorded. Wilcoxon signed-rank tests were used for statistical analysis. A two-tailed alpha value of <0.05 defined statistical significance. Our analysis was limited to the 33 patients whose predicted menstrual dating correlated with the obtained progesterone levels. During the follicular phase, we found significantly faster maximum (P < 0.0001) and average flow rates (P = 0.01), along with a shorter time-to-maximum flow (P < 0.0001) and shorter duration of flow (P < 0.0001), during the pre-catheterized void than the post-catheterized void. Similar results were observed in the secretory phase with the exception of a slightly higher residual volume (P = 0.05). No difference was seen in any measured uroflowmetry parameter when comparing similar voids between phases of the menstrual cycle. We conclude that when evaluating pre-menopausal patients, uroflowmetry may be scheduled and performed during either phase of the menstrual cycle. Neurourol. Urodynam. 19:147-152.
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There is marked interindividual variation in serum and tissue angiotensin-converting enzyme (ACE) levels for which the insertion (I)/deletion (D) polymorphism in intron 16 of the ACE gene is a marker. ACE inhibitors have important effects on morbidity and mortality in heart failure. The influence of this polymorphism on the response to ACE inhibitors in patients with heart failure is not known. We studied response by ACE genotype of 34 subjects in a randomised, double-blind, crossover study comparing 6 weeks of lisinopril (10 mg, o.d.) or captopril (25 mg, t.d.s.) on 24-h blood pressure (BP) profile and on renal function in patients with symptomatic heart failure [mean left ventricular ejection fraction (LVEF), 24%]. Glomerular filtration rate (GFR), 99mTc diethylenetriaminepentaacetic acid (DTPA), and ambulatory 24-h mean arterial pressure (MAP; Spacelabs 90207) were assessed at the beginning and end of treatment periods. There was a significant relation between ACE genotype and change in MAP with captopril (mm Hg; DD group, -0.5; ID, -4.7; II, -7.4; p = 0.02) but not to lisinopril (mm Hg DD, -6.0; ID, -6.6; II, -7.4; p = 0.89) in these patients. There was no significant relation between genotype and change in GFR with captopril (percentage change from baseline: DD, +7.9; ID, +13.1; II, -0.6; p = 0.45) or lisinopril (percentage change from baseline: DD, -0.1; ID, -3.0; II, -13.3; p = 0.39), but the decline in renal function tended to be greatest in II subjects. Whereas the results are not conclusive, there may be a significant interaction between ACE genotype and response to ACE inhibitors in patients with heart failure.
The effects of incremental infusion of angiotensin I on pressor and hormonal responses in relation to the angiotensin-converting enzyme (ACE) genotype were compared in healthy men of genotype DD (n = 8) and II (n = 8). The R(d)25 was the rate of angiotensin I infusion required to achieve a 25-mm Hg increase in diastolic pressure, and the R(s)25, that which caused a 25-mm Hg increase in systolic pressure. Changes in heart rate (HR25) were analysed at the time the R(d)25 was achieved. Serum ACE activity and plasma renin, angiotensin II, and aldosterone concentrations were measured at the start and end of the angiotensin I infusion. Serum ACE activity differed significantly between the genotypes with significantly higher mean values in DD subjects (46.3 +/- SEM 5.2 U/L) than II subjects (12.3 +/- 1.4 U/L; p < 0.001). Age, weight, and baseline blood pressure, heart rate, urinary sodium excretion, plasma renin, angiotensin II, and aldosterone concentrations did not differ between genotypes. The geometric mean infusion rates of angiotensin I required to achieve R(d)25 were 2.53 micrograms/min in II subjects and 2.67 micrograms/min in DD subjects (ratio of infusion rates, 0.95; 95% CI, 0.44-2.02; p > 0.05). The corresponding infusion rates for systolic blood pressure (R(s)25) were 4.47 micrograms/min in II subjects and 3.39 micrograms/min in DD subjects (ratio, 1.32; 95% CI, 0.49-3.55; p > 0.05). At the time of R(d)25, changes in heart rate from baseline were +1.2 beats/min for DD subjects and -9.5 beats/min for II subjects (diff II-DD = 10.7 beats/min; 95% CI, 6.7-14.8; p = 0.01). There were no differences in plasma renin, angiotensin, and aldosterone responses to angiotensin I infusion between the DD and II genotypes. We showed no difference in blood pressure or renin-angiotensin-aldosterone system responses to infusion of angiotensin I related to the deletion or insertion allele of the ACE gene polymorphism, but the study has insufficient power to exclude with certainty such differences. There was a significant difference between II and DD subjects in the chronotropic response to angiotensin I infusion.
BACKGROUND: The ACE gene is characterized by a polymorphism based on the presence (insertion [I]) or absence (deletion [D]) within intron 16 of a 287-basepair alu repeat sequence, resulting in three genotypes (DD and II homozygotes and ID heterozygotes). In 1992, the DD genotype was reported to be associated with an increased risk of myocardial infarction (MI). Subsequent studies have produced conflicting findings. To further evaluate the association of the ACE I/D genotype with MI risk, we carried out a meta-analysis of all the published studies. METHODS AND RESULTS: In total, 15 studies containing 3394 MI cases and 5479 control subjects were analyzed. The overall distribution of genotypes in the control subjects was 22.7% II, 49.0% ID, and 28.3% DD. The mean odds ratio for MI for DD versus ID/II genotypes across all studies was 1.26 (95% CI, 1.15, 1.39; P < .0001). Pairwise odds ratios were 1.36 (95% CI, 1.19, 1.55) for DD and II, 1.24 (95% CI, 1.11, 1.38) for DD and ID, and 1.09 (95% CI, 0.96, 1.23) for ID and II. The relative risk appeared to be increased in Japanese populations (2.55; 95% CI, 1.75, 3.70). CONCLUSIONS: Within the limitations of the available data, the meta-analysis therefore supports an association of the ACE D allele with MI risk and strengthens the justification for further evaluation in appropriately powered studies.
OBJECTIVES: We sought to prospectively investigate whether genetic variation at the angiotensin-converting enzyme gene locus defined by an insertion (I)/deletion (D) polymorphism influences the risk of myocardial infarction or prognosis after infarction, or both. BACKGROUND: It has been suggested that the deletion allele of the angiotensin-converting enzyme gene, and specifically the DD genotype, may increase the risk of myocardial infarction, although previous studies have produced conflicting reports. No studies have yet examined the effect of I/D polymorphism on survival after infarction. METHODS: Angiotensin-converting enzyme genotypes in 684 patients with myocardial infarction recruited at the time of the acute event through coronary care units in two centers were compared with those of 537 control subjects recruited from the base populations. All patients were followed up to assess the impact of the angiotensin-converting enzyme genotype on prognosis. RESULTS: We found no difference (p = 0.89) in the genotype distribution between patients and control subjects (patients DD 31%, ID 47%, II 22%; control subjects DD 30%, ID 48%, II 22%). The odds ratio for myocardial infarction for DD compared with II/ID genotype adjusted for age, gender and center was 1.16 (95% confidence interval [CI] 0.82 to 1.65, p = 0.44). The study had 90% power to detect a 1.5-fold increase in risk of myocardial infarction associated with the DD genotype. For one center, data were available for other risk factors (hypertension, diabetes, angina, previous myocardial infarction, smoking, body mass index, total and high density lipoprotein cholesterol) in both patients and control subjects. In a stepwise logistic regression analysis the odds ratio for DD versus ID/II genotypes remained nonsignificant (1.44, 95% CI 0.84 to 2.46, p = 0.20) for these subjects. Over a median follow-up period of 15 months (range 3 to 22), 155 patients (22.7%) died. There was no difference in mortality between subjects with the DD genotype and those with ID/II genotypes. (21.8% vs. 23.1%, p = 0.25). Likewise, there was no difference in the distribution of survival times in the two groups (p = 0.62). The study had 70% power to detect a 1.5-fold increase in mortality during follow-up associated with the DD genotype. CONCLUSIONS: We conclude that in the groups studied, genetic variation at the angiotensin-converting enzyme gene locus defined by I/D polymorphism does not significantly influence either the risk of or the short- to medium-term prognosis after myocardial infarction.
OBJECTIVE: Calcium antagonists are the only oral vasodilators shown to influence mortality in primary pulmonary hypertension, but the high doses required are often poorly tolerated. Amlodipine is a novel, relatively well tolerated, calcium antagonist. It has not been previously tested in humans with pulmonary hypertension. DESIGN: Calcium antagonists are claimed to be of benefit in the 20-30% of patients who respond--that is, whose mean pulmonary artery pressure and pulmonary vascular resistance decreased by 20% after acute administration. Increasing oral doses of amlodipine (up to 40 mg) were given and haemodynamic measurements were obtained by the use of indwelling pulmonary artery catheters 12 h after each dose. SETTING: Large teaching hospital, primary referral centre. PATIENTS: Six patients (four women; age range 37-78 years) with pulmonary hypertension (one with primary pulmonary hypertension, five with thromboembolic disease. MAIN OUTCOME MEASURES: Mean pulmonary artery pressure and pulmonary vascular resistance decreased by greater than 20% in two patients, mean pulmonary artery pressure decreased by greater than 20% in one patient with a pulmonary vascular resistance reduction of 19%. Thus, two of six patients responded to amlodipine and one partially responded. RESULTS: The whole group mean (SEM) pulmonary artery pressure decreased from 47.7 (4.2) to 41.7 (4.4) mm Hg and mean pulmonary vascular resistance from 8.6 (2.1) to 7.1 (1.8) Wood units. Cardiac output rose by a mean (range) of 4% (-20.8 to+20.8), heart rate by 8.8% (-10 to +33), and systemic systolic blood pressure decreased by 12% (-29.2 to -5.8) and diastolic blood pressure by 6.8% (-28.2 to+20.0). There were no symptoms of systemic hypotension. CONCLUSION: These results show that oral amlodipine can produce acute pulmonary vasodilatation in patients with pulmonary hypertension. Further studies are required, but amlodipine may prove to be of value in the treatment of primary pulmonary hypertension.
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