Search PubMed⌕ Search

Biomedical subjects

D Cole

Publications and source records attributed to D Cole.

At least 19 recordsLinked to original sources
PubMed1999

Follow-up of breast cancer in primary care vs specialist care: results of an economic evaluation.

A randomized controlled trial (RCT) comparing primary-care-centred follow-up of breast cancer patients with the current standard practice of specialist-centred follow-up showed no increase in delay in diagnosing recurrence, and no increase in anxiety or deterioration in health-related quality of life. An economic evaluation of the two schemes of follow-up was conducted concurrent with the RCT Because the RCT found no difference in the primary clinical outcomes, a cost minimization analysis was conducted. Process measures of the quality of care such as frequency and length of visits were superior in primary care. Costs to patients and to the health service were lower in primary care. There was no difference in total costs of diagnostic tests, with particular tests being performed more frequently in primary care than in specialist care. Data are provided on the average frequency and length of visits, and frequency of diagnostic testing for breast cancer patients during the follow-up period.

Breast Neoplasms↗
PubMed1998

Characterization of glucose transport activity reconstituted from heart and other tissues.

We examined several aspects of glucose transport reconstituted in liposomes, with emphasis on transporters of rat heart (mostly GLUT4) compared to those of human erythrocytes (GLUT1), and on effects of agents that modulate transport in intact cells. Several types of samples gave higher reconstituted activity using liposomes of egg lipids rather than soybean lipids. Diacylglycerol, proposed to activate transporters directly as part of the mechanism of insulin action, increased the intrinsic activity of heart transporters by only 25%, but increased the size of the reconstituted liposomes by 90%. The dipeptide Cbz-Gly-Phe-NH2 inhibited GLUT4 with a Ki of 0.2 mM, compared to 2.5 mM for GLUT1, which explains its preferential inhibition of insulin-stimulated glucose transport in adipocytes. Verapamil, which inhibits insulin- and hypoxia-stimulated glucose transport in muscle, had no effect on reconstituted transporters. Heart transporters had a higher Km for glucose uptake (13.4) than did GLUT1 (1.6 mM), in agreement with a recent study of GLUT1 and GLUT4 expressed in yeast and reconstituted in liposomes. Transporters reconstituted from heart and adipocytes were 40-70% inactivated by external trypsin, suggesting the presence of trypsin-sensitive sites on the cytoplasmic domain of GLUT4. NaCl and KCl both reduced reconstituted transport activity, but KCl had a much smaller effect on the size of the liposomes.

Animals↗
PubMed1998

Preventing disability from work-related low-back pain. New evidence gives new hope--if we can just get all the players onside.

Despite the publication in the mid-1990s of comprehensive practice guidelines for the management of acute low-back pain, both in the United States and elsewhere, this ubiquitous health problem continues to be the main cause of workers' compensation claims in much of the Western world. This paper represents a synthesis of the intervention studies published in the last 4 years and is based on a new approach to categorizing these studies that emphasizes the stage or phase of back pain at the time of intervention and the site or agent of the intervention. Current thinking suggests that medical management in the first 3-4 weeks after the onset of pain should be generally conservative. Several studies of rather heterogeneous interventions focusing on return to work and implemented in the subacute stage (3-4 to 12 weeks after the onset of pain) have shown important reductions in time lost from work (by 30% to 50%). There is substantial evidence indicating that employers who promptly offer appropriately modified duties can reduce time lost per episode of back pain by at least 30%, with frequent spin-off effects on the incidence of new back-pain claims as well. Finally, newer studies of guidelines-based approaches to back pain in the workplace suggest that a combination of all these approaches, in a coordinated workplace-linked care system, can achieve a reduction of 50% in time lost due to back pain, at no extra cost and, in some settings, with significant savings.

Absenteeism↗
PubMed1998

Socioeconomic and environmental covariates of premature mortality in Ontario.

This paper contributes to debates on the broad determinants of health and on the policy shift from curative to preventive and protective interventions. It addresses empirically the relative importance of influences on health with a multiple regression analysis of ecologic data from the 49 counties of Ontario. One model achieved high predictive power (that is, Adj R2 > 75%, p < 0.0001). Educational levels were a strong predictor of population health, showing a consistent inverse relationship with premature mortality ratios for both sexes and it was the strongest predictor for females. A low income variable supplied the strongest prediction for male mortality. This variable displayed a positive association with male mortality. Municipal expenditures on environmental protection exerted a negative effect on male mortality. These findings raise questions about the current directions of health policy in Ontario where the provincial government has reduced funding to social and environmental programs, while promising to maintain health care funding.

Adolescent↗
PubMed1997

Doxorubicin-induced acute changes in cytotoxic aldehydes, antioxidant status and cardiac function in the rat.

Doxorubicin (DOX)-induced cardiotoxicity is thought to be caused by free radical-mediated mechanisms. An in vivo rat model was developed to investigate the DOX-induced cascade of early biochemical changes focusing on the central role of the aldehydic lipid peroxidation products. Antioxidant status was evaluated by glutathione measurements. Creatine Kinase (CK) activity was measured as an index of cardiac injury. Development of functional abnormalities were documented by echocardiography. The results showed that aldehydes in rat plasma and heart tissues increased significantly following DOX treatment. The changes occurred early, peaked around 2 h after DOX administration, and the levels declined or returned to baseline value within 8-24 h. Toxic aldehyde levels including malondialdehyde, hexanal and 4-hydroxy-non-2-enal also increased. Acyloin levels, metabolic products of aldehydes, increased early and then decreased in plasma, and there was a significant decrease in heart tissues after DOX treatment. GSH levels decreased early, then increased by 24 h, while GSSG levels decreased initially, then increased after DOX treatment, suggesting early depletion of GSH and a later rebound phenomenon. CK levels were elevated after treatment. The functional abnormalities were documented by stress echocardiography in some rats although the changes were not consistent at such an early stage following treatment. Our data confirmed the involvement of free radicals, and suggested that the cytotoxic aldehydes play a central role in initiating the steps that lead to functional impairment of the myocardium following DOX administration. Scavengers and the metabolic removal of some of the aldehydes also play a role in protecting the myocardium against injury.

Aldehydes↗
PubMed1997

A multicenter, double-blind comparison of the effects of nefazodone and fluoxetine on sleep architecture and quality of sleep in depressed outpatients.

This study was an 8-week, randomized, double-blind, parallel-group investigation that compared the effects of nefazodone and fluoxetine on sleep architecture and on clinician- and patient-rated sleep measures in 43 outpatients with moderate to severe, nonpsychotic major depressive disorder and insomnia. Twenty-two patients received nefazodone 200 mg daily for 1 week, followed by 400 mg daily for 7 weeks. Twenty-one patients received fluoxetine 20 mg daily. Dosage increases (to 500 mg/day for nefazodone and 40 mg/day for fluoxetine) were available after day 29, depending on clinician judgement. Sleep parameters were measured during baseline phase, while patients were unmeasured and symptomatic, and at weeks 2, 4, and 8 of treatment. Nefazodone and fluoxetine were equally effective as antidepressants. However, compared with baseline, nefazodone increased sleep efficiency and reduced the number of awakenings and percent awake and movement time, whereas fluoxetine increased the number of awakenings and did not significantly alter sleep efficiency or percent awake and movement time. Although fluoxetine increased stage 1 sleep and rapid eye movement (REM) latency and reduced total percent REM sleep, nefazodone increased REM sleep, decreased REM latency, and did not alter stage 1 sleep. Differences between treatment groups, based on change from baseline, revealed greater sleep efficiency, fewer awakenings, less percent awake and movement time, less percent stage 1 and more REM sleep, and shorter REM latency for nefazodone compared with fluoxetine. Significantly greater improvement in clinician- and patient-rated sleep disturbance was found with nefazodone compared with fluoxetine. Nefazodone was associated with better sleep quality.

Adult↗
PubMed1997

Protein kinase C mediated anti-proliferative glucocorticoid-sphinganine synergism in cultured Pollard III prostate tumor cells.

PURPOSE: Experimental effort focused on the growth inhibition of an androgen-resistant prostatic carcinoma, using pharmacological inhibition of protein kinase C (PKC) as the therapeutic target. MATERIALS AND METHODS: Studies were performed in cell culture using the Pollard (PA) III androgen-insensitive spontaneous rat prostate tumor cells, and the human prostate tumor lines, PC-3 and LnCaP. Pharmacological agents included steroid hormones and PKC modulators; measured parameters of tumor growth/function included cell number, PKC activity and sphingolipid metabolism. RESULTS: Triamcinolone (TA) and sphinganine synergized to inhibit the proliferation rate of PA III prostate tumor cells by converging through separate mechanisms to inhibit protein kinase C. At five days of cell culture, 0.1 microM TA reduced both the soluble and particulate forms of PKC in association with a 35-40% reduction in cellular proliferation. Exogenous sphinganine, a competitive inhibitor at the regulatory domain of PKC had no anti-proliferative effect at 1 microM, but in combination with TA synergized to reduce proliferation 80-90%, three days in advance of any detectable inhibitory effect of TA alone on cell number. TA produced no discernable stimulation of endogenous free sphingosine production as evidenced by the lack of an effect on the activity of neutral membrane sphingomyelinase or in the turnover of total cellular sphingomyelin. Phorbol esters, but not cell permeable diglycerides, prevented the TA + sphinganine effect suggesting that a stable long term PKC activation was required for reversal. Steroid specificity studies of the synergistic response revealed that while other glucocorticoids mimicked TA, aldosterone was less active and representatives of the three major classes of sex steroids were inert. Tests of sphinganine specificity demonstrated that calphostin C, a chemically unrelated inhibitor of the regulatory site of PKC, also produced a supra-additive interaction with TA. Ceramides (C2 & C6), which were closely related chemically to sphinganine but lacked affinity for the regulatory subunit of PKC, were inactive in this system. Analyses of the cellular specificity of the TA-sphinganine synergism using the human prostate carcinoma cell lines PC-3 and LnCap revealed a true synergistic growth inhibition in the glucocorticoid receptor positive PC-3 line and no significant interaction in the glucocorticoid receptor negative LnCap cells. CONCLUSIONS: TA-induced reduction of PKC concentration coupled with sphinganine antagonism of PKC activation contributed to in a synergistic growth inhibition of an androgen resistant prostatic carcinoma.

Animals↗
PubMed1997

m-Calpain activation/depletion is associated with androgen-induced reduction of protein kinase C and proliferation of male accessory sex organ smooth muscle cells.

PURPOSE: In the guinea pig seminal vesicle smooth muscle (SVM), androgen-dependent proliferation and terminal differentiation appear to be coupled to protein kinase C (PKC). This is based on the observations that both the soluble (cytosolic) enzyme and the Triton X-100 solubilizable form of the particulate enzyme were reduced during proliferation but were androgen-resistant in the amitotic state of adults. The purpose of the present investigation was to determine if the reduction in PKC activity was linked to the translocation of the activated enzyme to acceptor sites in the Triton X-100 insoluble fraction of the cell or reflected enzyme depletion due to proteolysis by androgen-dependent activation of the u- and/or m-calpains. MATERIALS AND METHODS: SVM was harvested from treated animals, homogenized and separated into soluble and particulate components. The particulate material was further fractionated into Triton X-100 soluble and insoluble fractions. PKC activity was determined in all fractions using radioactive ATP. Cultures of pure smooth muscle cells from both human prostate and SVM were also employed to assess the role of calpain in smooth muscle growth. RESULTS: During androgen-induced proliferation, instead of a translocation of PKC activity to the Triton X-100 insoluble particulate fraction of the cell, PKC activity in this fraction was significantly reduced. The m-calpain was the only isoform detected in SVM. At the peak of androgen-induced DNA synthesis in pre-pubertal castrate animals, m-calpain decreased 45% whereas in proliferative resistant SVM of adult castrates the protease was not significantly affected by androgen treatment. In pure smooth muscle cultures from the SVM as well as human prostate glands calpeptin the cell permeable inhibitor of calpains produced a concentration-dependent inhibition (IC50 approximately equal to 35 microM) of cellular proliferation. CONCLUSIONS: Given that biochemical assays of calpain quantify the residual proenzyme and that upon activation calpain is rapidly degraded, our findings indicate that m-calpain activation occurs in association with androgen-induced degradation of PKC and SMC proliferation. Thus in vitro inhibition of m-calpain activation is antiproliferative. The relative resistance of m-calpain in adult SVM may be an important component of the terminal differentiation process in normal smooth muscle.

Androgens↗
PubMed1997

Phenotypic stability of a cytotoxic T-cell line directed against an immunodominant epitope of human carcinoembryonic antigen.

CTL lines have now been generated against defined peptides of a range of human tumor-associated antigens (TAAs). One of the potential uses of these epitope-specific CTLs is in adoptive transfer immunotherapy. This is a modality, however, that will require long-term in vitro culture of CTLs. To date, little has been reported concerning the phenotypic stability of human epitope-specific CTLs as a consequence of long-term in vitro propagation via peptide stimulation. We report here the serial phenotypic characterization of a CTL line directed against an immunodominant epitope (YLSGANLNL, designated CAP-1) of human carcinoembryonic antigen (CEA). This CTL line was derived from peripheral blood mononuclear cells of a patient with metastatic carcinoma who had been treated with a recombinant CEA-vaccinia vaccine in a Phase I trial; the CTLs were analyzed through 20 in vitro cycle passages of stimulation with CAP-1 peptide and interleukin 2 in the presence of autologous antigen-presenting cells. The CTL line was shown to be phenotypically stable in terms of high levels of cytokine (IFN-gamma, tumor necrosis factor, and granulocyte-macrophage colony-stimulating factor) production, expression of homing-adhesion molecules, ability to lyse peptide-pulsed targets, and ability to lyse human carcinoma cells endogenously expressing CEA in a MHC-restricted manner. Vbeta T-cell receptor gene usage was also analyzed. These studies thus present a rationale for the use of long-term cultured epitope-specific human CTLs, directed against a human TAA for potential adoptive transfer immunotherapy protocols.

Antigens, CD↗
PubMed1996

Routine follow up of breast cancer in primary care: randomised trial.

OBJECTIVE: To assess the effect on time to diagnosis of recurrence and on quality of life of transferring primary responsibility for follow up of women with breast cancer in remission from hospital to general practice. DESIGN: Randomised controlled trial with 18 month follow up in which women received routine follow up either in hospital or in general practice. SUBJECTS AND SETTING: 296 women with breast cancer in remission receiving regular follow up care at district general hospitals in England. MAIN OUTCOME MEASURES: Time between first presentation of symptoms to confirmation of recurrence; quality of life measured by specific dimensions of the SF-36 schedule, the EORTC symptom scale, and hospital anxiety and depression scale. RESULTS: Most recurrences (18/26, 69%) presented as interval events, and almost half (7/16, 44%) of the recurrences in the hospital group presented first to general practice. The median time to hospital confirmation of recurrence was 21 days in the hospital group (range 1-376 days) and 22 days in the general practice group (range 4-64). The differences between groups in the change in SF-36 mean scores from baseline were small: -1.8 (95% confidence interval -7.2 to 3.5) for social functioning, 0.5 (-4.1 to 5.1) for mental health, and 0.6 (-3.6 to 4.8) for general health perception. The change from baseline in the mean depression score was higher in the general practice group at the mid-trial assessment (difference 0.6, 0.1 to 1.2) but there was no significant difference between groups in the anxiety score or the EORTC scales. CONCLUSION: General practice follow up of women with breast cancer in remission is not associated with increase in time to diagnosis, increase in anxiety, or deterioration in health related quality of life. Most recurrences are detected by women as interval events and present to the general practitioner, irrespective of continuing hospital follow up.

Aftercare↗
PubMed1996

Kinesin force generation measured using a centrifuge microscope sperm-gliding motility assay.

To measure force generation and characterize the relationship between force and velocity in kinesin-driven motility we have developed a centrifuge microscope sperm-gliding motility assay. The average (extrapolated) value of maximum isometric force at low kinesin density was 0.90 +/- 0.14 pN. Furthermore, in the experiments at low kinesin density, sperm pulled off before stall at forces between 0.40 and 0.75 pN. To further characterize our kinesin-demembranated sperm assay we estimated maximum isometric force using a laser trap-based assay. At low kinesin density, 4.34 +/- 1.5 pN was the maximum force. Using values of axoneme stiffness available from other studies, we concluded that, in our centrifuge microscope-based assay, a sperm axoneme functions as a lever arm, magnifying the centrifugal force and leading to pull-off before stall. In addition, drag of the distal portion of the axoneme is increased by the centrifugal force (because the axoneme is rotated into closer proximity to the glass surface) and represents an additional force that the kinesin motor must overcome.

Animals↗
PubMed1996

Contraceptive efficacy, pharmacokinetics, and safety of Annuelle biodegradable norethindrone pellet implants.

OBJECTIVE: To evaluate the contraceptive efficacy, pharmacokinetics, and safety of two formulations of Annuelle (Endocon, Inc., South Walpole, MA) biodegradable norethindrone (NET) SC pellet implants. DESIGN: Prospective observational study. SETTING: Two clinical sites in the United States. PATIENT(S): Thirty-nine healthy, fertile, sexually active women. INTERVENTION(S): Nineteen women received a four-pellet system containing 174 mg NET; 20 women received a five-pellet system containing 266.5 mg NET. MAIN OUTCOME MEASURE(S): Contraceptive efficacy, median serum NET levels, adverse events. RESULT(S): No pregnancies were observed in 293 woman-months in the four-pellet group or in 375 woman-months in the five-pellet group. An initial burst in median serum NET levels occurred in the first 24 hours postinsertion followed by a steady decline over the next 3 years. Norethindrone levels varied considerably among women. The main side effect was bleeding abnormalities, which persisted in half the participants for up to 2 years. No serious adverse events were reported that were related to the pellets. Pellet insertion and removal generally were uncomplicated. CONCLUSION(S): Annuelle shows potential as an effective, safe contraceptive with distinct advantages over other long-acting agents, because it is biodegradable but can be removed if problems arise or if fertility is desired.

Adolescent↗
PubMed1995

Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma.

The gene encoding the cell cycle inhibitor p16INK4A (also known as p16, MTS1, CDKN2 and INK4) has been mapped to human chromosome band 9p21, a region that also contains a putative melanoma susceptibility gene. Although germline mutations in the coding region of the p16INK4A gene have been detected in some families with inherited melanoma, many other families show no evidence of such mutations and hence the role of p16INK4A in the development of this tumor is still unclear. In this report, we describe a family with inherited melanoma in which a novel mutation in exon 2 of the p16INK4A gene segregates with the disease. The mutant gene encodes a protein with an in-frame deletion of two amino acids (Asp96 and Leu97). We show that the mutant protein is functionally abnormal: it is unable to bind cdk4 in vitro and does not inhibit colony formation in tertiary passage rat embryo fibroblasts. Moreover, in a metastatic lesion from one patient the wild type p16INK4A allele was deleted and the mutant allele retained. We conclude that family members carrying this germline mutation in the p16INK4A gene are predisposed to melanoma. By extension, these findings implicate the p16INK4A gene in the development of some cases of familial melanoma.

Alleles↗