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Biomedical subjects

A Wakeling

Publications and source records attributed to A Wakeling.

At least 19 recordsLinked to original sources
PubMed1998

Delayed G-CSF after autologous progenitor cell transplantation: a prospective randomized trial.

G-CSF is given after autologous progenitor cell transplantation to accelerate neutrophil engraftment. Historically, G-CSF has been started on the day of progenitor cell infusion. To study the timing of the initiation of G-CSF after autologous peripheral blood progenitor cell (PBPC) transplantation, we conducted a prospective, randomized trial comparing the initiation of G-CSF therapy on day 0, day +3 or day +5 after autologous PBPC transplantation. Seventy patients with diagnoses of breast cancer, non-Hodgkin's lymphoma, Hodgkin's disease, or multiple myeloma were prospectively randomized to one of the three treatment arms. All patients were treated with a chemotherapy (only) preparative regimen. The source of hematopoietic reconstitution was PBPC alone (without autologous marrow), and all patients yielded a minimum of 2 x 10(6) CD34+ cells per kilogram. Times to neutrophil engraftment and platelet engraftment were identical in the three treatment groups, with neutrophil engraftment occurring at a median of 10, 11 and 11 days when starting G-CSF on day 0, day 3 or day 5, respectively. Time to platelet transfusion independence was 14, 11 and 14 days by treatment group. We conclude that delaying the initiation of G-CSF from day 0 to day +5 does not affect engraftment and results in cost savings.

Breast Neoplasms↗
PubMed1996

Epidemiology of anorexia nervosa.

Findings of epidemiological studies of the rates, incidence, and prevalence of eating disorder over time and in different populations are reviewed. Risk factors for anorexia nervosa and bulimia nervosa are also addressed. Methodological recommendations for future directions in epidemiological studies of eating disorders are presented.

Adolescent↗
PubMed1996

The use of risperidone in treatment-resistant schizophrenia: two case reports.

The role of risperidone in the management of treatment-resistant schizophrenia remains unclear. We describe two patients with treatment-resistant schizophrenia characterized by unremitting delusions, thought disorder and self-neglect who had a sustained improvement in their symptoms soon after starting risperidone. Risperidone may be a suitable alternative to clozapine in some patients unresponsive to conventional antipsychotics.

Adult↗
PubMed1995

The pure antiestrogen ICI 182,780 binds to a high-affinity site distinct from the estrogen receptor.

Both estrogen receptor-positive (ER+), tamoxifen-sensitive (5-21) and tamoxifen-resistant (5-23) subclones of the parental MCF-7 breast cancer cell line were used in competitive ligand binding studies involving either [3H]ICI 182,780 or 4-OH-[3H]tamoxifen (4OHT) displacement by unlabelled estradiol (E2) or the antiestrogens (AE) 4OHT and ICI 182,780. Neither radioligand was displaced significantly by E2 over a range of concentrations; binding was predominantly inhibited by the corresponding radio-inert ligand. Scatchard analysis of the data revealed that the binding capacities of both cell lines for ICI 182,780 were approximately 7-fold greater than the previously determined number of ER sites per cell, with the affinity being an order of magnitude less than that of E2 for ER. No difference was found between the TAM-sensitive and -resistant cells in their binding of either AE. When cells were preincubated with either E2, TAM or 4OHT at a high, fixed concentration to block the ER or AE binding sites (AEBS), respectively, displaceable binding of [3H]ICI 182,780 was still observed, indicating binding at a site other than the classical ER or previously described AEBS. Our results suggest that there is a specific, saturable and relatively high-affinity binding site for ICI 182,780 in MCF 5-21 and MCF 5-23 breast cancer cells. However, the physiological relevance of this binding site requires further clarification because in cell growth assays, E2 (at 1/10 the dose of ICI 182,780) overcame the inhibitory effect of the antiestrogen in both of the cell lines.

Binding Sites↗
PubMed1994

Growth inhibition of oestrogen receptor-positive human ovarian carcinoma by anti-oestrogens in vitro and in a xenograft model.

This paper presents results of the in vitro and in vivo effects of anti-oestrogens on the growth of human ovarian cancer cells. Tamoxifen and the "pure" anti-oestrogens, ICI 164,384 and ICI 182,780, inhibited the oestrogen-stimulated growth of the oestrogen receptor (ER)-positive PE04 and PE01 cell lines grown in culture, the latter two compounds being more potent than tamoxifen. In the absence of 17 beta-oestradiol (E2), tamoxifen, but not the pure anti-oestrogens, produced a small degree of growth stimulation in the PE01 and PE04 lines at concentrations between 10((7) and 10(-9) M. In contrast, growth of the ER-negative PE014 line was unaffected by E2 and all three anti-oestrogens. The effects of tamoxifen and ICI 182,780 on PE04 cells grown as xenografts in nude mice were also studied. Both anti-oestrogens produce significant growth inhibitory effects. These results indicate that ovarian carcinoma cells may be sensitive to anti-oestrogens in vitro and in vivo, and support the view that anti-oestrogens merit further clinical studies in patients with ER-positive tumours.

Adenocarcinoma↗
PubMed1993

Circumvention of tamoxifen resistance by the pure anti-estrogen ICI 182,780.

Both primary and acquired resistance to the growth-inhibitory effects of anti-estrogens (e.g., tamoxifen) limits the clinical usefulness of these drugs in the treatment of breast cancer. The new, steroidal anti-estrogen ICI 182,780 was tested for its ability to inhibit the proliferation of a tamoxifen-resistant variant of the parental MCF-7 human breast-cancer cell line. Two cell lines cloned from the MCF-7 line were used for these experiments: a tamoxifen-sensitive line, MCF 5-21, and a tamoxifen-resistant line, MCF 5-23. Compared with tamoxifen, ICI 182,780 appeared to be 150 and 1540 times more effective in inhibiting cell growth in the 5-21 and 5-23 sub-lines respectively. ICI 182,780 completely circumvented tamoxifen resistance at a concentration of (5 to 10) x 10(-9) M in this model. Based on IC50 concentrations, the 5-23 line was 22-fold more resistant to tamoxifen than the 5-21 line, but only 2-fold more resistant to ICI 182,780, reducing relative resistance by 10-fold in the resistant line. There were no differences in ER parameters between the 2 lines. ER numbers/cell were: 40500 and 34800 and the KD 0.48 and 0.15 x 10(-9) M in the 5-21 and 5-23 cells respectively. In the 5-23 cells, the concentrations of ICI 182,780 and tamoxifen resulting in a 50% inhibition of 3H-estradiol binding were 2.3 x 10(-8) M and 1 x 10(-6) M, respectively (cf. estradiol 0.89 x 10(-9) M). Thus, one potential mechanism for the increased effectiveness of ICI 182,780 may relate to the increased affinity of this drug for the estrogen receptor as compared with tamoxifen.

Binding Sites↗
PubMed1993

Differential effects of estrogen, tamoxifen and the pure antiestrogen ICI 182,780 in human drug-resistant leukemia cell lines.

ICI 182,780, a potent, new steroidal antiestrogen without apparent agonist activity, appears to be a potent modulator of the classic multidrug resistance (MDR) phenotype in the CEM/A7, CEM/VLB100 and K562/VIN100 MDR cell lines. This reagent had no effect on the respective parental CCRF-CEM and K562 cell lines. The use of 1.25 microM ICI 182,780 resulted in a 6- to 7-fold decrease in doxorubicin resistance in the CEM/A7 and CEM/VLB100 cell lines. A dose-response effect was observed at ICI 182,780 concentrations of up to 5 microM. As compared with tamoxifen (TAM), ICI 182,780 was 2 and 4 times more effective in the K562/VIN100 and CEM/A7 cell lines, respectively. ICI 182,780 at 0.625 microM increased [3H]-daunomycin uptake (P < 0.0001) as effectively as 5 microM TAM in the resistant CEM/A7 line. Drug-efflux studies showed that 5 microM ICI 182,780 significantly decreased drug efflux as compared with 5 microM TAM (P < 0.0001). Estradiol (EST) at 10 microM increased doxorubicin resistance by 1.2-1.3 times in the CEM/A7 and CEM/VLB100 cell lines and significantly decreased drug accumulation (P = 0.002) and retention (P < 0.001) in the CEM/A7 cell line. However, the addition of 10 microM EST to 1-2 microM ICI 182,780 did not inhibit the ability of ICI 182,780 to modulate doxorubicin resistance in the two resistant cell lines. Using reverse-phase high-performance liquid chromatography (HPLC) to measure lipophilicity, we found no apparent association between the ability of ICI 182,780, TAM or EST to modulate resistance and their relative hydrophobicity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Anorexia nervosa of late onset.

Forty-two female anorexia nervosa patients, with onset of first illness at 25 or more years of age, are described and compared with 143 patients with onset of first illness between the ages of 15 and 20 years. The data support the view that the older group forms part of the total population of anorexia nervosa patients, but that age exerts a pathoplastic influence on psychopathology and psychosocial stressors. Older patients lost more weight, but did not have significantly higher rates of concurrent mood disorder.

Adolescent↗
PubMed1992

Differential changes in alpha- and beta-adrenoceptor linked [45Ca2+] uptake in platelets from patients with anorexia nervosa.

[45Ca2+] Uptake was studied in response to adrenaline, isoprenaline, noradrenaline, and (Bu)2cAMP in platelets from patients with anorexia nervosa. In both controls and anorectics, adrenaline, isoprenaline, noradrenaline, and (Bu)2cAMP stimulated [45Ca2+] uptake. In receptor subtype characterisation studies on control platelets, adrenaline-stimulated [45Ca2+] uptake was blocked by yohimbine (an alpha 2-adrenoceptor antagonist) and the specific beta 2-adrenoceptor antagonist ICI 118,551, but not by atenolol (a beta 1-antagonist). Isoprenaline action was blocked by ICI 118,551, but not by yohimbine. Noradrenaline-stimulated [45Ca2+] uptake was blocked by yohimbine but not by ICI 118,551. In platelets from anorectic patients, there was a significant increase in noradrenaline-stimulated [45Ca2+] uptake, a significant diminution in adrenaline and isoprenaline-stimulated [45Ca2+] uptake, but no significant difference in (Bu)2cAMP-stimulated [45Ca2+] uptake, when compared with controls. Basal uptake was also significantly enhanced in anorectics and was found to be inhibited with verapamil but not adrenoceptor antagonist. These data firstly indicate that both alpha 2- and beta 2-adrenoceptor activation elicits [45Ca2+] uptake by platelets. It is proposed that this stimulated [45Ca2+] uptake does not reflect changes in cytosolic Ca2+ but to localized changes of Ca2+ at the plasma membrane, possibly associated with receptor activation, per se. The respective increase and decrease of alpha- and beta-adrenoceptor activity in platelets from anorectic patients is in accord with other reports of changes of adrenoceptor number and type in platelets and other cells from anorectic patients. There may also be an increase in calcium channel activity in platelets from anorectics.

Adolescent↗
PubMed1991

Circumvention of doxorubicin resistance in multi-drug resistant human leukaemia and lung cancer cells by the pure antioestrogen ICI 164384.

ICI 164384, a new steroidal antioestrogen, entirely devoid of oestrogenic activity, modulates doxorubicin resistance in vitro. At non-cytotoxic concentrations, ICI 164384 potentiated the cytotoxicity of doxorubicin in a dose-dependent manner in both the classical multi-drug resistant (MDR) human leukaemia cell lines CEM/VLB 100 and CEM/VLB 1000 and the human small cell lung cancer cell line H69 LX4. ICI 164384 had no effect on the two respective parental cell lines, CEM/CCRF and H69 P. None of these cell lines expressed the oestrogen receptor. In comparative studies at concentrations ranging from 1.25 to 10 mumols/l, ICI 164384 was significantly more effective (1.2-6-fold) than tamoxifen in reducing the IC50 of doxorubicin in the CEM/VLB 100 line. In resistant cells, ICI 164384 increased 3H-daunomycin accumulation in a dose-dependent manner and was significantly more effective than tamoxifen at concentrations ranging from 2.5 to 10 mumol/l. ICI 164384 reduced the efflux of daunomycin from resistant cells more effectively than tamoxifen. These studies suggest that ICI 164384 is an effective modulator of MDR.

Carcinoma, Small Cell↗
PubMed1990

Abnormal eating attitudes in London schoolgirls--a prospective epidemiological study: outcome at twelve month follow-up.

The occurrence and course of eating disorder in a large representative population of 15-year-old London schoolgirls has been assessed using a two-stage survey methodology. Attempts to control weight were common and often transient. Dieting was in the great majority of girls found to be a benign practice without progression to more extreme concerns about food and weight. However, a small proportion of dieters did become cases and formed the majority of new cases found at follow-up. The relative risk of dieters becoming cases was eight times that of non-dieters. Many factors conventionally associated with eating disorder were associated more with attempting weight control than caseness. These included pre-morbid personality, pre-morbid obesity and family weight pathology. Other factors, including social class, career choice and psychosexual development, had no association either with attempting weight control or caseness.

Adolescent↗
PubMed1988

A cognitive behavioural group approach for the treatment of bulimia nervosa--a preliminary study.

A group treatment for bulimia nervosa based on a cognitive behavioural approach is described. Eight women with a self reported average of 14 binging episodes per week attended a weekly group for 15 weeks. The techniques used in the group are described. Outcome measures included self reported frequency of binging episodes, eating attitudes, depression and anxiety. These were assessed both pre and post treatment. In addition binge frequency was assessed at 3 and 6 month follow up. Binging frequency decreased over the treatment period to an average of 1.1 per week and of 1.9 per week at 6 month follow up. Significant changes in eating attitudes, and a reduction in depression and anxiety were obtained over the treatment period. Although this study was not controlled it may represent a promising step towards the development of a cost-effective treatment for this common condition.

Adolescent↗
PubMed1988

Diminished [3H] ouabain binding and 86Rb influx by leukocytes in anorexia nervosa.

Leukocyte Na-K ATPase was assessed in ten patients with anorexia nervosa. The indices of Na-K ATPase measured were 86Rb influx and [3H]-ouabain binding. Both 86Rb influx and [3H]-ouabain binding were significantly lower in patients with anorexia nervosa than in controls. Following weight gain (4.1 to 11.9 kg) in seven patients both 86Rb influx and [3H]-ouabain binding increased in each patient to levels similar to those in controls, although the patients still remained underweight. Acute oral glucose challenge (75 g) also resulted in an increase in 86Rb influx and [3H]-ouabain binding in each of the eight patients tested. There was a significant correlation between 86Rb influx and [3H]-ouabain binding. We conclude that the leukocytes of patients with anorexia nervosa have a significantly diminished number of Na-K ATPase units with a parallel decrease in 86Rb influx. Weight gain and acute glucose challenge result in an increase in both indices of Na-K ATPase. Nutrition appears to play an important role in the modulation of this enzyme.

Adolescent↗
PubMed1988

Structural brain changes in patients with anorexia nervosa.

Twenty-five patients with anorexia nervosa were compared with 17 normal healthy control subjects in terms of their cerebral computed tomographic (CT) scan appearances. The patients displayed significantly greater ventricular and sulcal enlargement when compared to control subjects. There were no relationships between the CT scan appearance and clinical indices of illness severity or weight loss in the patient group. In 14 patients who had repeat scans after attaining normal body weight, no significant change was observed in the ventricular appearance, but there was a significant lessening in the degree of sulcal widening.

Adult↗
PubMed1988

Abnormal eating attitudes in London schoolgirls--a prospective epidemiological study: factors associated with abnormal response on screening questionnaires.

One thousand and ten unselected London state schoolgirls were screened by questionnaire to identify an 'at risk' cohort displaying abnormal eating attitudes and two control cohorts, one with probable general psychiatric morbidity, one without. Members of all cohorts were assessed at interview for the presence of eating disorder and for putative risk factors implicated in the development of anorexia nervosa. A prevalence rate of 0.99% was detected for clinical eating disorder and 1.78% for the partial syndrome of eating disorder. Factors specifically associated with abnormal eating attitudes were identified, in particular, current or past overweight, history of amenorrhoea and perceived stress in school and social life. Some commonly accepted risk factors for eating disorders were discovered to be associations with general psychiatric morbidity. These were perceived parental pressure to eat more, taking exercise to lose weight, perceived stress at home and reporting a family history of anxiety or depression. Other well reported putative risk factors for eating disorder, including social class, birth order, age at menarche, obsessional personality and weight related career choice were not associated specifically with abnormal eating attitudes in schoolgirls. These findings represent cross-sectional data at entry into a prospective epidemiological study.

Adolescent↗
PubMed1988

Vitamin D deficiency and low osteocalcin concentrations in anorexia nervosa.

The calcium, vitamin D, and osteocalcin concentrations were investigated in 17 patients with anorexia nervosa. Serum 25-hydroxyvitamin D (25 OHD) concentrations below normal were observed in 15 (88%); only two patients has serum 1,25 dihydroxycholecalciferol (1,25(OH)2D) concentrations below normal. Serum parathyroid hormone (PTH) concentration was also normal in all except these two patients. Serum osteocalcin concentration was below normal in seven of 14 patients. Although a low concentration of serum 25 OHD is common in patients with anorexia nervosa in the United Kingdom, 1,25(OH)2D concentrations are usually normal. Hypovitaminosis D with secondary hyperparathyroidism is relatively uncommon. The subnormal osteocalcin concentrations observed in these patients probably reflect diminished osteoblastic activity, which may contribute to their osteopenia.

1-Carboxyglutamic Acid↗
PubMed1987

Cognitive impairment, emotional disorder and length of stay of elderly patients in a district general hospital.

All patients over 65 in a district general teaching hospital (n = 204) were screened for cognitive impairment and emotional disorder using the Clifton Assessment Procedures for the Elderly, the Mini-Mental State and the General Health Questionnaire. Patients scoring in the disordered range were psychiatrically assessed. These procedures gave an estimated prevalence of cognitive impairment of 22 per cent in the 164 patients satisfactorily assessed. Forty-three per cent of patients scored beyond the GHQ cut-off, but there was a high false positive rate. Cognitively impaired patients had a significantly longer hospital stay than the unimpaired. The majority (60 per cent) of these patients could not be discharged because of lack of an appropriate place elsewhere. Amongst all elderly patients whose discharge was prevented in this way, the cognitively impaired were markedly over-represented. The data have implications for the efficient use of hospital beds and for the welfare of elderly patients in acute hospitals.

Affective Symptoms↗