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Biomedical subjects

I A Cree

Publications and source records attributed to I A Cree.

At least 91 records · Page 5Linked to original sources
PubMed1994

Expression of the p53 tumour suppressor gene product is a determinant of chemosensitivity.

Many cytotoxic agents act by causing DNA damage, and the p53 tumour suppressor gene is known to be involved in the cellular response to DNA damage. Since inactivation of p53 is common in many tumours, we wondered if this would affect the sensitivity of cancer cells to cytotoxic agents. We have shown that this is indeed the case in transformed mouse cell lines with and without a mutated p53 gene; p53 "knockout" mouse fibroblasts, and normal human skin fibroblasts treated with an anti-sense p53 oligonucleotide. In addition, we have demonstrated a correlation between p53 protein expression in human breast cancer specimens and their chemosensitivity. The results show that inactivation or mutation of p53 renders cells more sensitive to those cytotoxic drugs whose primary mechanism of action is DNA damage.

Animals↗
PubMed1994

Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol.

The purpose of the present study was to assess the degree of protection of inhaled salmeterol against exercise-induced bronchoconstriction (EIB) after chronic compared with single dosing in patients with asthma. Twelve patients with exercise-induced asthma took part in a randomized double-blind crossover study to compare the duration of action of inhaled salmeterol 50 micrograms twice daily for 4 weeks with that of placebo. A standardized exercise test was performed at 6 h and 12 h after dosing on the first and last day of each treatment period. Salmeterol produced significant protection against EIB at 6 and 12 h after the first dose in comparison with placebo, whereas there was no significant attenuation of EIB after 4 weeks of chronic treatment with salmeterol. The percentage fall in FEV1 after exercise challenge at 6 h was (first dose): placebo 34.8 +/- 4.9% vs. salmeterol 11.9 +/- 2.8% (P < 0.05); (4 weeks): placebo 32.9 +/- 5.3% vs. salmeterol 24.0 +/- 4.4% (NS). These results suggest that tachyphylaxis may develop to the functional antagonism of salmeterol against EIB.

Administration, Inhalation↗
PubMed1994

Measurement of cell migration stimulated by interleukin 8: use of ATP chemiluminescence.

The reliability of methods for the measurement of chemotaxis is a problem which many previous studies have attempted to solve. However, it has recently been shown that the number of cells migrating through a filter can be measured by determining their ATP content by chemiluminescence. We have adapted this method to use microplates with a 24-well format. This allows cells traversing the membranes to be harvested by centrifugation. The modified method has been used to measure the chemotactic activity of interleukin 8 (IL-8) for human polymorphonuclear leukocytes (PMNL). There was a dose response to IL-8, with an optimal concentration of 10(-8) micrograms/ml. The main advantages of this ATP-based cell migration assay were found to be its speed, reproducibility and ease of use.

Adenosine Triphosphate↗
PubMed1994

The influence of storage on cytotoxic drug activity in an ATP-based chemosensitivity assay.

The use of viability assays to assess the effect of antineoplastic agents on cell lines and tumor cells is an important investigative tool and may have clinical relevance. Such assays require very small quantities of drugs and it is the practice of many laboratories to freeze aliquots of drugs for use in these assays as required. We have investigated the stability of 11 different agents in an ATP-based chemosensitivity assay which is being evaluated for clinical use. The results show that most drugs maintain their biological activity well when frozen at -20 degrees C for periods up to 24 months, or occasionally at room temperature. However, 4-hydroperoxycyclophosphamide and mitomycin C are exceptions to this rule, and should not be kept frozen for more than 2-3 months. Cisplatin is unstable when frozen and then thawed, but maintained activity at room temperature for at least 6 months. Since biological activity may not correlate completely with chemical stability, further studies on the effect of storage are required, but it seems unlikely that the appropriate use of frozen aliquots is a major source of error in tumor chemosensitivity assays.

Adenosine Triphosphate↗
PubMed1994

Detection of tumour necrosis factor alpha in sarcoidosis and tuberculosis granulomas using in situ hybridisation.

AIMS: To determine the site of tumour necrosis factor alpha (TNF alpha) product and mRNA in granulomas. METHOD: In situ hybridisation with digoxigenin labelled or biotinylated oligonucleotide probes was used to demonstrate the presence of total mRNA, and then the presence of TNF alpha mRNA in the biopsy specimens of 37 granulomas (31 sarcoidosis, six tuberculosis). RESULTS: TNF alpha mRNA was detected in epithelioid cells, giant cells, and lymphocytes in the granulomas. Some sarcoidosis specimens did not contain detectable mRNA for TNF, but did contain TNF peptide in the epithelioid or giant cells on immunostaining. This may have been due to stored TNF present in cells in which mRNA for TNF is no longer being produced. CONCLUSION: The results suggest that giant cells should not be regarded as effete cells, as they contain large amounts of mRNA and seem to be actively producing TNF alpha.

Antisense Elements (Genetics)↗
PubMed1994

Phagocyte function and cytokine production in community acquired pneumonia.

BACKGROUND: It is possible that many deaths from pneumonia may involve the generation of inflammatory mediators and tissue damage by activated phagocytes. To test this hypothesis phagocyte function, plasma levels of interleukin 6 (IL-6), tumour necrosis factor alpha (TNF alpha), and soluble interleukin 2 receptor (IL-2R), disease severity, and outcome have been examined in 46 patients with community acquired pneumonia. METHODS: Polymorphonuclear leucocyte (PMNL) and monocyte function were measured daily by chemiluminescence in these patients during the first week of admission, and cytokine levels were subsequently determined by ELISA. A series of 61 healthy individuals were used as a control group for the chemiluminescence results. RESULTS: There was evidence of phagocyte, particularly PMNL, activation on admission in 76% of the patients. Most patients (86%) also had raised IL-2R levels on admission. IL-6 and unbound TNF alpha were present in 23% and 41% of patients at varying times during the course of the disease. There was little correlation between measurements of cytokine or phagocyte levels and outcome or indicators of disease severity, although this may be because of the small number of patients included in this preliminary study. CONCLUSIONS: These results are consistent with the hypothesis that activated phagocyte function and raised levels of circulating cytokines may contribute to the pathogenesis of community acquired pneumonia. There are striking similarities in this respect between pneumonia, adult respiratory distress syndrome, and sepsis.

Adolescent↗
PubMed1994

Comparison of salmeterol with placebo in mild asthma: effect on peripheral blood phagocyte function and cytokine levels.

beta 2-Adrenergic agonists are widely prescribed for the symptomatic relief of asthma, but are not thought to alter the underlying pathogenesis. However, it has been suggested that salmeterol, a new beta-agonist with prolonged bronchodilatory action, may have anti-inflammatory properties. A double-blind crossover study of 4 weeks of inhaled salmeterol versus placebo was performed using a chemiluminescence assay to measure peripheral phagocyte function before and after each treatment period. Circulating cytokines [interleukin-1 beta (IL1 beta), IL4, IL6, IL2 receptor (IL2R)] were also measured. Although salmeterol caused a significant improvement in spirometry, there was no apparent modulation of phagocyte or cytokine activity. No evidence was obtained to support a clinically significant anti-inflammatory action of salmeterol.

Adult↗
PubMed1994

TNF and pneumonia.

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Community-Acquired Infections↗
PubMed1993

Departmental audit in histopathology.

Audit is now part of any laboratory service. Histopathology is no exception, and we have set up a system which allows us to review 4% of our specimens. These specimens are identified using a random number generator and reviewed by a consultant pathologist. Both slides and wet specimens are reviewed and graded according to a set scheme. The results from the first year of operation (1990) show a high rate of accuracy with no serious diagnostic disagreements between the auditor and the reporting pathologist. However, some errors which we would wish to prevent were detected and the audit has allowed us to take corrective measures. In our opinion, this form of audit is useful and necessary to maintain good clinical practice. The cost is considerable--histopathology is by its nature labour intensive. Recognition of this fact by health boards is essential if such systems are to continue.

Biopsy↗
PubMed1993

Heat-stable opsonins in tuberculosis and leprosy.

We have examined heat-stable opsonins to 4 species of gamma-irradiated mycobacteria (M. tuberculosis (H37Rv), M. avium (28A), M. scrofulaceum and M. leprae (cd 103)) in complement-depleted sera collected from Indonesian subjects with tuberculosis (106 patients),-leprosy (24 patients) and controls (40 hospital workers and 41 factory workers) indirectly by microtitre plate chemiluminescence (CL) assay and compared the results with antibody levels. The results indicate that there is a wide range of opsonic capacity for mycobacteria in complement-depleted sera. There was a poor correlation between the opsonic capacity as measured by CL and the anti-mycobacterial antibody content of sera measured by ELISA, suggesting that anti-mycobacterial antibody has little influence on the uptake of mycobacteria. However, a non-specific heat-stable opsonin appears to be present in some sera. Conversely, some sera from tuberculosis or leprosy patients suppress the production of reactive oxygen species from normal phagocytes in vitro when stimulated with M. tuberculosis. The relevance of this inhibition and the presence of heat-stable opsonins to the pathogenesis of tuberculosis have yet to be determined, but it is possible that the presence of opsonins may inhibit dissemination of tubercle bacilli to other organs.

Adolescent↗
PubMed1993

Heterogeneity of chemosensitivity in human breast carcinoma: use of an adenosine triphosphate (ATP) chemiluminescence assay.

Cancer chemotherapy is currently given to patients with breast carcinoma on the basis of data from response rates in patients with advanced disease, or from the results of clinical trials of adjuvant therapy. However, individual tumours may vary in their response to particular cytotoxic drugs: optimal therapy for a population of patients may not be the correct treatment choice in individual cases. In this study we have used an ATP-based non-clonogenic chemosensitivity assay (TCA-100) to investigate the heterogeneity of chemosensitivity of human breast carcinoma to a number of cytotoxic drugs, both as single agents and in combination. Tissue was obtained from 33 patients. Most samples were excision biopsies, but sufficient tumour cells were obtained from three needle biopsies and three pleural effusions for assays to be performed. The results show wide variation in the response of individual breast tumours to single agents, but most tumours show sensitivity to the commonly used combination regimens. The TCA-100 assay may provide useful information to support the choice of regimen for breast cancer chemotherapy.

Adenosine Triphosphate↗
PubMed1992

Macrophage and epithelioid cell nuclear morphology in leprosy.

The spectrum of disease in leprosy is characterised by the presence of macrophages in lepromatous lesions and epithelioid cells in tuberculoid granulomas. Since changes in nuclear shape occur during macrophage activation, we have measured nuclear morphology by planimetry in biopsies across the leprosy spectrum. The results show no significant correlation of any of the parameters of nuclear morphology measured between different lesions or between biopsies from the centre and edge of the same lesion. There were no differences between the Ridley-Jopling groups. However, several parameters which measure the degree of ellipticity of the nuclei showed strong correlation with granuloma size in untreated leprosy patients. This suggests that local pressure effects may influence epithelioid cell and macrophage nuclear morphology in leprosy lesions.

Adult↗
PubMed1992

A novel tissue preservation medium for immunoperoxidase staining of skin biopsies.

The requirement for unfixed tissue is a major drawback in the use of immunohistochemistry for the diagnosis of inflammatory and neoplastic disease. We describe the use of a novel gel transport medium (U.K. Patent No. WO 90/07703, international patent applications pending) to preserve unfixed skin biopsies from allergic contact dermatitis reactions for 1 week prior to frozen section and immunohistochemistry for leucocyte antigens. The medium can be used with biopsies up to 6 mm3 and does not require any alteration in the usual frozen section or immunohistochemical staining procedures. The results show a subjective improvement in both morphology and staining quality. We believe this to be due to improved cutting of the sections and reduced background staining of collagen. This transport medium should be of considerable benefit to the provision of a clinical service, because it allows tissue for immunohistochemical examination to be taken at locations distant from the pathology laboratory.

Cryopreservation↗
PubMed1992

Preservation of keratin expression in oral mucosa using a novel transport medium.

Cellular expression of keratins (intermediate filaments) can be demonstrated by immunocytochemistry using unfixed tissue. However, for practical reasons, provision of fresh tissue to the laboratory is often difficult. Recently a fresh tissue transport medium (Patent applied for) has been developed which allows keratin immunocytochemistry to be performed up to 4 days after biopsy. In this study oral mucosal biopsies from 10 patients were hemisected, half placed in the new transport medium at 4 degrees C and the other half immediately frozen in liquid nitrogen. After 4 days frozen sections of both halves of the biopsies were stained by immunocytochemistry using various antikeratin antibodies. The morphology and staining characteristics of the two halves of the biopsies were then assessed. No significant difference could be found in either morphology or preservation of keratin expression in specimens stored in transport medium, as compared to those in liquid nitrogen. This new transport medium may offer considerable advantage for the provision of a histologic and immunocytochemical diagnostic service.

Cacodylic Acid↗
PubMed1991

Impairment of vasomotor reflexes in the fingertips of leprosy patients.

A method is described for eliciting fingertip vasomotor reflexes by inspiratory gasp and contralateral hand cold challenge. The results of the two tests are reproducible on replicate testing and, when taken together, have proved reliable for detection of impairment of autonomic reflexes in 10 newly registered leprosy patients who did not have any obvious deformity. Similar, but less severe, impairment of vasomotor reflexes was noted in a group of 10 fully treated, apparently cured ex-leprosy patients, none of whom showed clinically obvious neuropathy. Both the new patients and the ex-patients were significantly different from healthy contacts and from healthy Europeans, who were indistinguishable by this test. Evidence is presented suggesting that impairment of these vasomotor reflexes is mainly due to damage to the efferent pathway in the peripheral nerves. The method might prove valuable for investigation of early nerve damage in new patients or during reversal reactions in leprosy at a stage before irreversible damage is done.

Adult↗
PubMed1991

Impairment of fingertip vasomotor reflexes in leprosy patients and apparently healthy contacts.

Fingertip blood-flow velocity and its control by vasomotor reflexes were studied in leprosy patients and in healthy controls with a laser Doppler flowmeter. In newly registered patients, the flow was significantly lower than in the healthy controls, and even lower values were recorded in the long-standing patients with lower limb ulcers and/or deformity. The newly registered patients showed substantially impaired vasomotor reflex responses in the fingertips to cold challenge of the opposite hand or deep inspiratory gasp. Low blood flow and impairment of vasomotor reflexes were more prominent in those leprosy patients who showed clinical evidence of neuropathy and/or histological evidence of reaction in a punch biopsy of leprosy skin lesions. This aspect of dysautonomia to cold challenge was particularly prominent in apparently healthy, fully treated ex-patients. There was an unexpectedly high prevalence of impairment of vasomotor reflexes in newly registered and apparently healthy, adequately treated leprosy patients. The method is very sensitive, and it remains to be established whether the lesions it detects are nonprogressive residues, or previous nerve damage, or an indication of on-going nerve damage. A minority of leprosy contacts showed impairment of vasomotor reflexes. Those with two or more affected fingers were more likely to have had a higher level of exposure to Mycobacterium leprae than those with one or no affected fingers. The cause of this unexpected impairment of fingertip vasomotor reflexes in a minority of leprosy control workers has not yet been determined.

Adolescent↗
PubMed1990

Granular cell tumour of the larynx.

A granular cell tumour may present as clinically innocuous lesions on the vocal cords and the diagnosis is usually made by histopathology. However, the granular cells characteristic of this tumour may not be obvious and accompanying epithelial hyperplasia may be interpreted by the pathologist as invasive squamous cell carcinoma. Good communication between pathologist and surgeon is required to ensure that clinically benign lesions on the vocal cords are not misdiagnosed. The diagnosis of granular cell tumour can be confirmed by immunocytochemical staining for S100 antigen.

Adult↗