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Biomedical subjects

L J Duncan

Publications and source records attributed to L J Duncan.

At least 19 recordsLinked to original sources
PubMed1998

Executive function in first-episode schizophrenia.

BACKGROUND: We tested the hypothesis that schizophrenia is primarily a frontostriatal disorder by examining executive function in first-episode patients. Previous studies have shown either equal decrements in many cognitive domains or specific deficits in memory. Such studies have grouped test results or have used few executive measures, thus, possibly losing information. We, therefore, measured a range of executive ability with tests known to be sensitive to frontal lobe function. METHODS: Thirty first-episode schizophrenic patients and 30 normal volunteers, matched for age and NART IQ, were tested on computerized test of planning, spatial working memory and attentional set shifting from the Cambridge Automated Neuropsychological Test Battery. Computerized and traditional tests of memory were also administered for comparison. RESULTS: Patients were worse on all tests but the profile was non-uniform. A componential analysis indicated that the patients were characterized by a poor ability to think ahead and organize responses but an intact ability to switch attention and inhibit prepotent responses. Patients also demonstrated poor memory, especially for free recall of a story and associate learning of unrelated word pairs. CONCLUSIONS: In contradistinction to previous studies, schizophrenic patients do have profound executive impairments at the beginning of the illness. However, these concern planning and strategy use rather than attentional set shifting, which is generally unimpaired. Previous findings in more chronic patients, of severe attentional set shifting impairment, suggest that executive cognitive deficits are progressive during the course of schizophrenia. The finding of severe mnemonic impairment at first episode suggests that cognitive deficits are not restricted to one cognitive domain.

Adolescent↗
PubMed1998

Smooth pursuit and saccadic abnormalities in first-episode schizophrenia.

BACKGROUND: Previous studies of oculomotor dysfunction in schizophrenia have tended to concentrate on abnormalities of smooth pursuit eye tracking in chronic medicated patients. We report the results of a study of smooth pursuit, reflexive and antisaccade performance in drug naive and antipsychotic treated first-episode schizophrenic patients. METHODS: Smooth pursuit and saccadic eye movements were recorded in 36 first-episode schizophrenic patients and 36 controls matched for age and estimated IQ. The schizophrenic patients were divided into drug-naive (N = 17) and antipsychotic treated groups (N = 19). RESULTS: Smooth pursuit velocity gain was significantly lower than controls only in the drug-naive patients. The treated patients did not differ significantly from either the controls or the untreated group. In an antisaccade paradigm both treated and drug-naive schizophrenic patients demonstrated an increased number of errors, but only drug-naive patients also demonstrated an increased latency in initiating correct antisaccades. CONCLUSIONS: These impairments are unlikely to be due to a generalized deficit in oculomotor function in the schizophrenic groups, as there were no differences between the groups in saccadic metrics on a reflexive saccade task. The results show that both smooth pursuit and saccadic abnormalities are present at the onset of schizophrenia and are integral to the disorder.

Adolescent↗
PubMed1997

Control of aromatase activity in breast tumours: the role of the immune system.

Cytokines such as interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF alpha), have been identified as important regulators of aromatase activity in fibroblasts derived from normal and malignant breast tissues, and may play an important role in controlling aromatase activity in breast tumours. The major source of such cytokines within breast tumours remains to be established but macrophages and lymphocytes, which can infiltrate tumours, have been identified as a potential source of aromatase stimulatory cytokines. To obtain further insight into the possible role played by the immune system in cancer development, and in particular its ability to regulate aromatase activity via cytokine production, we have obtained peripheral blood monocytes and lymphocytes from an immunosuppressed kidney transplant recipient, receiving cyclosporin A therapy, and a woman with breast cancer. Monocytes and lymphocytes were stimulated with lipopolysaccharide (LPS), and the conditioned medium (CM) collected from these cells was tested for its ability to stimulate aromatase activity in fibroblasts derived from normal breast tissue from a woman undergoing lumpectomy for the removal of a breast tumour. The white blood cell count was lower for the immunosuppressed patient, mainly because of the reduction in the number of monocytes and lymphocytes. The ability of CM from the monocytes and lymphocytes of the immunosuppressed patient to stimulate aromatase activity was significantly reduced (68% and 82% for monocytes and lymphocytes, respectively) compared with that of CM from the cells of the woman with breast cancer. It is possible, therefore, that immunosuppression, which has been found to be associated with a reduction in the incidence of de novo breast cancer in kidney transplant recipients, may exert its effect by inhibiting cytokine production by the cells of the immune system and thus oestrogen synthesis. In contrast to the stimulatory effects that TNF alpha has on aromatase activity in breast fibroblasts, in MCF-7 breast cancer cells, which possess low aromatase activity, it reduced activity. However, the extent of inhibition of aromatase activity in these epithelial cells was much lower than the marked stimulation which it can induce in breast fibroblasts.

Adult↗
PubMed1995

Predictors of recurrence for patients with small (one centimeter or less) localized breast cancer (T1a,b N0 M0).

BACKGROUND: The frequency of small (< or = 1 cm) axillary lymph node negative invasive breast cancers (T1a,b N0 M0) is increasing because of wider implementation of breast cancer screening. Identification of prognostic factors for these patients has been based largely on retrospective pathology review. The authors analyzed histologic factors recorded in the original pathology reports to determine predictors of recurrence for patients with T1a,b N0 M0 breast cancer. METHODS: Two hundred eighteen patients were studied. Potential prognostic factors including measured millimeter tumor size in three dimensions, histologic grade, nuclear grade, and presence or absence of lymphatic vessel invasion were documented prospectively in routine surgical pathology reports of a large community (nonuniversity based) hospital. Follow-up was performed annually by the tumor registry. RESULTS: With a median follow-up of 6.9 years (range, 3-15.8 years), overall recurrence free survival was 93%. Poor nuclear grade (hazard ratio, 5.8; 95% confidence interval, 1.70-19.82; P = 0.004) and lymphatic vessel invasion (hazard ratio, 4.6; 95% confidence interval, 1.34-15.61; P = 0.01) were independent predictors of recurrence. Only 10% of patients had cancers with both poor nuclear grade and lymphatic vessel invasion and their 67% 7-year recurrence free survival (RFS) rate was significantly lower than the 92% RFS rate observed for patients with one of these two factors (P = 0.007) and the 99% RFS for patients with neither poor risk factor (P = 0.0001). CONCLUSIONS: The combination of poor nuclear grade and lymphatic vessel invasion identifies a very small subset (10%) of patients with T1a,b N0 M0 breast cancer with a significant relapse risk that warrants consideration of adjuvant systemic therapy. However, the majority of patients with T1a,b N0 M0 breast cancer have an exceptionally good prognosis.

Adult↗
PubMed1995

The role of cytokines and sulphatase inhibitors in regulating oestrogen synthesis in breast tumours.

Synthesis of oestrogens within breast tissues makes an important contribution to the high concentrations of oestradiol which are found in breast tumours. The activities of the enzymes involved in oestrogen synthesis, i.e. the aromatase, oestradiol dehydrogenase (E2DH) and oestrone sulphatase (E1-STS), can be stimulated by several growth factors and cytokines. As it is possible that some of these factors may be derived from cells of the immune system (macrophages and lymphocytes), the effects of basic fibroblast growth factor (bFGF) and interleukin-2 (IL-2), which are produced by these cells, on E2DH activity was examined in MCF-7 cells. Treatment of these cells with bFGF resulted in a dose-dependent increase in E2DH reductive activity whereas IL-2 was inactive at the concentration tested. To obtain further evidence that factors produced by macrophages and lymphocytes can modulate the activities of enzymes involved in oestrogen synthesis, conditioned medium was collected from these cells and found to stimulate both E1-STS and E2DH activities. In addition to understanding the control of oestrogen synthesis in breast tumours an inhibitor to block the synthesis of oestrone via the oestrone sulphatase pathway was developed. Oestrone-3-O-sulphamate (EMATE) is a potent, irreversible, inhibitor of E1-STS. A single dose of EMATE (10 mg/kg) inhibited tissue E1-STS activity in rats by more than 95% for up to 7 days, indicating that this compound may have considerable therapeutic potential for the treatment of breast cancer. Evidence is also reviewed that another steroid sulphatase, dehydroepiandrosterone sulphate sulphatase, may have a crucial role in regulating cytokine production and that this may indirectly control tumour oestrogen synthesis.

Breast Neoplasms↗
PubMed1995

The role and proposed mechanism by which oestradiol 17 beta-hydroxysteroid dehydrogenase regulates breast tumour oestrogen concentrations.

Synthesis of the biologically active oestrogen, oestradiol, within breast tumours makes an important contribution to the high concentrations of oestrogens which are present in malignant breast tissues. In breast tumours, oestrone is preferentially converted to oestradiol by the Type I oestradiol 17 beta-hydroxysteroid dehydrogenase (E2DH). Several growth factors, such as insulin-like growth factor Type I, and cytokines, such as Tumour Necrosis Factor alpha (TNF alpha), have been shown to stimulate E2DH activity in MCF-7 breast cancer cells. As little is known about the regulation of Type I E2DH expression and activity in other breast cancer cell lines, the expression and activity of this enzyme was examined in other oestrogen receptor positive and also oestrogen receptor negative breast cancer cell lines. As it is possible that E2DH activity may be limited by co-factor availability, the effects of exogenous co-factors on enzyme activity in these cell lines was also investigated. For T47D and BT20 breast cancer cells, the addition of exogenous co-factors was found to enhance enzyme activity. TNF alpha, in addition to stimulating E2DH activity in MCF-7 cells, also increased activity in T47D and MDA-MB-231 cells, although to a lesser extent than in MCF-7 cells. An investigation of signalling pathways involved in the regulation of E2DH activity revealed that stimulation of both the protein kinase C (PKC) and PKA pathways may be involved in regulation of E2DH activity. As several growth factors and cytokines have now been found to be involved in regulating E2DH activity, the role that macrophages and lymphocytes have in supplying these factors and the mechanism by which these factors may stimulate tumour growth, is also reviewed.

Breast↗
PubMed1995

IL-6sR: release from MCF-7 breast cancer cells and role in regulating peripheral oestrogen synthesis.

The interleukin-6 soluble receptor (IL-6sR) may regulate the ability of IL-6 to stimulate oestrogen synthesis in breast cancer cells and breast tumours. Significant aromatase activity was detectable in IL-6 stimulated fibroblasts derived from subcutaneous adipose tissue, but the combination of IL-6sR plus IL-6 resulted in a marked 21-fold stimulation of aromatase activity. To examine the control of IL-6sR release, the effects of oestradiol, 4-hydroxytamoxifen (4-OHT), dexamethasone, TPA, TNF alpha or IL-6 on this process was examined using MCF-7 breast cancer cells. Oestradiol, TNF alpha and dexamethasone all markedly increased IL-6sR release. While 4-OHT had a small stimulatory effect on IL-6sR release, it blocked the ability of oestradiol to increase IL-6sR release. Significant concentrations of IL-6sR were also detected in conditioned medium collected from lymphocytes and macrophages and in cytosols prepared from normal and malignant breast tissues. These results indicate that IL-6sR may have an important role in potentiating the effect of IL-6 on oestrogen synthesis in breast cancer cells. The abilities of oestradiol or tamoxifen to potentiate or inhibit the IL-6 stimulation of oestrogen synthesis in breast cancer cells may result from their effects on IL-6sR release.

Antigens, CD↗
PubMed1994

Stimulation of aromatase activity in breast fibroblasts by tumor necrosis factor alpha.

The conversion of androstenedione to estrone, the reaction mediated by the aromatase enzyme complex, may make an important contribution to the synthesis of estrogens in breast tissues. In the present study, the effect of the cytokine. TNF alpha, on aromatase activity was examined in breast fibroblasts derived from normal and malignant breast tissue. TNF alpha (2.5-10.0 ng/ml), in the presence of stripped fetal calf serum and dexamethasone, significantly stimulated fibroblast aromatase activity in a dose-dependent manner. IL-1 and IL-6 also stimulated fibroblast aromatase activity, but no marked synergism between TNF alpha and IL-1 or IL-6 was detected. Using a specific radioimmunoassay, significant concentrations of TNF alpha were detected in samples of breast cyst fluid and breast tumor cytosol, which had previously been shown to stimulate aromatase activity, but not in conditioned medium from breast tumor-derived fibroblasts. As TNF alpha may be preferentially expressed and produced in the adipose tissue component of the breast, this cytokine may have an important role in regulating estrogen synthesis in normal and malignant breast tissues.

Androstenedione↗
PubMed1994

The interaction of cytokines in regulating oestradiol 17 beta-hydroxysteroid dehydrogenase activity in MCF-7 cells.

Oestradiol 17 beta-hydroxysteroid dehydrogenase (E2DH) has a pivotal role in the regulation of oestradiol (E2) concentrations in normal and malignant breast tissues. Previous studies have suggested that a number of cytokines can stimulate E2DH activity to increase the conversion of oestrone (E1) to E2. In this investigation we have examined the effect of TNF alpha, interleukin-1 beta (IL-1 beta) and IL-6 on E2DH activity in MCF-7 breast cancer cells. These cytokines may be produced by breast tumours and their presence in conditioned medium (CM) from tumour-derived fibroblasts was also measured to assess their possible contribution to its E2DH stimulatory activity. Treatment of MCF-7 cells with IL-1 beta and TNF alpha (5 ng/ml) significantly increased (P < 0.001) reductive E2DH (red-E2DH, the conversion of E1 to E2) activity. In contrast, IL-6 at a concentration of 100 ng/ml produced little, if any, stimulation of reductive activity. Combinations of all three cytokines acted synergistically to stimulate red-E2DH activity. No cytokine, either alone or in combination, affected oxidative (E2-->E1) activity. Significant concentrations of IL-6 and IL-1 beta were detected in CM, but the stimulation of red-E2DH activity was much greater than that which could be explained by their levels alone. It is concluded that these cytokines may play an important role in regulating E2DH activity in breast cancer cells and may act synergistically in vivo to enhance the formation of E2 in breast tumours.

17-Hydroxysteroid Dehydrogenases↗
PubMed1994

Regulation of estradiol 17 beta-hydroxysteroid dehydrogenase expression and activity by retinoic acid in T47D breast cancer cells.

Estradiol 17 beta-hydroxysteroid dehydrogenase (17 beta HSD) mediates the interconversion of estrone and estradiol in endocrine-responsive tissues such as the breast. The control of 17 beta HSD expression by all-trans-retinoic acid (RA) in T47D breast cancer cells was examined using a specific 17 beta HSD complementary DNA probe. Two main 17 beta HSD messenger RNA (mRNA) transcripts of 2.2 and 1.3 kilobases (kb) were detected, of which only the 1.3-kb mRNA was regulated. RA increased expression of the 17 beta HSD 1.3-kb mRNA in a dose- and time-dependent manner, and the increased expression of this mRNA by RA was inhibited by a 10-fold excess of a RA antagonist Ro 41-5253. Insulin-like-growth factor-I, interleukin-1, and estradiol, previously shown to increase 17 beta HSD activity in breast cancer cells, had little effect on 17 beta HSD gene expression. To relate the effect of increased 17 beta HSD 1.3-kb mRNA expression to 17 beta HSD activity, the conversion of estrone to estradiol (reductive) and that of estradiol to estrone (oxidative) were measured in intact T47D cell monolayers. Whereas RA increased 17 beta HSD reductive activity, it had no effect on oxidative activity. The addition of excess NAD increased 17 beta HSD oxidative activity in control and RA-treated cells, but the addition of NADH had no effect on 17 beta HSD reductive activity. These results suggest that the increased expression of the 17 beta HSD 1.3-kb mRNA induced by RA is associated with an increase in 17 beta HSD reductive activity, but that endogenous cofactor levels may determine the direction in which this enzyme acts in T47D cells.

Breast Neoplasms↗
PubMed1986

Reversal of insulin resistance in type 1 diabetes following initiation of insulin treatment.

The biological action and pharmacokinetics of insulin were assessed in nine type 1 (insulin-dependent) diabetic patients before and after 3 months conventional insulin treatment, and in seven age and weight-matched non-diabetic controls, by means of the euglycaemic insulin clamp technique. The mean (+/- S.E.) metabolic clearance rate of insulin, when infused at 1 mU/kg/min, was similar in untreated and treated diabetic patients and in controls (22.7 +/- 2.0, 19.3 +/- 3.8, and 22.9 +/- 3.3 ml/kg/min) but, when infused at 6 mU/kg/min, was greater (p less than 0.01 and less than 0.01) in untreated patients (18.0 +/- 2.5 ml/kg/min) than in treated patients (11.5 +/- 1.4 ml/kg/min) and controls (12.7 +/- 1.3 ml/kg/min). Insulin-mediated glucose disposal was reduced (p less than 0.01 and less than 0.01) at insulin infusion rates 1 and 6 mU/kg/min in untreated patients (18.5 +/- 1.9 and 33.8 +/- 4.5 mumol/kg/min) when compared with controls (35.8 +/- 3.4 and 62.0 +/- 4.7 mumol/kg/min) and was improved (p less than 0.01 and less than 0.01) following insulin treatment (36.1 +/- 4.6 and 64.8 +/- 4.2 mumol/kg/min). Daily insulin requirement fell by 33% following 3 months insulin treatment with improvement in mean HbA1 from 16.3 +/- 0.7 to 8.2 +/- 0.4%, but without significant increase in endogenous insulin secretion. The 'honeymoon phenomenon', which has traditionally been attributed exclusively to resurrection of endogenous insulin release, may also be related to normalization of insulin action following institution of insulin treatment.

3-Hydroxybutyric Acid↗
PubMed1985

Influence of insulin antibodies on pharmacokinetics and bioavailability of recombinant human and highly purified beef insulins in insulin dependent diabetics.

Sixteen insulin dependent diabetics of long standing, with undetectable fasting plasma C peptide concentrations, and eight non-diabetic controls were each infused intravenously with biosynthetic human and highly purified beef insulin (1 mU/kg/min) while euglycaemia was maintained by a Biostator. No difference was observed between the two insulins in respect of insulin pharmacokinetics or biological action. The diabetics showed appreciable insulin resistance, manifested by a 40% reduction in the rate of insulin mediated glucose disposal, which was unrelated to the presence of insulin antibodies. Insulin binding antibodies, however, increased insulin's clearance rate and distribution space and prolonged its pharmacological and biological half lives. The rate at which insulin action was lost, after an intravenous infusion, was more rapid in diabetics without insulin antibody binding than in controls. In respect of their influence on insulin pharmacokinetics, moderate concentrations of insulin antibodies may be of positive advantage to all diabetics without endogenous insulin secretion and are not responsible for the insulin resistance of type 1 diabetes.

Adult↗
PubMed1985

Vitiligo in diabetes mellitus.

We studied the association between vitiligo and diabetes mellitus, and found that vitiligo is associated with insulin-dependent diabetes but not with non-insulin-dependent diabetes. This gives further weight to the theory that vitiligo is an autoimmune disease.

Adolescent↗
PubMed1984

Insulin action and pharmacokinetics in insulin treated diabetics during the third trimester of pregnancy.

Insulin action and pharmacokinetics were compared, using the euglycaemic insulin clamp technique, in seven insulin-treated diabetics during the third trimester of pregnancy and one to three weeks post-partum. At an insulin infusion rate of 1 mU/kg/min, insulin mediated glucose disposal was significantly greater (p less than 0.02) following delivery (1.194 +/- 0.138 mmol/m2/min) than in pregnancy (0.761 +/- 0.072 mmol/m2/min) and the rate of decline in insulin mediated glucose disposal, at the end of the insulin infusion, was significantly greater (p less than 0.02) following delivery (24.78 +/- 4.22 mumol/m2/min2) than in pregnancy (15.17 +/- 2.00 mumol/m2/min2). The metabolic clearance rate, distribution space and pharmacological half-life of insulin were not significantly altered by pregnancy. These findings show that the third trimester of pregnancy is associated with steady state insulin resistance accompanied by a reduced rate of insulin deactivation, but normal insulin pharmacokinetics.

Adult↗
PubMed1984

Glycosylated haemoglobin and serum insulin antibodies in type I diabetes.

Type 1 diabetics receiving once (Group 1, n = 72) and twice (Group 2, n = 48) daily subcutaneous injections of conventional beef insulin were compared, on a cross-sectional basis, in respect of insulin antibody binding by serum and total glycosylated haemoglobin (HbA1). Patients in Group 1 had higher insulin antibody binding (25.2 +/- 15.8% vs 17.0 +/- 13.9%; p less than 0.01) and higher HbA1 levels (12.5 +/- 2.0% vs 11.0 +/- 1.8%; p less than 0.001) than patients in Group 2. An inverse correlation (tau = -0.28, p less than 0.01) was observed between HbA1 and insulin antibody binding in C-peptide non-secretors of Group 1 but not in Group 1 C-peptide secretors, nor in C-peptide secretors and/or non-secretors of Group 2. It is suggested that in Type 1 diabetics who receive a single daily insulin injection and who have no endogenous insulin secretion, insulin antibodies may aid glycaemic control by prolonging insulin action.

Adult↗
PubMed1984

A comparison of the biological actions and pharmacokinetics of intravenously infused highly purified beef and biosynthetic human insulins in normal man.

By means of the euglycaemic insulin clamp technique the rate of insulin-mediated peripheral glucose disposal (GDR) was compared in response to intravenous infusions of highly purified beef insulin (BI) and biosynthetic human insulin (BHI), infused at 1 and 6 mU/kg/min, in healthy volunteers. The metabolic clearance rates of BI and BHI were similar at the lower insulin infusion rate and were both greater than those observed at the higher insulin infusion rate, which were also similar, implying the process of insulin clearance to be saturable. The GDRs were similar in response to infusions of BI and BHI at each insulin infusion rate. The rates of insulin deactivation were similar, having discontinued BI and BHI infusions at 1 mU/kg/min.

Animals↗