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Biomedical subjects

G Brown

Publications and source records attributed to G Brown.

At least 73 records · Page 4Linked to original sources
PubMed2001

Glucose-induced oscillations in cytoplasmic free Ca2+ concentration precede oscillations in mitochondrial membrane potential in the pancreatic beta-cell.

Using dual excitation and fixed emission fluorescence microscopy, we were able to measure changes in cytoplasmic free Ca(2+) concentration ([Ca(2+)](i)) and mitochondrial membrane potential simultaneously in the pancreatic beta-cell. The beta-cells were exposed to a combination of the Ca(2+) indicator fura-2/AM and the indicator of mitochondrial membrane potential, rhodamine 123 (Rh123). Using simultaneous measurements of mitochondrial membrane potential and [Ca(2+)](i) during glucose stimulation, it was possible to measure the time lag between the onset of mitochondrial hyperpolarization and changes in [Ca(2+)](i). Glucose-induced oscillations in [Ca(2+)](i) were followed by transient depolarizations of mitochondrial membrane potential. These results are compatible with a model in which nadirs in [Ca(2+)](i) oscillations are generated by a transient, Ca(2+)-induced inhibition of mitochondrial metabolism resulting in a temporary fall in the cytoplasmic ATP/ADP ratio, opening of plasma membrane K(ATP) channels, repolarization of the plasma membrane, and thus transient closure of voltage-gated L-type Ca(2+) channels.

Adenosine Triphosphate↗
PubMed2001

Cell proliferation and CD11b expression are controlled independently during HL60 cell differentiation initiated by 1,25 alpha-dihydroxyvitamin D(3) or all-trans-retinoic acid.

When 1 alpha,25-dihydroxyvitamin D(3) (D(3)) induces HL60 cells to differentiate to monocytes, a burst of approximately three shortened cell cycles ("maturation divisions") precedes exit from cell cycle and completion of maturation. Here we show that similar maturation divisions occur during neutrophil differentiation induced by all-trans-retinoic acid (ATRA), but without shortening of the cell cycle. Both ATRA and D(3) initiate these maturation divisions as cells pass through a "window of sensitivity" during early G1. We also investigated whether the initiation of maturation divisions and of the expression of CD11b, an early-expressed maturation marker, are linked. Cells treated with D(3) or ATRA start to express CD11b after 9--14 h, before completing the first maturation division. Elutriation was used to isolate small HL60 cells (almost all in G1) and larger cells (in G1 and S phases) from unsynchronized populations. When these were cultured with D(3) or ATRA, most reentered cycle synchronously, multiplied, and differentiated. Following D(3) treatment, the G1-enriched small cells expressed CD11b slightly faster than unsynchronized cultures or fractions dominated by late G1 cells and/or S phase cells. D(3)-induced CD11b expression occurred at a similar rate even in G1 cells that were held at the G1/S boundary by thymidine. In conclusion, changes in the control of the cell cycle that characterize the onset of monocytic and neutrophil differentiation are only triggered in early G1, but CD11b expression can be initiated from most points in the cell cycle. Differentiating agents must therefore regulate the proliferation and the maturation of differentiating myeloid cells by mechanisms that are at least partly independent.

Antineoplastic Agents↗
PubMed2001

Up-regulation of steroid sulphatase activity in HL60 promyelocytic cells by retinoids and 1alpha,25-dihydroxyvitamin D3.

HL60 promyeloid cells express both classes of oestrogen receptor (ERalpha and ERbeta). We show that hydrolysis of oestrone sulphate by steroid sulphatase is a major source of oestrone in HL60 cells, and that most of the released oestrone is not metabolized further to 17beta-oestradiol. Treatment of HL60 cells with retinoids or 1alpha,25-dihydroxyvitamin D3 increased steroid sulphatase mRNA and activity in parallel with the induction of CD11b, an early marker of myeloid differentiation that is expressed before the differentiating cells stop proliferating. Use of agonists and antagonists against retinoid receptor-alpha and retinoid receptor-X revealed that both classes of retinoid receptor can drive steroid sulphatase up-regulation. Steroid sulphatase activity fluctuates during the cell cycle, being highest around the transition from G1 to S phase. During the differentiation of HL60 cells induced by all-trans-retinoic acid or 1alpha,25-dihydroxyvitamin D3, there is increased conversion of 17beta-oestradiol into oestrone by an oxidative 17beta-hydroxysteroid dehydrogenase. Treatment of Caco-2 colon adenocarcinoma cells with all-trans-retinoic acid or 1alpha,25-dihydroxyvitamin D3 also increases 17beta-oestradiol oxidation to oestrone. An increase in local oestrone production therefore occurs in multiple cell types following treatment with retinoids and 1alpha,25-dihydroxyvitamin D3. The possible involvement of locally produced oestrogenic steroids in regulating the proliferation and differentiation of myeloid cells is discussed.

17-Hydroxysteroid Dehydrogenases↗
PubMed2001

Synergistic growth inhibition of prostate cancer cells by 1 alpha,25 Dihydroxyvitamin D(3) and its 19-nor-hexafluoride analogs in combination with either sodium butyrate or trichostatin A.

Prostate cancer is a major cause of male cancer death. In vitro and in vivo data support a role for 1 alpha,25 Dihydroxyvitamin D(3) (1 alpha,25(OH)(2)D(3)) in regulating the growth and differentiation of the normal prostate gland yet prostate cancer cells appear significantly less sensitive to this action. Vitamin D(3) receptor (VDR) content or mutational status do not correlate clearly with the antiproliferative effects of 1 alpha,25(OH)(2)D(3) and therefore it is unclear why prostate cancer cell lines are significantly less sensitive to this action. We hypothesized that the antiproliferative responses of prostate cancer cells to 1 alpha,25(OH)(2)D(3) are suppressed by a process involving histone deacetylation. Sodium butyrate (NaB) and trichostatin A (TSA) are inhibitors of histone deacetylase (HDAC) activity. Low doses of NaB or TSA (300 microM and 15 nM respectively), which alone were relatively inactive, synergized with 1 alpha,25(OH)(2)D(3) in liquid and semi-solid agar to inhibit the growth of LNCaP, PC-3 and DU-145 prostate cancer cells. Still greater synergy was observed between vitamin D(3) hexafluoride analogs and either NaB or TSA. The mechanism appeared to involve neither the cyclin-dependent kinase inhibitor, p21((waf1/cip1)) nor cell cycle arrest, but rather induction of apoptosis. These data suggest that cells dysregulate the normal pro-apoptotic signals of 1 alpha,25(OH)(2)D(3) during prostate cancer development by a mechanism involving histone deacetylation. Combination therapy with potent vitamin D(3) analogs and clinically approved HDAC inhibitors may overcome this lesion and improve the treatment of both androgen-dependent and independent prostate cancer.

Antineoplastic Agents↗
PubMed2001

Mode of delivery and postpartum morbidity among HIV-infected women: the women and infants transmission study.

Cesarean delivery before onset of labor and rupture of membranes (i.e., scheduled cesarean delivery) is associated with a lower risk of vertical transmission of HIV. The following a priori hypotheses were tested: among HIV-infected women, scheduled cesarean delivery is associated with a higher risk of postpartum morbidity, longer hospitalization, and a higher risk of rehospitalization than spontaneous vaginal delivery. Postpartum morbidity occurred following 178 of 1,186 (15%) of deliveries during 1990 to 1998 in The Women and Infants Transmission Study. The most commonly reported postpartum morbidity events were: fever without infection, hemorrhage or severe anemia, endometritis, urinary tract infection, and cesarean wound complications. Several time trends were observed: the median duration of ruptured membranes decreased (p < .001), intrapartum antibiotic use increased (p < .001), the median antepartum plasma HIV RNA concentration decreased (p < .001), and the incidence of any postpartum morbidity decreased (p = .02). With spontaneous vaginal delivery as the reference category, both scheduled (odds ratio [OR] = 4.69; 95% confidence interval [95% CI], 2.03-10.84), and nonscheduled (OR, 2.50; 95% CI, 1.24-5.04) cesarean deliveries were associated with fever without infection; with urinary tract infection (OR, 3.79; 95% CI 1.04-13.85; OR, 3.86; 95% CI, 1.55-9.60, respectively), and with any postpartum morbidity (OR, 3.19; 95% CI 1.69-6.00; OR, 4.10; 95% CI, 2.71-6.19, respectively). Nonscheduled cesarean deliveries were more likely to be complicated by endometritis (OR, 6.98; 95% CI, 3.53-13.78). Adjusted ORs relating mode of delivery and each of the outcomes (fever without infection, urinary tract infection, endometritis, and any postpartum morbidity) were similar to unadjusted ORs. Results of this analysis indicate scheduled cesarean delivery is associated with an increased risk of any postpartum morbidity and, specifically, postpartum fever without infection. The potential for postpartum morbidity with scheduled cesarean delivery should be considered in light of possible adverse events associated with other interventions to decrease the risk of vertical transmission of HIV. Counseling of HIV-infected pregnant women regarding scheduled cesarean delivery as a possible intervention to decrease maternal-infant transmission of HIV should include discussion of these results, as well as new data as they become available, regarding the incidence and severity of postpartum morbidity events among HIV-infected women according to mode of delivery.

Cesarean Section↗
PubMed2001

Magnetic-field modulation experiments on colossal magnetoresistance samples: first results.

Recently we have observed a small change in the width, sigma, of the Mn-O pair distribution function when a IT magnetic field is applied. To improve our sensitivity to magnetic-field-induced changes, we have developed a magnetic field modulation technique. At each X-ray energy we collect two data points, one with field on and the other with field off: as a result we collect two scans simultaneously. The difference in these two traces provides a measure of the magnetic-field-induced change. The results for the modulation measurements will be compared to the earlier work using static magnetic fields.

Calcium Compounds↗
PubMed2001

The benefits of a broader perspective in case-finding for disease management of depression: early lessons from the PROSPECT Study.

The PROSPECT (Prevention of Suicide in Primary Care Elderly - Collaborative Trial) Study evaluates collaborative care for the treatment of current depressive disorders in older primary care patients. Using screening data, we evaluate implications of expanding the focus to additional patients who report taking psychotropic medication or having a history of depression. Some 13.8% of the patients screened were taking a psychotropic medication and 7.3% were both taking an antidepressant and had a Center for Epidemiologic Studies - Depression Scale (CES-D) score of > 15. Patients who reported current antidepressant use and those with a history of depression also had elevated CES-D scores. Conversely, most patients having an elevated CES-D score also reported taking an antidepressant or having a history of depression. These latter criteria for potential caseness yielded a larger number of patients than those identified by the CES-D alone. More comprehensive approaches to the management of depression should attend to patients already taking psychotropic medication and symptomatic patients with a history of depression, as well as those with current syndromal depression.

Aged↗
PubMed2001

Widespread expression of the nonclassical class I Qa-2 antigens in hemopoietic and nonhemopoietic cells.

We reexamined expression patterns of one of the best characterized mouse class Ib MHC molecules, Qa-2. Transcripts encoding glycosylphosphatidylinositol-linked and soluble forms of Qa-2 are expressed in all organs except brain. The membrane-bound Qa-2 proteins are detectable, to varying degrees, in many cell types of immunological interest: on professional antigen-presenting cells capable of inducing anti-Qa-2 allogeneic responses, on thymic epithelial cells essential for T-cell positive selection, on mature as well as immature thymocytes, in immunologically privileged sites (testis/spermatazoa), and on cells implicated in mucosal immunity (lymphoid-derived and epithelial gut cells and hepatocytes). Although Qa-2 has a nearly ubiquitous tissue distribution similar to H2-Kb and Db molecules, the relative levels of Qa-2 and class Ia displayed on cell surfaces vary in a cell-specific fashion. Analyses of primary cell lines derived from normal mouse tissues also support the conclusion that Qa-2 is present in all cells that can express class Ia antigens. In contrast, tumor lines from Qa-2-positive mice are frequently Qa-2 deficient, suggesting that the Qa-2-negative phenotype of malignant cells is selected in vivo.

Animals↗
PubMed2001

Bioavailability study of oral and intravenous OGT 719, a novel nucleoside analogue with preferential activity in the liver.

PURPOSE: Although oral fluoropyrimidine prodrugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers. METHOD: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m2) OGT 719. RESULTS: Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated. CONCLUSION: The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.

Administration, Oral↗
PubMed2001

The impact of virtual simulation in palliative radiotherapy for non-small-cell lung cancer.

BACKGROUND AND PURPOSE: Radiotherapy is widely used to palliate local symptoms in non-small-cell lung cancer. Using conventional X-ray simulation, it is often difficult to accurately localize the extent of the tumour. We report a randomized, double blind trial comparing target localization with conventional and virtual simulation. METHODS: Eighty-six patients underwent both conventional and virtual simulation. The conventional simulator films were compared with digitally reconstructed radiographs (DRRs) produced from the computed tomography (CT) data. The treatment fields defined by the clinicians using each modality were compared in terms of field area, position and the implications for target coverage. RESULTS: Comparing fields defined by each study arm, there was a major mis-match in coverage between fields in 66.2% of cases, and a complete match in only 5.2% of cases. In 82.4% of cases, conventional simulator fields were larger (mean 24.5+/-5.1% (95% confidence interval)) than CT-localized fields, potentially contributing to a mean target under-coverage of 16.4+/-3.5% and normal tissue over-coverage of 25.4+/-4.2%. CONCLUSIONS: CT localization and virtual simulation allow more accurate definition of the target volume. This could enable a reduction in geographical misses, while also reducing treatment-related toxicity.

Carcinoma, Non-Small-Cell Lung↗
PubMed2001

Cortical network dynamics during verbal working memory function.

This study is an exploratory investigation of the regional timing of cortical activity associated with verbal working memory function. ERP activity was obtained from a single subject using a 124-channel sensor array during a task requiring the monitoring of imageable words for occasional targets. Distributed cortical activity was estimated every 2.5 ms with high spatial resolution using real head, boundary element modelling of non-target activity. High-resolution structural MRI was used for segmentation of tissue boundaries and co-registration to the scalp electrode array. The inverse solution was constrained to the cortical surface. Cortical activity was observed in regions commonly associated with verbal working memory function. This included: the occipital pole (early visual processing); the superior temporal and inferior parietal gyrus bilaterally and the left angular gyrus (visual and phonological word processing); the dorsal lateral occipital gyrus (spatial processing); and aspects of the bilateral superior parietal lobe (imagery and episodic verbal memory). Activity was also observed in lateral and superior prefrontal regions associated with working memory control of sensorimotor processes. The pattern of cortical activity was relatively stable over time, with variations in the extent and amplitude of contributing local source activations. By contrast, the pattern of concomitant scalp topography varied considerably over time, reflecting the linear summation effects of volume conduction that often confound dipolar source modelling.

Adult↗
PubMed2001

Non-invasive methods of assessing angiogenesis and their value in predicting response to treatment in colorectal cancer.

BACKGROUND: Tumour neoangiogenesis can be assessed non-invasively by measuring angiogenic cytokine concentrations in peripheral circulation and by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). The aim of this study was to assess whether these methods can predict and monitor response to treatment in patients with rectal cancer treated with preoperative chemoradiotherapy. METHODS: Serum and plasma vascular endothelial growth factor levels were measured in 31 patients with T3/T4 rectal cancers before quantitating tumour permeability (ln Ktrans) by DCE-MRI. Sixteen patients receiving preoperative chemoradiotherapy had serial vascular endothelial growth factor (VEGF) and DCE-MRI measurements. Response to treatment was assessed using World Health Organization criteria. RESULTS: Serum VEGF and ln Ktrans correlated before treatment (r = 0.48, P = 0.01). Responsive tumours (n = 8) had higher pretreatment permeability values than non-responsive tumours (n = 8) (mean ln Ktrans - 0.46 and - 0.72 respectively; P = 0.03). Compared with pretreatment values, responsive tumours showed a marked reduction in permeability at the end of treatment (mean ln Ktrans - 0.46 and - 0.86 respectively; P = 0.04). Pretreatment serum VEGF levels were not statistically different between the two groups. CONCLUSION: Rectal tumours with higher permeability at presentation appear to respond better to chemoradiotherapy than those of lower permeability. This may allow preselection of appropriate tumours for these regimens, with patients with low-permeability tumours being considered for alternative therapies.

Colorectal Neoplasms↗
PubMed2001

Impaired fear conditioning but enhanced seizure sensitivity in rats given repeated experience of withdrawal from alcohol.

Repeated experience of withdrawal from chronic alcohol treatment increases sensitivity to seizures. It has been argued by analogy that negative affective consequences of withdrawal also sensitize, but repeated experience of withdrawal from another sedative-hypnotic drug, diazepam, results in amelioration of withdrawal anxiety and aversiveness. We tested whether giving rats repeated experience of withdrawal from alcohol altered their ability to acquire a conditioned emotional response (CER). Male Hooded Lister rats were fed a nutritionally complete liquid diet as their only food source. Different groups received control diet, or diet containing 7% ethanol. Rats receiving ethanol diet were fed for either 24 days (Single withdrawal, SWD), or 30 days, with two periods of 3 days, starting at day 11, and 21, in which they received control diet (Repeated withdrawal, RWD). All rats were fed lab chow at the end of their liquid diet feeding period. Starting 12 days after the final withdrawal, groups of Control, SWD and RWD rats were given pentylenetetrazole (PTZ; 30 mg/kg, i.p.) three times a week, and scored for seizures. The occurrence of two successive Stage 5 seizures was taken as the criterion for full PTZ kindling. Other groups of control, SWD and RWD rats were trained to operate levers to obtain food, and were then exposed, in a fully counterbalanced design, to light and tone stimuli which predicted unavoidable footshock (CS+), or which had no consequences (CS-). Rats consumed approximately 17.5 g/kg/day of ethanol, resulting in blood alcohol levels of approximately 100 mg/dL. Repeated administration of PTZ resulted in increasing seizure scores. RWD rats achieved kindling criterion faster than either Control or SWD rats. No differences were seen in the groups in flinch threshold to footshock (0.3 mA). At a shock intensity of 0.35 mA, Control, but not RWD or SWD rats showed significant suppression to the CS+ CS- presentation did not affect response rates. The three groups differed in their response to pairing the CS+ with increasing shock levels, the Controls remaining more sensitive to the CS+. SWD rats showed significant suppression of lever pressing during CS+ presentations only at 0.45 and 0.5 mA, and RWD rats only at 0.5 mA. Giving rats repeated experience of withdrawal from chronic ethanol results in increased sensitivity to PTZ kindling, but reduces their ability to acquire a CER. Withdrawal kindling of sensitivity to anxiogenic events does not seem to occur under circumstances which give rise to kindling of seizure sensitivity.

Acoustic Stimulation↗
PubMed2001

Clinical assessment of dental students: values and practices of teachers in restorative dentistry.

OBJECTIVES: To investigate the values and practices of assessment of the clinical practice of dental students by a sample of teachers in restorative dentistry. DESIGN: A questionnaire, based on the above objectives, was designed, piloted and redesigned. Its content was based on evidence-based good practice in assessment. Structured items in the questionnaire required responses on (i) frequency of use and (ii) estimates of value of various approaches and characteristics of the assessment systems that respondents were using. SETTING: The 14 undergraduate dental schools of the United Kingdom. SUBJECTS: Full-time clinical teachers of restorative dentistry in adults (comprising conservation (including endodontics), periodontology and prosthodontics). RESULTS: A total of 153 usable questionnaires were returned (response rate 70.8%), and 38 statistically significant differences were reported (of which 35 were very highly significant), based on the correlated t statistic. Values were in line with evidence-based good practice, but practices were not in line with values. Particularly noteworthy were the high values attached to objective structured clinical examinations, self- and peer-assessment, portfolio-based learning, feedback to students, the use of objective criteria, communication skills and oral health education. The corresponding frequency of usage of these aspects was relatively low. The reported aims of courses in restorative dentistry were not matched by the profile of assessment practices. CONCLUSIONS: The findings have implications for the development of student learning, assessment procedures and the management of quality and enhancement of dental programmes. Although this is a report of only one study, it relates to the major clinical component of undergraduate programmes in dentistry. The findings imply that the time is ripe for a reappraisal of approaches to the assessment of clinical competence in dentistry.

Clinical Competence↗
PubMed2001

The use of ultrasound by breast surgeons in outpatients: an accurate extension of clinical diagnosis.

AIMS: To assess the accuracy of breast ultrasound scan (USS) performed by a surgeon in outpatients and to evaluate the additional contribution of USS to clinical diagnosis. METHODS: A prospective study of 302 patients with symptomatic breast disease (322 lumps) was performed. Group 1 consisted of 213 clinic USS of lumps surgically removed for appropriate clinical indications. In Group 2, a USS was performed on 231 lumps by both the surgeon and radiologists as part of triple assessment. Each clinic USS was compared to the surgical pathology (Group 1) or USS performed by the radiologist (Group 2). RESULTS: In Group 1 (n=213), 89 lumps were proven benign and 124 malignant on histology. Ultrasound scans performed by the surgeon compared to histology had a sensitivity of 98.3% and specificity of 91.7%. An abnormal clinic USS heightened the index of suspicion in 22/213 (10.3%) of cases felt clinically to be benign but subsequently confirmed malignant on histology. Fifty-seven lumps felt to be indeterminate clinically were correctly identified on USS by surgeon as benign (n=56) or malignant (n=1). In Group 2 (n=231), there was complete concordance of USS scans by surgeon and radiologists in 197 (96%) and complete discordance in eight (3.9%) patients. Of the discordant scans, the surgeon correctly identified 7/8 diagnoses on histology. A USS examination by the radiologists provided a correct diagnosis of 6/14 scans scored by the clinician as indeterminate. CONCLUSION: USS performed in outpatients by a breast surgeon is accurate and a useful adjunct to clinical assessment. This enables rapid diagnosis in one-stop breast clinics, selecting difficult diagnostic procedures for USS by radiologists at the same visit.

Adult↗