Biomedical subjects
B Curran
Publications and source records attributed to B Curran.
An urban epidemic--an audit of an inner city young persons' clinic.
In 1996 a young persons' clinic was set up at the Archway Sexual Health Clinic. A retrospective case note review of all attendees for 7 months in 1999 was performed to assess the demography and incidence of sexually transmitted infections (STIs) amongst attenders of the clinic. There were 567 attendances, comprising 364 individuals (331 women and 33 men). Ten per cent of attendees were less than 16 years of age, and 48% were 16-18 years. Fifty-eight per cent were from ethnic minorities. Chlamydial and gonococcal infection was identified in 21.3% and 8.4%, respectively. Thirty-five per cent of new presentations by women involved pregnancy testing, 28.6% were positive. The introduction of the clinic has been successful judged both by the amount of attendances and diseases diagnosed. Specific provision of services for this group needs to be addressed by all sexual health providers.
The pro-inflammatory cytokine interleukin-18 impairs long-term potentiation and NMDA receptor-mediated transmission in the rat hippocampus in vitro.
The effects of the pro-inflammatory cytokine interleukin-18 (IL-18) were investigated on both normal and isolated N-methyl-D-aspartate (NMDA) receptor-mediated field excitatory post synaptic potentials (fEPSP) and on the induction of long-term potentiation (LTP) in the rat dentate gyrus in vitro. Bath perfusion with IL-18 (100 ng/ml) for 20 min prior to high-frequency stimulation had no significant effect on baseline synaptic transmission or paired pulse depression, but did impair the induction of LTP (115.7+/-8.8% versus 150.8+/-8.1% in vehicle control slices, n=6, P<0.05 at 60 min). Further analysis demonstrated that IL-18 significantly depressed the amplitude of pharmacologically isolated NMDA receptor-mediated fEPSP (NMDA-fEPSP; 77.4+/-4.3% of baseline compared to controls at 1 h; P<0.05, n=7), an effect that may underlie the impairment of LTP by IL-18. This action of IL-18 on LTP and NMDA-fEPSPs was attenuated in full by pretreatment of slices with exogenously applied IL-1 receptor antagonist (IL-1ra, 100 ng/ml), the naturally occurring antagonist of IL-1 type 1 receptors. This ability of IL-1ra to block the inhibitory effects of IL-18 is likely to be receptor-specific as no reversal of the tumour necrosis factor-alpha-induced inhibition of LTP was seen with IL-1ra administration (110.7+/-5.4% versus tumour necrosis factor-alpha-treated slices; 107.4+/-8.7%, P=0.6, n=6). These are the first experiments providing evidence of a direct neuromodulatory role for IL-18 in synaptic plasticity.
Where goest the Peacock?
Since the treatment of the first patient in 1994, the Peacock system has maintained its presence as the dominant method of intensity-modulated radiation therapy (IMRT) delivery. Currently in use at nearly 80 institutions, over 8000 patients have been treated using the system. Peacock treatments have been delivered to sites throughout the body, including CNS, head & neck, prostate, liver, kidney, lung, mediastinum, and extremities. IMRT, however, is a young and rapidly evolving treatment methodology. As institutions have explored new ways of improving radiation therapy with intensity-modulated techniques, the requirements for the Peacock system have also expanded. More sophisticated planning algorithms have been implemented to satisfy these new requirements, as well as better tools for treatment verification and quality assurance. In addition, new delivery techniques are being examined to improve the ability of IMRT to increase target volume doses while limiting organ-at-risk doses. One such technique, using helical tomotherapy (Peacock is an example of sequential tomotherapy), is currently being evaluated at one institution. Both techniques use narrow, modulated delivery beams. However, helical tomotherapy requires continuous movement of the couch during radiation, similar to helical CT. This work reviews the development of tomotherapy with the Peacock system. It then looks at current IMRT treatment techniques using tomotherapy, and how the field has broadened since the first treatments were delivered. Finally, it looks at the future of tomotherapy techniques, and how these techniques will adapt to the changing requirements for radiation therapy.
Immunohistochemical expression of nm23 in primary invasive malignant melanoma is predictive of survival outcome.
The objective of this study was to determine the utility of nm23 as an immunohistochemical indicator of prognosis in a large series (157 cases) of malignant melanoma and also in two subsets within this group: stage 1 tumours, whether in radial or vertical growth phase (140 cases); and stage 1 tumours in which a vertical growth phase component was positively identified (123 cases). A secondary objective was to explore the relationship between the immunohistochemical expression of nm23 and established clinical and histological indicators of prognosis in each of these three groups. In all groups it was found that strong immunoreactivity correlated positively with survival and inversely with indicators of poor prognosis, in keeping with transfection and mRNA studies and also with many immunohistochemical studies of other tumour types. That these findings are at variance with earlier reported immunohistochemical studies of melanoma highlights the importance of large case numbers of primary invasive tumours in studies which set out to explore the relationship between immunoreactivity and survival.
Replication error phenotype, clinicopathological variables, and patient outcome in Dukes' B stage II (T3,N0,M0) colorectal cancer.
AIMS: To examine the relation between the replication error (RER) phenotype and other genetic events, clinical features, and long term survival in patients with Dukes' B stage II (T3,N0,M0) colorectal cancer. METHODS: RER phenotype was investigated in 159 patients by PCR amplification of microsatellite marker loci on chromosomes 5q, 17p, 17q, and 18q from tumour DNA extracted from archival tissue. Data on activating c-Ki-ras mutations were available from a previous study. Immunohistochemical detection of p53 and c-erbB-2 expression was performed on paraffin wax embedded tissue. RESULTS: Of 159 colorectal cancers studied, 22 (14%) were RER+ while 137 (86%) were RER- for two or more loci. RER+ tumours were more commonly located in the right colon, tended to be larger than RER- tumours, and were more often poorly differentiated than RER- cancers. No significant associations were seen between RER status and the presence of a mutant c-Ki-ras gene, or between RER status and p53, c-erbB-2, or c-myc gene expression. Univariate survival analysis showed that outcome was similar in RER+ and RER- cases. Multivariate survival analysis showed that the relative risk of death for patients with RER+ cancers was 0.95 that of patients with RER- cancers. CONCLUSIONS: The results suggest that, while the RER phenotype may be associated with some differences in tumour pathology (site, size, differentiation), it is not associated with the genetic alterations studied or with significant differences in long term survival.
Non-invasively determined ambulatory venous pressure.
In view of the resemblance of exercise-induced plethysmographic changes with those obtained by direct venous pressure measurement, we decided to use a combination of photoplethysmography (PPG) and hydrostatic pressure calibration to determine the PPG/pressure relationship. A standard foot dorsiflexion exercise involving stepwise position changing was performed which induced hydrostatic pressure changes that were recorded as the heart-probe distance. A logarithmic PPG/pressure relationship was identified and the resulting ambulatory venous pressure (AVP) was obtained from the PPG/pressure curve. Simultaneous direct AVP was recorded in 14 patients scheduled for venous surgery. 'Non-invasive AVP only' was determined in 24 normal control subjects with a mean value of 19.24 mmHg (+/-8.79 SD). In the patient group, the direct AVP values were 40.00 mmHg (+/-10.83 SD) compared with the PPG values of 33.07 mmHg (+/-12.94 SD). The resulting correlation was r = 0.8850. By utilizing stepwise leg elevation, a reliable PPG/pressure curve can be established which, in turn, permits AVP determination. It is suggested that this non-invasive AVP determination may serve as a screening test to evaluate non-invasively venous hemodynamics.
Dosimetric verification of a commercial inverse treatment planning system.
A commercial three-dimensional (3D) inverse treatment planning system, Corvus (Nomos Corporation, Sewickley, PA), was recently made available. This paper reports our preliminary results and experience with commissioning this system for clinical implementation. This system uses a simulated annealing inverse planning algorithm to calculate intensity-modulated fields. The intensity-modulated fields are divided into beam profiles that can be delivered by means of a sequence of leaf settings by a multileaf collimator (MLC). The treatments are delivered using a computer-controlled MLC. To test the dose calculation algorithm used by the Corvus software, the dose distributions for single rectangularly shaped fields were compared with water phantom scan data. The dose distributions predicted to be delivered by multiple fields were measured using an ion chamber that could be positioned in a rotatable cylindrical water phantom. Integrated charge collected by the ion chamber was used to check the absolute dose of single- and multifield intensity modulated treatments at various spatial points. The measured and predicted doses were found to agree to within 4% at all measurement points. Another set of measurements used a cubic polystyrene phantom with radiographic film to record the radiation dose distribution. The films were calibrated and scanned to yield two-dimensional isodose distributions. Finally, a beam imaging system (BIS) was used to measure the intensity-modulated x-ray beam patterns in the beam's-eye view. The BIS-measured images were then compared with a theoretical calculation based on the MLC leaf sequence files to verify that the treatment would be executed accurately and without machine faults. Excellent correlation (correlation coefficients > or = 0.96) was found for all cases. Treatment plans generated using intensity-modulated beams appear to be suitable for treatment of irregularly shaped tumours adjacent to critical structures. The results indicated that the system has potential for clinical radiation treatment planning and delivery and may in the future reduce treatment complexity.
Theoretical considerations of monitor unit calculations for intensity modulated beam treatment planning.
A treatment planning system to compute intensity modulated radiotherapy (IMRT) treatments using inverse planning was investigated. The system was designed to optimize the intensity patterns required to treat a specified target volume with specified normal structure constraints. A beam model that uses the convolution of pencil beams was used to compute the dose distributions. A multileaf collimator leaf-setting sequence intended to produce the intensity pattern was computed along with the monitor units required to deliver each of a number of fixed-gantry modulated fields. Computer calculations are commonly verified using an independent manual procedure. It is difficult to calculate treatment delivery monitor units for this variant of IMRT using manual methods. Since manual calculations are not feasible, it is important both to understand and to verify the calculation of treatment monitor units by the planning system algorithm. A formal analysis was made of the dose calculation model and the monitor unit calculation embedded in the algorithm. Experimental verification of the dose delivered by plans computed with the methodology demonstrated an agreement of better than 4% between the dose model and measurements.
Combination of pressure and velocity parameters in the non-invasive diagnosis of aorto-iliac disease.
Three different femoral artery flow velocity parameters in combination with segmental pressure measurements were evaluated for their respective diagnostic value in identifying the presence or absence of hemodynamically significant aorto-iliac disease. A total of 60 patients (119 legs) were examined both non-invasively and with arteriography. Doppler flow velocities were recorded using a 5-MHz CW Doppler velocity metering system. Of the three parameters used (peak velocity, decay time and deceleration), a decay time of 220 ms yielded the most practical discriminant value. The accuracy increases when in addition the upper thigh/arm pressure ratio values are considered. The results indicate that the combination of femoral artery decay time with the upper thigh/arm pressure index provides a simple and accurate non-invasive screening method to confirm or rule out aorto-iliac disease. This helps to determine whether the patient is a candidate for arteriography and for potential surgical intervention.
Loss of heterozygosity and microsatellite instability at the DCC and nm23 loci in Duke's B colorectal carcinoma.
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Determination of testicular function after torsion by DNA flow cytometry of serial fine-needle aspirates.
OBJECTIVE: To determine the efficacy of DNA flow cytometric analysis of testicular percutaneous fine-needle aspirates in the assessment and follow-up of testicular function after torsion, and to determine the relationship between the duration of torsion and testicular injury. MATERIALS AND METHODS: Three groups of 15 adult rats underwent a 720 degrees torsion, with fixation of the mesorchial ligament, for 1, 3 or 5 h. Bilateral aspirations, performed 7, 21 and 35 days after torsion were examined by flow cytometry. Testes were harvested and evaluated histologically using Johnsen's scoring. RESULTS: Irreversible testicular injury occurred in all three groups of rats, with loss of function after 1 h and loss of viability after 3 and 5 h. The results from flow cytometry suggested significant contralateral testicular injury (P < 0.025) but this was not supported by the histological evaluation. There was a strong correlation between the testicular function assessed by flow cytometry and by Johnsen's scoring of histological specimens (r2 = 0.95). CONCLUSION: The assessment of testicular aspirates by flow cytometry allows testicular function to be followed after torsion in rats, and potentially in humans. Using DNA flow cytometry, the temporal course of the twisted testis in the adult rat was determined; contralateral testicular injury following the reversal of torsion could not be excluded.
Ploidy profile of morphologically normal squamous epithelium adjacent to high grade cervical intraepithelial neoplasia.
We have investigated the ploidy profile of morphologically normal mucosa adjacent to high grade CIN (n = 16) and also from normal cervix (n = 18). DNA ploidy was assessed using flow cytometry and image analysis. All cases were diploid by both modalities. Our results show that morphologically normal squamous mucosa has a stable ploidy profile even when it lies adjacent to high grade CIN. This finding supports the view that high grade CIN is a neoplastic expansion of transformed cells rather than the result of a field change effect.
Identification of Euro-Americans, Afro-Americans, and Amerindians from palatal dimensions.
Seven measurements were taken on 414 Euro-American, Afro-American, and Amerindian palates in an attempt to evaluate differences in dental arcade shape among these three groups. Width measurements across the palate at the first incisor, canine, second premolar, and second molar were taken directly on the dental arcade. The distances along the sagittal plane from the front of the palate to the level of these teeth were calculated from measurements taken between the right central incisor and the canine, second premolar and second molar. Discriminant functions computed from the measurements properly classified palates by group 66.0% of the time if sex is unknown. If sex is known to be male, other functions properly classified 65.7% of the sample; for sex known to be female 72.0% correct classification was achieved. Because these percentage are more than twice that expected from probability theory alone, it is concluded that the seven measurements are useful in determining ethnic group.
An image analysis study of DNA content in early colorectal cancer.
The DNA content of 168 consecutive T3,N0,M0 (Dukes' B, Astler-Coller B2) colorectal cancers was studied using image analysis on formalin-fixed paraffin-embedded tissues. 72 cases (43%) were classified as diploid and the remaining 96 (57%) as non-diploid. After a median follow-up period of 6.7 years, a significant survival advantage was found for diploid compared with non-diploid cases (logrank test; P = 0.008). The long-term (8 year) survival rate was 70% for diploid and 46% for non-diploid tumours. Subgroup analysis showed that the survival advantage conferred by tumour diploidy was greatest in large (> or = 5 cm) cancers and was found both in colonic and rectal cancer cases. These data indicate that tumour ploidy status measured by image analysis might be useful in determining risk of colorectal cancer recurrence and death in patients following resection of early colorectal cancer.
Proliferation indexes--a comparison between cutaneous basal and squamous cell carcinomas.
AIMS: To compare differences in cell proliferation indexes and apoptotic indexes between cutaneous basal and squamous cell carcinomas, in an attempt to suggest an explanation for the differences in their biological behaviour. METHODS: Forty cases of cutaneous basal cell carcinoma (BCC) and 40 cases of moderately and well differentiated squamous cell carcinoma (SCC) were retrieved from the archives. Sections, 4 microns thick, were cut from formalin fixed, paraffin wax embedded tissue in each case and stained with haematoxylin and eosin. These were then examined for mitotic and apoptotic figures per 1000 cells. Sections from the same cases were also immunostained with the mouse monoclonal antibody Ki67 (MIB1); positive nuclear staining was counted per 1000 cells. RESULTS: No significant differences were found between the mitotic indexes and apoptotic indexes in these tumours. There was, however, a significant difference in Ki67 (MIB1) staining, with greater staining in the squamous cell carcinomas. CONCLUSION: Estimation of the mitotic and apoptotic indexes did not reveal any differences between these two tumour types. The proliferation indexes, assessed by Ki67 immunostaining, did differ. This may be one of the factors underlying the more aggressive behaviour of SCC.
DNA ploidy, expression of p53 protein and metastatic behaviour of gastric carcinoma.
DNA ploidy of 57 gastric carcinomas with metastases (12 liver, 1 adrenal, 4 ovary and 48 lymph node) were measured by flow cytometry. DNA anueploidy was significantly related to liver metastases: 9 out of 12 gastric carcinomas with liver metastases were anueploid (75%) as compared to 13 out of 45 (28.8%) of cases without liver metastases (P < 0.01); the one gastric carcinoma with adrenal metastasis was also anueploid. DNA ploidy was not related to ovarian or lymph node metastases. Another interesting finding was that all of 3 gastric carcinomas with liver metastases which showed a diploid DNA pattern, expressed p53 protein, while all of 3 carcinomas with liver metastases but no p53 protein expression were anueploid. The expression of p53 protein was not related to ovarian metastases. The results suggested that an anueploid DNA pattern and the expression of p53 protein are both objective markers valuable in predicting high risk potential of metastases to the liver, and that the combined detection of these markers can be a most useful method in the follow-up of patients with gastric carcinoma in detecting those at high risk of developing metastases following surgical resection. Also the poorer prognosis of patients with gastric carcinoma showing an anueploid DNA pattern may be related to the development of distant organ metastases through the blood vascular system. Furthermore, the clone of gastric carcinoma cells which accumulate p53 protein or show an anueploid DNA pattern may have a causative role in the development of liver (& adrenal) metastases.
DNA ploidy status in 84 ocular melanomas: a study of DNA quantitation in ocular melanomas by flow cytometry and automatic and interactive static image analysis.
Deoxyribonucleic acid (DNA) ploidy was quantified in 84 ocular melanomas (median follow-up, 11-years) by flow cytometry, CAS 200 interactive image analysis, and Pathology Image Processing Environment (PIPE; Department of Quantitative Pathology, Free University, Amsterdam, The Netherlands) automatic image analysis (75). Overall, 32.1% of the melanomas were aneuploid, 2.3% were tetraploid, and 66.6% were diploid. Pathology Image Processing Environment analysis estimated DNA ploidy in 12 tumors that were unprocessable by flow cytometry. Of 10 tumors that were diploid by flow cytometry, PIPE detected stemline aneuploidy in five and some aneuploid cells in five more. Seven tumors were aneuploid by PIPE but diploid by CAS 200, five of which contained occasional DNA aneuploid cells on the CAS 200 histograms. Pathology Image Processing Environment analysis quantified tumor samples with an average of 500 (250 to 1,050) cells in less than 10 minutes. All cells classified as spindle A according to the Callender system (more than 10,000) were diploid. Spindle B and epithelioid cells occupied both diploid and aneuploid peaks on the DNA histograms. Dioxyribonucleic acid variables did not correlate with established prognosticators, such as Callender cell type, largest tumor dimension, or glaucoma, nor did they reach significance by univariate and multivariate analyses. The value of these findings as a diagnostic support in uveal melanoma, particularly in combination with fine needle aspiration biopsy, is discussed.