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Biomedical subjects

J M Dunn

Publications and source records attributed to J M Dunn.

At least 19 recordsLinked to original sources

Exfoliative cytology in the diagnosis of breast disease.

A total of 393 nipple discharge or scrape smears from 360 women were examined cytologically over a 12-year period. Twenty-nine breast cancers (8 per cent) have been histologically confirmed in this group, of which 16 had malignant smear cytology (sensitivity 55 per cent). Nine patients with breast cancer and positive cytology had impalpable tumours. Two of these cancers were not detected by any other investigation. Thirteen patients with nipple discharge had false-negative cytology, but there were no false-positive results (specificity 100 per cent). All patients with expressible or spontaneous nipple discharges and those with skin changes at the nipple should undergo examination of cytological smears.

Breast Neoplasms

The Grb2 binding domain of mSos1 is not required for downstream signal transduction.

Cellular Ras proteins are activated primarily by specific guanine-nucleotide releasing factors such as the Son of Sevenless (Sos) proteins. This activation event is thought to occur in response to plasma membrane localization of a complex containing Sos and a small adapter protein Grb2. We have isolated a dominant mutant allele of mSos1 which transforms Rat1 cells, yet is no longer able to bind Grb2. Biochemical experiments reveal that the subcellular distribution of this truncated Sos protein is not altered with respect to the wild type Sos protein. These data argue against a role for Grb2 in the direct recruitment of Sos proteins to the plasma membrane and suggest that Grb2 may function to overcome negative regulation of Sos by its C terminus.

Adaptor Proteins, Signal Transducing

Surgical treatment for venous ulcers: is it worthwhile?

We have reviewed the results of treatment of 159 consecutive limbs presenting with a clinical diagnosis of venous ulcer in 140 patients (70 male, aged 28-90 years, median 66 years). Of the patients, 61% were referred because of severe pain and 53% of the ulcers had been present > 2 years. Patients were evaluated clinically and by Doppler, with selective use of venography, photoplethysmography, arteriography and latterly duplex scanning. Seventy-one limbs had surgery to the superficial veins, 18 limbs had arterial reconstruction, and 10 limbs had skin grafting alone. There was one operative death after arterial reconstruction but none after venous surgery. Patients were followed up for 1-5 years (median 3 years). Of those who had been treated surgically, healing was achieved in 88%, and ulcers healed in 52% of those treated non-operatively. In all, 18% of the ulcers recurred in each group. These results show a favourable association between appropriate venous and arterial surgery and the healing of venous ulcers, with relief of pain. They support a policy of thorough evaluation and appropriate surgical treatment in these patients.

Adult

Comparison of radioligand assay and immunostaining for epidermal growth factor receptor in human breast cancer.

Epidermal growth factor (EGF) receptor status is a useful prognostic indicator in women with breast cancer. Lack of standardization and correlation of methodology for the detection of EGF receptor has hampered its further evaluation. EGF receptor status was ascertained by immunohistochemistry and radioligand assay in 120 breast cancers. Of 52 tumours negative for EGF receptor on radioligand assay, 47 were negative on immunohistochemistry and, of 68 tumours positive for the receptor on assay, 52 were positive on immunohistochemistry. If the more widely evaluated radioligand assay is assumed to be the 'gold standard', immunohistochemistry has a sensitivity of 81 per cent and a specificity of 91 per cent.

Biomarkers, Tumor

Chronic alterations in cardiac mechanics after fetal closed heart operation.

Pulmonary artery banding was performed in 8 fetal sheep at 125 days' gestation to evaluate the feasibility of fetal closed cardiac operation. At 135 days' gestation, the fetuses were delivered and the cardiac mechanics were evaluated using a modified Langendorff isolated heart preparation. Two of the 8 fetuses aborted spontaneously 2 and 7 days after operation. Six fetuses (75%) survived the 10 days after delivery. The left ventricular cardiac mechanics in the banded fetuses (group I) were compared with those in 8 control fetuses (group II). All fetal hearts in both groups displayed a significant volume-pressure relationship. The volume-pressure curve was found to be shifted upward and to the left in the fetal hearts after pulmonary artery banding. The left ventricles subjected to increased in utero preload secondary to pulmonary artery banding were capable of generating greater peak systolic and developed pressures. Because the fetal heart manifests a Starling type of preload reserve, as such, it demonstrates that the possibility exists for subsequent fetal development to be altered by intrauterine intervention.

Animals

Scrape cytology in the diagnosis of Paget's disease of the breast.

Eczema of the nipple is an important symptom presenting to the general surgeon in the out-patient department. The diagnosis of Paget's disease of the nipple has traditionally been made by incision biopsy necessitating at least a local anaesthetic. We present 14 patients with nipple skin change, in whom the technique of scrape cytology was used to identify patients with Paget's disease. In our series eight cases of Paget's disease were successfully identified by scrape cytology with no false negatives or positives. We suggest that this is a quick, easy, non-invasive method of screening eczema of the nipple in the out-patient clinic.

Breast Diseases

Outpatient clinic review after arterial reconstruction: is it necessary?

After arterial reconstruction, patients have traditionally been followed up in clinic in the long term. We have pursued a policy of limited clinic follow-up, with an 'open access' service for suspected graft failure (and latterly duplex scanning surveillance for vein grafts). This policy was assessed by measurement of the success of self-referral, graft patency and patient satisfaction after operation for lower limb ischaemia in 173 patients. At median follow-up of 50 months, 61 (35%) patients had died and 45 (25%) had required amputation. Of those with salvaged limbs and available for follow-up, 55 (86%) patients reported continuing symptomatic improvement with a graft patency rate of 80%. During the review period, 27 (42%) patients had presented themselves on suspicion of graft occlusion and 14 (52%) of these had required surgical intervention. Of the patients, 45 (70%) found a single postoperative clinic visit helpful, and the majority thought that further visits would not have been helpful to them. Limited clinic appointments seem especially desirable for elderly patients for whom journeys are an imposition, as well as reducing travel costs, and giving surgeons more time to deal with new referrals. These results suggest that properly educated patients present themselves when signs of graft occlusion occur, and there is little to be gained by regular long-term clinic follow-up in vascular surgical practice.

Adult

Medullary thyroid carcinoma.

Medullary thyroid carcinoma accounts for 5-10 per cent of thyroid malignancies and occurs sporadically, and in three familial settings with autosomal dominant inheritance. Calcitonin, a 32 amino acid 3.5-kDa protein, is a biochemical marker of the tumour. Serum levels correlate with disease burden. Treatment initiated by screening allows disease removal at a premalignant phase: C cell hyperplasia. Genetic linkage studies locate the multiple endocrine neoplasia type 2A gene near the centromere of chromosome 10. Flanking genetic markers may allow polymorphic probes to examine DNA from a once-only blood sample to identify affected individuals. At what age thyroidectomy should be carried out in these patients is unclear.

Biomarkers, Tumor

Correlation between p53 mutations and antibody staining in breast carcinoma.

Abnormalities of the p53 gene and protein were examined in 81 primary breast carcinoma samples. Using a polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) analysis, mutations in p53 exons 5-8 were identified in 13 of 81 tumours (16 per cent) and confirmed by DNA sequencing. Positive staining for p53 protein was detected in ten of 77 (13 per cent) of these tumours using polyclonal CM1 antibody on formalin-fixed tissue. Mutations detected by PCR-SSCP analysis were more common in grade III tumours (P = 0.015), but no correlation was found with tumour size, node status or level of epidermal growth factor receptor expression. A p53 mutation was associated with positive antibody staining in only two patients. Positive immunohistochemical staining using a p53 antibody may detect p53 protein expression, but this may not correlate directly with an underlying mutation in the hot spot region examined.

Adult

Pressure-volume relationship of the fetal lamb heart.

In contrast to the adult heart, the fetal heart reportedly has little functional reserve. With increased clinical emphasis on fetal cardiac diagnosis, neonatal surgery, and the potential for future fetal cardiac intervention, it is essential that we better understand fetal cardiac function. Therefore, to demonstrate the extent of fetal cardiac preload reserve, we studied 10 fetal lambs using an isolated, isovolumic, blood-perfused heart preparation. We maintained constant afterload, inotropic state, coronary blood flow, heart rate, and perfusate blood gas values. As left ventricular (LV) volume (preload) was incrementally increased, LV end-diastolic pressure and LV peak systolic pressure were recorded. Linear regression analysis demonstrated that increases in LV developed pressures were predicted by the LV volume, demonstrating the presence of the Frank-Starling mechanism in each case. The plateau of the Starling pressure-volume curve occurred at an LV end-diastolic pressure of 12.5 +/- 4.79 mm Hg (95% confidence interval, 9.07 to 15.9 mm Hg), lower than the plateau expected in the adult heart. This implies that, in the management of fetal and immature neonatal hearts, preload reserve plays an important but limited role in cardiac reserve.

Animals

Epidermal growth factor receptor determination on tumour imprints.

Epidermal growth factor receptor (EGFR) is a sensitive prognostic indicator in women with breast cancer. A new technique for the detection of EGFR on breast cancer imprints is described and evaluated in relation to immunohistochemistry on frozen sections. The standard streptavidin-biotin method using the R1 antibody on frozen sections was modified for use on tumour imprints. In the first group (group 1 imprints) 43 tumours were assessed by frozen section and imprint staining. The group 1 imprint method had a sensitivity of 50% and a specificity of 89% compared with the frozen sections. Further modifications were made for the following 32 tumours (group 2) and this method had a much improved sensitivity of 94% while specificity was preserved. This method is simple and could be performed in any hospital histopathology department.

Bacterial Proteins

Diagnostic and therapeutic aspects of fine-wire localization biopsy for impalpable breast cancer.

During the first 2 years (July 1989 to July 1991) of the Avon Breast Screening Service, fine-wire localization biopsy was indicated in 213 impalpable breast lesions. A total of 144 lesions were benign and 69 malignant. Only four of 213 lesions (1.9 per cent) were not excised at the first localization. Factors influencing reoperation in the 69 patients with malignant impalpable lesions were examined. There was a significant association (P < 0.001) between parenchymal disturbances on mammography and invasive carcinoma, and between non-invasive carcinoma and microcalcification (P < 0.001). In 31 patients the localization biopsy was the only surgical procedure. Thirty-eight patients required further surgery: 12 underwent further local excision and 26 mastectomy. Reoperation was more frequent in patients with calcification than in those with parenchymal disturbance (P < 0.001). The most frequent indications for mastectomy were inadequate excision of widespread comedo ductal carcinoma in situ or invasive ductal carcinoma combined with extensive ductal carcinoma in situ. Fine-wire localization biopsy was a combined therapeutic and diagnostic procedure in 31 of 69 women with impalpable screen-detected lesions. The majority of patients required further surgery because radiological abnormalities underestimated the extent of disease.

Biopsy, Needle

How do retinoblastoma tumours form?

The causes of retinoblastoma (RB) can now be described with considerable accuracy, although many details are still unclear. Understanding the genetic changes leading to RB has provided an awareness of general mechanisms of cancer development and progression, previously only suspected. From the basic understanding have come new diagnostic technologies that are now ready to be applied directly to RB patients and their families, and a rational approach, based on this understanding, will help us to develop new therapies that avoid the severe complications of conventional treatment.

Chromosomes, Human, Pair 13

Mechanisms of loss of heterozygosity in retinoblastoma.

Retinoblastoma (RB) tumors arise when both alleles of the RB1 gene are inactivated by two mutational events (M1 and M2). M1 can be an initial germline or somatic mutation; M2 is frequently loss of heterozygosity (LOH), which makes the cell homozygous or hemizygous for the original mutation. LOH is the major mechanism by which many cancers are initiated. To further delineate the mechanism of LOH, we screened a total of 37 RB tumors for LOH by Southern blot analysis. The tumors were from 17 bilaterally and 17 unilaterally affected patients. Nineteen of 30 informative tumors (63%) from 27 patients showed LOH. Proximal and distal flanking markers on chromosome 13 were informative in 13 tumors, allowing evaluation of the mechanisms by which LOH occurred. Mitotic recombination was implicated in 6 (46%) of the 13 tumors.

Blotting, Southern

Validity of a cardiorespiratory fitness test for men with mental retardation.

The purpose of this study was to validate a field test of cardiorespiratory fitness for men with mental retardation. The subjects were 19 healthy young men (26 +/- 6 yr) with moderate mental retardation (IQ = 48 +/- 11). Each subject underwent a maximal treadmill test after a three-phase familiarization process. Each subject also completed a 1-mile walk test twice (Rockport Fitness Walking Test = RFWT). The correlation coefficients between peak VO2 on the treadmill and the two 1-mile walks varied from 0.78 to 0.83. When weight, height, age, heart rates of 1-mile walks, and their combinations were held constant, the correlations were strengthened. Using multiple correlation analysis the best equation for predicting peak VO2 was: Peak VO2 = 101.92 - 2.356(mile-1 time) - 0.42(weight). This model accounted for 85% of total variance. The standard error of estimate was 4.06 ml.kg-1.min-1. The test-retest reliability of the RFWT for the 19 subjects used in this study was very high (R = 0.97). This finding suggests that the RFWT is a valid and reliable field test for this population and appears to be a valid indicator of cardiorespiratory fitness for these men with mental retardation.

Adult

Myxedema coma.

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