Certificate in basic oral health promotion.
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Certification↗
Biomedical subjects
C O'Sullivan
Publications and source records attributed to C O'Sullivan.
Abnormal ventricular long-axis function in systemic sclerosis.
STUDY OBJECTIVE: To assess possible effects of systemic sclerosis on ventricular function. DESIGN: Retrospective analysis of patients referred for echocardiographic examination to assess ventricular function. SETTING: Tertiary referral center for cardiac and chest diseases equipped with invasive and noninvasive facilities. PATIENTS: Thirty-four patients with clinical diagnosis of systemic sclerosis, aged 49 +/- 12 years; 24 had pulmonary fibrosis and 10 did not. There were 21 normal controls of similar age. MEASUREMENTS: Two-dimensional guided M-mode echocardiographic recordings of the left ventricular minor and long axis at the left and septal sites and right ventricle were obtained. Transmitral and transtricuspid Doppler flow velocities were also obtained with ECG and phonocardiogram. RESULTS: In 24 patients with pulmonary fibrosis, long-axis excursion was reduced 2.1 +/- 0.5 vs 2.7 +/- 0.4 cm/s as was peak rate of shortening and lengthening, 8.5 +/- 3.3 vs 10.8 +/- 2.4 cm/s and 7.5 +/- 2.5 vs 12 +/- 3.6 cm/s, respectively (p < 0.001), at the right side compared with 10 patients without. The onset of right long-axis shortening and lengthening was delayed with respect to the Q wave of the ECG and P2 of the phonocardiogram (p < 0.001 in both vs controls). The onset of tricuspid forward flow from the second heart sound was also delayed in the two groups, 110 +/- 15 ms and 100 +/- 20 ms vs 80 +/- 15 ms, respectively (p < 0.001). Right ventricular late diastolic filling velocities were increased 35 +/- 15 and 35 +/- 12 cm/s vs 20 +/- 10 cm/s in both groups (p < 0.01), and hence E:A ratio reduced 1.25 +/- 0.5 and 1.4 +/- 0.3 vs 1.9 +/- 0.4, respectively (p < 0.001). Pulmonary flow acceleration time was reduced only in patients with pulmonary fibrosis, 105 +/- 30 ms vs 125 +/- 30 ms (p < 0.001). At the left side, total long-axis excursion was reduced only in patients with pulmonary fibrosis (p < 0.01), while peak shortening and lengthening rates were reduced in both groups (p < 0.05). The onset of shortening from the Q wave and lengthening from the second heart sound were both delayed in the two groups with the latter greatly delayed in patients with pulmonary fibrosis (p < 0.05). CONCLUSIONS: Right and left ventricular long-axis function is frequently abnormal in patients with systemic sclerosis. Abnormalities are more profound in patients with CT evidence of pulmonary fibrosis than in those without. We suggest that these disturbances are due to myocardial fibrosis which, from the anatomic distribution of longitudinally directed fibers, is likely to have been subendocardial.
Blood Flow Velocity↗
Tumour-associated leucocytes: friends or foes in breast carcinoma.
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Antigens, Neoplasm↗
Spinal cord tumors in children: long-term results of combined surgical and radiation treatment.
The authors report a series of 31 children under 17 years of age with primary spinal cord tumors who underwent radiation treatment following decompression laminectomy with or without tumor resection between 1959 and 1990. The tumors consisted of 15 astrocytomas, 11 ependymomas, one mixed glioma, one gangliolioma, and three of unknown histology. Ten- and 20-year survival rates and 10- and 20-year relapse-free survival rates for the 28 patients with known histology were 80% and 53%, and 73% and 67%, respectively. Eleven patients (35%) had no resection, 14 (45%) had a partial resection, and six (19%) had a grossly complete resection. Eight patients (26%) are dead: five due to recurrent tumor, two due to a second malignant tumor, and one due to intercurrent disease. primary tumor relapse or progression occurred in nine patients (29%), four of whom were salvaged. A second malignant tumor developed in four patients (13%), two of whom died. Local control of the tumor was finally achieved in 26 cases (84%), despite either grossly incomplete or no resection in 25 of these cases (81%). These statistics suggest that radiation treatment without resection may achieve long-term control in children with astrocytoma or ependymoma of the spinal cord.
Adolescent↗
Adenovirus-mediated gene transfer for cystic fibrosis: quantitative evaluation of repeated in vivo vector administration to the lung.
Adenoviral vectors have an important role as in vivo gene delivery vehicles in developing human gene therapy for the fatal pulmonary component of cystic fibrosis. In this study we evaluated the immune responses to wild-type adenovirus and replication-deficient, first generation adenoviral (Av1) vectors in the cotton rat (Sigmodon hispidus) and then quantitatively evaluated the efficiency of gene delivery and expression of single and repeated in vivo administration of Av1 vectors to the respiratory tract. Av1 vector reporter gene expression was quantitatively evaluated by employing a luciferase expression vector (Av1Luc1) and measuring luciferase activity in whole lung tissue homogenates by routine luminometry. Gene transfer and expression in naive animals (e.g. first Av1 vector dose) was efficient. A repeat dose also resulted in successful gene transfer and expression, although at a significantly reduced level (p < 0.01) compared with naive animals. This reduction inversely correlated with serum human adenovirus neutralizing antibody (HANA) titers. Importantly, increasing doses of Av1Cf2, an Av1 vector expressing the human CFTR cDNA, resulted in a graded HANA response consistent with a lack of in vivo replication. These observations have significant implications for repeated administration of adenoviral vectors to the lungs of individuals with cystic fibrosis.
Adenoviruses, Human↗
Secretion of epidermal growth factor by macrophages associated with breast carcinoma.
By means of a cytokine release assay we have shown that in cell populations derived from primary breast carcinoma, epidermal growth factor (EGF) is secreted by cells with the characteristic morphological and immunophenotypic profile of activated macrophages (positive for CD68, CD16, CD25). EGF secretion was observed in 11 (31%) of 35 primary tumours. Secretion of EGF by normal or malignant epithelial cells was not observed. We found no association between EGF secretion by the primary tumour and recognised clinical indices of prognosis.
Adult↗
Differential pulse voltammetric determination of 7-hydroxycoumarin in human urine.
The electrochemical behaviour of 7-OH-coumarin at the bare glassy carbon electrode has been studied using differential pulse voltammetry, and based on anodic detection of this metabolite at 0.66 V (vs SCE) using DC amperometry, a method has been developed for the determination of 7-OH-coumarin levels in urine samples, and a pharmacokinetic profile established.
Electrodes↗
Development of an antibody-based amperometric biosensor to study the reaction of 7-hydroxycoumarin with its specific antibody.
An amperometric biosensor, based on an anti-7-hydroxycoumarin (7-OH-coumarin) antibody immobilized at the surface of a glassy carbon electrode, and contained behind a cellulose dialysis membrane, is described. The electrochemical behaviour of this metabolite at the bare glassy carbon electrode was found to be well defined by using differential-pulse voltammetry, and a 90% decrease in peak height was observed on binding of the antibody to the antigen, which occurs at the electroactive site of 7-OH-coumarin. The kinetics of the antibody-antigen reaction was investigated and a first-order reaction was observed with k = 0.0329 mA min-1. This system provides a novel method for studying antibody specificity and the kinetics of such antibody-antigen interactions.
Antibodies↗
Shortened left ventricular filling time in dilated cardiomyopathy: additional effects on heart rate variability?
OBJECTIVE: To assess possible mechanical influences underlying the reduced heart rate variability in patients with dilated cardiomyopathy. DESIGN: Comparison of standard non-spectral indices of heart rate variability with echocardiographic Doppler measures of left ventricular function in patients and normal controls. PATIENTS: 20 patients with dilated cardiomyopathy and 15 normal subjects of similar ages were studied. METHODS: Standard non-spectral indices of heart rate variability were measured over 24 hours. These were correlated with left ventricular cavity size, shortening fraction, and isovolumic relaxation time measured by M mode echocardiography, and the duration of functional mitral regurgitation and left ventricular filling time assessed by continuous wave Doppler. RESULTS: Mean RR interval and estimates of short term variability (root mean square difference of successive RR intervals, proportion of adjacent RR intervals > 50 ms different, and SD indices) were not different from normal. The overall mean (SD) of the RR interval (65 (35)), and SD of five minute mean RR intervals (55 (30)), however, were reduced compared with normal values (115 (40) and 105 (45); p < 0.01 for both). Neither correlated with left ventricular cavity size or shortening fraction, but both were strongly related to left ventricular filling time (coefficient of variation, r = 0.82 and r = 0.81 respectively). Correlation persisted when the SD was corrected for RR interval (r = 0.69) although this correlation was not found in the controls. In individual patients, the difference between RR interval at the time of echo and minimum value during the 24 hours, a measure of ability to increase heart rate, also correlated closely with filling time (r = 0.92). CONCLUSION: As the duration of functional mitral regurgitation is effectively fixed, its presence can limit the time available for left ventricular filling in dilated cardiomyopathy when heart rate is high. This may become the mechanism by which maximum heart rate is set, becoming fixed to optimise cardiac output. This manifestation of dilated cardiomyopathy may be an important factor in reduction of heart rate variability in these patients.
Adult↗
Microalbuminuria and coronary heart disease in non-diabetics.
Microalbuminuria (or urinary albumin excretion rates (AER) above normal limits) is associated with coronary heart disease (CHD) particularly in diabetics. To determine the sensitivity and specificity of AER for CHD in a non-diabetic population we prospectively studied 115 consecutive patients undergoing coronary angiography and 66 undergoing exercise electrocardiography (ECG). There was no relationship between AER and the severity of CHD determined by angiography (Gensini-scored). While microalbuminuria (AER > 20 micrograms/minute) was 91% specific it had low sensitivity (12%). Microalbuminuria is not a sensitive indicator of CHD in a non-diabetic population.
Aged↗
The reinvention of traditional medicine in western North Carolina.
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Complementary Therapies↗
Activating point mutations of the gsp oncogene in human thyroid adenomas.
The gene for the alpha polypeptide chain (alpha s) of the heterotrimeric G protein Gs can be activated to the putative oncogene gsp by specific point mutations at codons 201 and 227. Such mutations have been reported in 40% of human growth hormone-secreting pituitary adenomas and in a single autonomously functioning thyroid adenoma. We examined an archival series of 45 differentiated human thyroid tumors by polymerase chain reaction amplification and oligonucleotide hybridization to identify point mutations at each of the affected codons. Successful amplification was achieved in 38 cases, and activating mutations were identified in 5 of 13 (38%) autonomously functioning adenomas, but in none of 16 nonfunctioning adenomas, six papillary carcinomas, or three follicular carcinomas. Our results confirm that the gsp oncogene is involved in the pathogenesis of autonomously functioning tumors but do not support a role in other thyroid tumors.
Adenoma↗
Abnormalities of the p53 tumour suppressor gene in human pancreatic cancer.
The tumour suppressor gene p53 has been found to be mutated or inactivated at high frequency in several common human tumours. We have examined a series of exocrine pancreatic carcinomas for over-expression of mutant forms of p53 by immunohistochemistry with a panel of specific antibodies. We found immunodetectable p53 in 13 of 22 (60%) frozen pancreatic cancers and seven of 13 pancreatic cell lines. One of the antibodies, CM1, recognises p53 in formalin-fixed, paraffin-embedded archival material and using this reagent we found immunodetectable p53 in 28 of 124 (23%) pancreatic cancers. We have successfully demonstrated the presence of point mutations by direct sequencing of genomic DNA extracted from archival tissue showing CM1 immunoreactivity. We conclude that p53 activation is an important event in human pancreatic tumorigenesis and that the CM1 antibody can detect a proportion of cases of overexpression of mutant p53 in archival pathological material.
Antibodies, Monoclonal↗
Urokinase-plasminogen activator, a new and independent prognostic marker in breast cancer.
Urokinase plasminogen activator (UK-PA) is a serine protease implicated in cancer invasion and metastasis. In this investigation, patients with breast cancers containing high levels of UK-PA antigen had significantly higher risk of early disease recurrence and shorter overall survival than did patients with low levels of the protein. In univariate analysis, UK-PA was a more powerful discriminator for disease-free interval than axillary node status, tumor size, or estradiol receptor. For overall survival, UK-PA as a prognostic marker, was of similar magnitude to axillary node status but stronger than that of tumor size or estradiol receptor. In multivariate analysis, for both disease-free interval and survival, UK-PA was an independent risk factor, being independent of tumor size, axillary node status, and estradiol receptor. UK-PA appears to be a new and independent prognostic marker in breast cancer.
Antigens, Neoplasm↗
Urokinase plasminogen activator and prognosis in breast cancer.
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Breast Neoplasms↗
Detection of polymorphic epithelial mucins in the serum of systemic breast cancer patients using the monoclonal antibody, NCRC-11.
Serum from patients with systemic breast cancer was found to contain elevated levels of polymorphic epithelial mucin (PEM) as detected using an immunoradiometric assay employing the monoclonal antibody NCRC-11. PEM was partially purified from pooled sera from these patients and the complex, polymorphic, high-molecular-mass (greater than 400 kDa) mucin was identified by sodium dodecylsulphate/polyacrylamide gel electrophoresis, Western blotting and immunostaining with the NCRC-11 antibody. Serial serum samples from 16 patients with metastatic breast cancer were assayed for circulating PEM defined by the monoclonal antibody NCRC-11. The clinical course of disease in these patients was assessed independently as progressive, static or responsive. Increasing NCRC-11 antigen levels correlated with disease progression in 6/7 patients, and decreasing antigen levels correlated with an objective response to treatment in 5/6 patients. Measurement of NCRC-11-defined PEM antigen in patients undergoing therapy for metastatic breast cancer showed an overall accuracy of 75%.
Antibodies, Monoclonal↗
Immunological and structural features of the protein core of human polymorphic epithelial mucin.
The protein core of high mol. wt polymorphic epithelial mucin (PEM--approximately 400 kDa glycoprotein) which is associated with breast carcinomas, consists of a repeating 20 amino acid peptide motif [Gendler et al. (1988) J. biol. Chem. 263, 12,820-12,823]. Monoclonal antibodies C595 (anti-urinary mucin) and NCRC-11 (anti-breast carcinoma cells), and other antibodies against human milk fat globule membranes, were found to recognize determinants present within this 20 amino acid peptide. A model of the peptide was developed based on hydropathicity and structure prediction calculations and these indicated that the repeated structure is dominated by a hydrophilic domain of seven amino acids, extending into two flanking beta turns. NMR analysis of the 20 amino acid peptide was undertaken to probe the secondary structure. Epitope mapping experiments involving solid phase synthesis of overlapping heptapeptides in the repeat unit identified the minimum structures for antibody binding as Arg-Pro-Ala-Pro and Arg-Pro-Ala for the C595 and NCRC-11 antibodies, respectively. These determinants were found within the predicted hydrophilic turn region domain of the peptide. The epitopes for six other PEM-reactive monoclonal antibodies were also determined to reside within the predicted hydrophilic turn domain. This evidence is in accord with the disposition of this region of the PEM peptide core being at the exterior of the glycoprotein where it would be accessible to antibody recognition and binding events.
Amino Acid Sequence↗
Polymorphic epithelial mucin from the sera of advanced breast cancer patients--isolation and partial characterisation.
The anti-breast carcinoma monoclonal antibody (MAb), NCRC-11 defines a polymorphic epithelial mucin (PEM) which is elevated in the circulation of advanced breast carcinoma patients. Here we describe the purification and partial characterisation of this component from patients' sera and its use in the production of a second generation MAb, C568 (IgM). Pooled sera was fractionated by immunoaffinity and size-exclusion chromatography and the purity of preparations assessed by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting. Serum-derived PEM shows a similar pattern of electrophoretic mobility to PEM isolated from primary breast tumour tissue and migrates as several bands in 4% SDS polyacrylamide gels (Mr greater than 400,000). The epitope expression of PEMs isolated from either source is also similar, with both bearing topographically distinct determinants for several anti-mucin MAbs. The immunoreactivities of antibodies C568 and NCRC-11 were unaffected by boiling, reduction and alkylation, or by enzyme desialylation of PEM. Periodate oxidation and proteolytic digestion have suggested that the antigenic determinant for C568 is carbohydrate in nature whilst that of NCRC-11 is peptidic. In accord with the mucinous nature of the molecule, serum-derived PEM is susceptible to reductive beta-elimination, elutes in the void volume of a Sepharose CL-4B column and has a buoyant density of 1.45 g ml-1.
Antibodies, Monoclonal↗