Biomedical subjects

K H Moore

Publications and source records attributed to K H Moore.

At least 37 records · Page 2Linked to original sources

PubMed2001

Pharmacokinetics of zidovudine and lamivudine in neonates following coadministration of oral doses every 12 hours.

A phase I, repeat-dose, open-label study was conducted to determine the pharmacokinetics and safety of zidovudine and lamivudine, coadministered orally every 12 hours, in 16 neonates whose mothers were infected with human immunodeficiency virus type 1 (HIV-1). The prospective mothers had been stabilized on a zidovudine/lamivudine regimen since week 36 of pregnancy to prevent mother-to-child transmission of HIV. During 1 week postpartum, the mothers received zidovudine 300 mg plus lamivudine 150 mg every 12 hours and breastfed. Neonatal treatment was initiated 12 hours following birth with 4 mg/kg of zidovudine suspension plus 2 mg/kg of lamivudine solution every 12 hours; this regimen was continued for 1 week. Between days 1 and 7 of neonatal treatment, the neonatal oral clearance (CL/F) of zidovudine and lamivudine increased by 2-fold (p < 0.001) and 1.6-fold (p = 0.004), respectively, possibly reflecting maturation of intestinal hepatic and renal function occurring during the first week of life. Day 7/day 1 ratios for exposure (area under the serum concentration-time curve [AUC]) and maximum observed serum concentration (Cmax) were 0.48 and 0.63, respectively, for zidovudine and 0.64 and 0.73, respectively, for lamivudine. At the time of delivery, the geometric mean cord/maternal concentration ratio was 1.24 for zidovudine and 1.12 for lamivudine, indicating free passage of each drug across the placenta. The maternal and neonatal treatment regimens were well tolerated. The results of this study confirm that in the neonate, a convenient regimen combining zidovudine 4 mg/kg and lamivudine 2 mg/kg, administered orally every 12 hours, provides zidovudine serum exposure very similar to that reported with the standard neonatal zidovudine regimen of 2 mg/kg every 6 hours, as well as lamivudine serum exposure within the range reported in adults receiving lamivudine 150 mg twice a day and children receiving 4 mg/kg twice a day.

Adult↗

PubMed2001

Pharmacokinetics and tolerability of GW420867X, a nonnucleoside reverse transcriptase inhibitor, following single escalating doses in healthy male volunteers.

The aim of the current study was to characterize the pharmacokinetics of GW420867X, a new nonnucleoside reverse transcriptase inhibitor, using a single escalating dose protocol in healthy volunteers. Four dose levels were investigated in sequential order: 300, 600, 900, and 1200 mg, with a ratio of 4:1 subjects receiving active or placebo treatment, respectively. Following single-dose administration, GW420867X was readily absorbed with a median time to peak concentration of 3 to 5 hours. GW420867X plasma exposure (AUC) was dose proportional but variable within the 300 to 1200 mg dose range. Less than dose-proportional increases were observed for Cmax. The terminal elimination t(1/2) was 50 hours, which supports once-daily dosing in future studies. Plasma trough concentrations of GW420867X at 24 hours after dosing were many fold greater than the in vitro IC50 HIV-1(HXB2) in MT4 cells. GW420867X was generally well tolerated following single-dose administration up to 900 mg; increased central nervous system-related adverse events were observed at higher doses. GW420867X had a favorable pharmacokinetic and safety profile that would enable this drug to be explored in future clinical studies with HIV-1 infected patients at doses that would provide appropriate safety and efficacy.

Adolescent↗

PubMed2001

Phosphorylation of nucleoside analog antiretrovirals: a review for clinicians.

Nucleoside analogs (zidovudine, didanosine, zalcitabine, stavudine, abacavir, lamivudine) have been administered as antiretroviral agents for more than a decade. They undergo anabolic phosphorylation by intracellular kinases to form triphosphates, which inhibit human immunodeficiency virus replication by competitively inhibiting viral reverse transcriptase. Numerous methods are used to elucidate the intracellular metabolic pathways of these agents. Intracellular and extracellular factors affect intracellular phosphorylation. Lack of standardization and complexity of methods used to study phosphorylation in patients limit interpretation of study results and comparability of findings across studies. However, in vitro and in vivo studies give important insights into mechanisms of action, metabolic feedback mechanisms, antiviral effects, and mechanisms of toxicity, and have influenced dosing regimens of nucleoside analogs.

Animals↗

PubMed2001

A novel clinical evaluation of childhood incontinence and urinary urgency.

PURPOSE: There are few clinic based objective tools for the evaluation of urinary urgency and incontinence in children. We report on the known method of frequency volume chart, and describe 2 new tools to determine their effectiveness and reliability. MATERIALS AND METHODS: The mean and standard deviation values for affected children in each age group from 5 to 12 years were calculated from 321 consecutive frequency volume charts. Two new child-based scoring tools quantifying urinary urgency were developed to measure the sensation of urgency and the intensity of response at urge (visual analog score 1 and 2). These tools were tested for reliability. As the quantification of incontinence is problematic in children, a new system of documenting functional severity of leakage per day was designed (Dry Pie) and also tested for reliability. RESULTS: Age related mean bladder storage volumes and standard deviations were established for children with incontinence. The novel urgency visual analog measure proved reliable, although only scale 2 would be useful in clinical practice. The incontinence Dry Pie diary was also shown to be reliable for 2 weeks and easily completed at home by the children. CONCLUSIONS: As a result of this study clinic based intervention can include reliable quantification of urinary urgency (visual analog scale 2) and a functional measure of the severity of incontinence (Dry Pie).

Child↗

PubMed2001

A pilot study of the home application of transcutaneous neuromodulation in children with urgency or urge incontinence.

PURPOSE: We evaluated the efficacy of transcutaneous neuromodulation to treat urinary urgency and urge incontinence in children with nonneurological bladder dysfunction. MATERIALS AND METHODS: Surface neuromodulation was delivered via skin electrodes away from the genital region for a short duration daily on a home treatment basis. Clinical outcome was measured by 3 tools previously tested for reliability including the frequency volume chart, urgency visual analog scale and accident diary ("Dry Pie"). RESULTS: After at least 1 month of application dryness had improved in 73.3% of children, mean urgency score had improved to equate action at urge as being 'easy to hold on' and there was a significant increase in mean voided volume. CONCLUSIONS: Initial evaluation of the home application of surface neuromodulation in children with urgency and/or urge incontinence revealed positive results and warrants a randomized controlled investigation. The finding that children were not completely dry with this treatment in isolation suggests that further study is needed to identify optimal treatment duration and stimulus intensity.

Child↗

PubMed2000

Oral zidovudine during labor to prevent perinatal HIV transmission, Bangkok: tolerance and zidovudine concentration in cord blood. Bangkok Collaborative Perinatal HIV Transmission Study Group.

OBJECTIVES: To evaluate tolerance for the oral administration of zidovudine (ZDV) during labor and measure the resulting ZDV concentrations in umbilical cord blood. DESIGN: A cross-sectional study of women in a placebo-controlled trial of short-course ZDV (twice a day from 36 weeks' gestation until labor and every 3 h during labor) to prevent perinatal HIV transmission in Bangkok. METHODS: Umbilical cord blood was collected. Sixty control specimens and specimens from 372 women (182 in the ZDV group, 190 in the placebo group) were tested for ZDV by radioimmunoassay (lower detection limit < 1 ng/ml). RESULTS: All women in the ZDV group took one or more labor dose, 170 (93%) took their last dose within 3 h of delivery, and only five (3%) experienced nausea or vomiting, a proportion similar to the placebo group. The median concentration of ZDV in the cord blood in the ZDV group was 252 ng/ml (range, < 1-1133 ng/ml); 31 (17%) specimens were less than 130 ng/ml (0.5 microM), the concentration thought to be active against HIV in vitro. Median concentrations were 189 ng/ml in specimens from women taking one or two labor doses, 290 ng/ml in those taking three or four doses, and 293 ng/ml in those taking more than four doses (P < 0.01). The ZDV concentration was not associated with time since the last dose, body weight, or perinatal transmission. CONCLUSION: Oral intrapartum ZDV was feasible and well tolerated. Most ZDV concentrations in the cord blood after oral dosing during labor were at therapeutic concentrations but were lower than those reported after continuous intravenous administration. Although concentrations were not associated with perinatal transmission, these data do not exclude the possibility that intrapartum and neonatal chemoprophylaxis is effective.

Administration, Oral↗

PubMed2000

Attitudes to vaginal/urethral touching and device placement in women with urinary incontinence.

Because of recent development of a number of intravaginal and urethral occlusive devices for the treatment of urinary incontinence, we aimed to develop a linear analog scale that measured women's attitudes to becoming familiar with their genital anatomy and to placing devices into or upon the vagina or urethral orifices. We also investigated whether such attitudes were affected by previous tampon or diaphragm use, or were age dependent. After pilot studies, a 10-item questionnaire was given to 104 consecutive incontinent women, only 30% of whom were quite comfortable about the concept of touching their genitalia: this attitude was age dependent. Only 21% were quite willing to insert a continence device into their vagina: this attitude varied weakly with age but was significantly affected by previous tampon or diaphragm usage. Only 15% felt very comfortable about placing a continence device on to their urethra, but the likelihood of a positive response to this concept was not at all affected by age and was only slightly more common in previous tampon users. Thus older women are less likely to understand the anatomy of their genitalia or to be comfortable about the idea of exploring it, but age is no barrier to willingness to employ urethral or vaginal continence devices per se. We suggest that such a linear analog questionnaire may help gynecologists determine which patients might respond well to the use of vaginal or urethral continence devices.

Adult↗

PubMed2000

In vitro contractile responses of detrusor to carbachol and neurokinin A, in children with recurrent urinary tract infection or day wetting.

OBJECTIVE: To investigate whether a history of recurrent urinary tract infection (UTI) and/or the presence of day-wetting/urge symptoms might influence the contractile responses to the cholinergic agonist carbachol or to the sensory neuropeptide neurokinin A (NKA) in the urinary bladder in children. PATIENTS AND METHODS: Small detrusor strips were taken from the margin of the cystotomy incision of the bladder dome during surgery to correct vesico-ureteric reflux (VUR) in 62 children (aged 4 months to 12 years) or for unrelated bladder conditions in five controls (aged 3 months to 13 years). Concentration-response curves to carbachol and NKA were constructed using organ-bath techniques, and results compared for age, sex, weight of the detrusor strip, UTI history or day-wetting syndrome. RESULTS: The contractile responses to NKA were no different for any of the features investigated. The contractile response to carbachol and NKA in detrusor from control and VUR patients was not significantly different. The children with a history of UTI were significantly older than those without. The contractility in response to carbachol was greater in older girls (aged 4-12 years) than younger girls (< 4 years) and than in all boys (< 4 years and 4-12 years; ANOVA P = 0.013). The mean (SEM) maximum contractile response to carbachol in the group of 20 young children (4-30 months) with previous UTI was 3.0 (0.3) g, whereas the maximum response in the age-matched group of 11 without UTI was 1.8 (0.3) g (P = 0.046). There were no significant differences in maximum responses between those with day-wetting and those without (aged > 4 years), although there was a significant difference in pD2 value, at 6.19 (0.13) and 5.58 (0.14), respectively (P = 0.018). CONCLUSION: Carbachol produced a larger contractile response in detrusor from children with a history of UTI than from those without, indicating possible alterations in muscarinic receptor characteristics. An increased sensitivity to muscarinic stimulation in day-wetting children was also suggested, whereas NKA is unlikely to be involved in any of these pathophysiological conditions.

Adolescent↗

PubMed2000

The relative incidence of detrusor instability and bacterial cystitis detected on the urodynamic-test day.

OBJECTIVE: To determine whether patients with detrusor instability (DI) were more likely to have bacterial cystitis or significant bacteriuria on the urodynamic-test day than were women with a stable bladder. PATIENTS AND METHODS: A catheter specimen of urine was cultured (overnight in air) from 862 consecutive women at the time of urodynamic testing. The upper urinary tract was imaged, with cystoscopy when indicated, to exclude upper tract lesions or malignancy. The percentage of patients with pure idiopathic DI and those with mixed DI/genuine stress incontinence (GSI), in whom the urine culture was positive, was compared with the percentage who had a stable bladder (pure GSI or urodynamically normal) and a positive urine culture, both for the entire dataset and for women aged > or <65 years. Data were also analysed to detect the converse relationship; in those women found to have bacterial cystitis, the relative risk of being found urodynamically unstable or stable was determined. RESULTS: The likelihood of bacterial cystitis occurring in patients with idiopathic DI (5.6%) was significantly greater than that in patients with GSI (1.1%; P = 0.009, Fisher's exact test). The proportion of patients with DI and significant bacteriuria (15. 4%) was significantly greater than that in patients with GSI (7.9%; P = 0.02). In patients with combined pure and mixed DI, bacterial cystitis was significantly more likely to occur (6.3%) than in GSI (P < 0.001), but bacteriuria was no more likely (12.5%, P = 0.09). Conversely, of those women found to have bacterial cystitis, the relative risk of having an unstable bladder was increased (+1.56), but for those with bacteriuria the relative risk of detrusor instability was not increased. CONCLUSION: There was a significant association between idiopathic DI and bacterial cystitis, and we suggest that in some women with an unstable bladder, urinary infection may enhance detrusor contractility. Nevertheless, large-scale studies are needed of the temporal relationship between the onset of bacterial cystitis and the onset of DI.

Adult↗

PubMed2000

Angiotensin II in child urinary bladder: functional and autoradiographic studies.

OBJECTIVES: To investigate the receptors for angiotensin II (AII, reported to be a potent contractile agent in human urinary bladder), using functional and autoradiographic techniques in child and adult bladder specimens. Materials and methods Bladder specimens were obtained from 61 children (aged 4 months to 12 years) undergoing ureteric reimplantation for vesico-ureteric reflux, and from 10 adults undergoing cystectomy. After overnight storage, the mucosa was removed and isometric contractions obtained from detrusor muscle strips in the presence of phosphoramidon (10 micromol/L). Only one concentration of AII was added to each preparation because of tachyphylaxis. The response to KCl (124 mmol/L) was 43% of that to carbachol (100 micromol/L). Sections of child bladder were radio-labelled with the ligand [125I]Sar1,Ile8-AII and binding sites visualized using emulsion autoradio- graphy. RESULTS: The potency of AII was similar in child and adult detrusor strips, with mean (SEM) pD2 values of 6.9 (1.0) (n = 25) and 6.7 (0.2) (n = 9) respectively, and the maximum responses (to 10 micromol/L AII) rather low (39% and 49%, respectively, P > 0.05), compared with carbachol (100 micromol/L). There were no age- or gender-related differences. Responses to AII in strips from children under 3 years old were antagonized by the AT1 receptor antagonist losartan (1 micromol/L) but not by the AT2 receptor antagonist PD 123319 (1 micromol/L), indicating interaction with the AT1 receptor. Sections of child bladder radiolabelled with [125I]Sar1,Ile8-AII showed moderate specific binding over detrusor muscle and arterioles, with denser specific binding over subepithelial blood vessels. Specific binding was inhibited by co-incubation with losartan (10 micromol/L) but not with PD 123319 (10 micromol/L). CONCLUSION: AII was a weak contractile agent of detrusor strips, with no significant differences in potency between child and adult bladder samples. These data show the presence of functional AT1 but not AT2 receptors in child detrusor smooth muscle.

Adult↗

PubMed2000

Conservative management for urinary incontinence.

Gynaecologists have become increasingly aware of the need to offer conservative therapy for genuine stress incontinence. There is good objective evidence from randomized controlled trials to support the use of supervised pelvic floor exercises. The efficacy of biofeedback therapy, vaginal cone weights and electrostimulation therapy is variable and requires further study to identify those women who will benefit the most. The mainstay of therapy for detrusor instability/sensory urgency remains bladder training, which has proven objective efficacy, but new treatments such as transcutaneous electrical nerve stimulation (TENS) offer promise. Finally, for certain groups of women with mixed stress and urge leak, a new range of vaginal and urethral devices provide useful additional options. The specific requirements for future research are discussed.

Biofeedback, Psychology↗

PubMed2000

Localization of messenger ribonucleic acid for adrenomedullin and adrenomedullin receptor in the human placenta in normal pregnancies and pregnancies complicated by oligohydramnios.

OBJECTIVE: The purpose of this study was to identify the placental expression of adrenomedullin and adrenomedullin receptor messenger ribonucleic acid and compare them between placentas from pregnancies associated with oligohydramnios as a result of uteroplacental insufficiency and placentas from normal pregnancies. STUDY DESIGN: Total ribonucleic acid was extracted from the amnion, chorion, cotyledon, umbilical vein, and umbilical artery in 5 normal placentas and 3 placentas from pregnancies complicated by oligohydramnios. A cell line known to express messenger ribonucleic acid of adrenomedullin and its receptor was used to optimize the polymerase chain reaction and served as a positive control preparation in all experiments. Semiquantitative reverse transcriptase-polymerase chain reaction results for adrenomedullin and adrenomedullin receptor were compared between tissues as densitometric ratios of adrenomedullin or adrenomedullin receptor messenger ribonucleic acid to beta(2)-microglobulin messenger ribonucleic acid. Results were analyzed with a Kruskal-Wallis 1-way analysis of variance. Immunohistochemical staining with an antibody to human adrenomedullin was used to localize adrenomedullin in all tissue types. RESULTS: Messenger ribonucleic acid sequences for adrenomedullin and adrenomedullin receptor genes were identified in all tested placental tissue components. Within the normal placentas the expressions of adrenomedullin and adrenomedullin receptor messenger ribonucleic acid sequences did not differ statistically between the tissue components. Within placentas from patients with oligohydramnios the expressions of adrenomedullin and adrenomedullin receptor messenger ribonucleic acid did not differ statistically between the tissue components. When normal placentas were compared with placentas from pregnancies complicated by oligohydramnios, however, a 5-fold increase in adrenomedullin messenger ribonucleic acid and a 3-fold increase in adrenomedullin receptor messenger ribonucleic acid were seen in placentas from patients with oligohydramnios. Adrenomedullin immunoreactivity was present in all tissues studied. CONCLUSION: The expression of messenger ribonucleic acid for both adrenomedullin and its receptor in these tissue components implies that placental tissues function in both synthesis and action of adrenomedullin. The increased adrenomedullin messenger ribonucleic acid expression in the umbilical artery and the elevated adrenomedullin receptor messenger ribonucleic acid expression in the cotyledons of placentas from patients with oligohydramnios may represent a local fetoplacental physiologic adaptive response to vascular compromise.

Adrenomedullin↗

PubMed2000

A population pharmacokinetic analysis of zanamivir in subjects with experimental and naturally occurring influenza: effects of formulation and route of administration.

The pharmacokinetics of zanamivir were evaluated in subjects from three phase I single-center and two phase II multicenter, randomized, double-blind, multidose, placebo-controlled trials. A total of 96 phase I subjects received zanamivir (3.6 to 16 mg) intranasally two or six times daily for 4 to 5 days beginning 4 hours before or 1 to 2 days after inoculation with influenza virus. A total of 75 phase II subjects with influenza or a history of exposure to naturally occurring influenza virus were administered zanamivir as an intranasal spray (3.4 mg/nostril), inhaled powder (10 mg), or combination of intranasal and inhaled formulations twice daily for 5 days. Population parameters (including demographic factors, zanamivir formulation, infection-related variables, and concurrent medication use) were estimated by a nonlinear mixed-effect modeling software program (NONMEM) using a one-compartment model with first-order absorption and conditional estimation algorithm. Formulation and route of administration were the most significant factors affecting the pharmacokinetics of zanamivir. Relative bioavailability of the inhaled powder to the intranasal drops and spray was 2.3 and 1.6, respectively. No significant differences in pharmacokinetic parameters were observed when demographic variables, indices of infection, or concurrent medication use were considered in either phase I or phase II population analyses.

Administration, Inhalation↗

PubMed2000

Autoradiographic localization of tachykinin and calcitonin gene-related peptide receptors in adult urinary bladder.

PURPOSE: In bladder, sensory afferent nerve fibers contain the "sensory neuropeptides" substance P (SP), neurokinin A (NKA) and calcitonin gene-related peptide (CGRP), which interact with tachykinin NK-1 and NK-2 receptors and CGRP receptors, respectively. The purpose of this study was to examine the autoradiographic distribution of these three receptor types in the human bladder, to determine whether the anatomic location of the receptors was consistent with their known functional roles. MATERIALS AND METHODS: Specimens of urinary bladder from 9 patients (58-74 years) were obtained at cystectomy. Frozen sections of dome were labeled with [125I]-Bolton-Hunter [Sar9,Met(O2)11]-SP (NK-1 receptors), [125I]-[Lys5,Tyr(I2)7,MeLeu9,Nle10]-NKA(4-10) (NK-2 receptors) and [125I]-rat CGRP-I. Binding sites were visualized using emulsion autoradiography. RESULTS: NK-1 receptors were found over the endothelium of arterial blood vessels within the detrusor muscle and lamina propria, and over small vessels in the subepithelium. NK-2 receptors were seen over the detrusor muscle and very sparsely over blood vessels, whereas CGRP receptors were expressed densely over the smooth muscle layer of arteries and arterioles, and weakly over collecting venules. NK-1 and CGRP receptors were not observed over the detrusor muscle. CONCLUSIONS: Although the afferent nerves contain all three peptides, not all cell types express receptors for each peptide. The general distribution of receptors is in good agreement with the location of nerves, and with the known actions of SP and CGRP as vasodilator agents, and of NKA (but not SP or CGRP) in contracting the detrusor muscle.

Aged↗

PubMed1999

The pharmacokinetics of lamivudine phosphorylation in peripheral blood mononuclear cells from patients infected with HIV-1.

OBJECTIVE: To assess the pharmacokinetics of lamivudine phosphorylation in peripheral blood mononuclear cells (PBMC) from patients infected with HIV-1. DESIGN: Single-center, open-label, randomized, two-period, cross-over study in 10 asymptomatic, antiretroviral-experienced, HIV-1-infected patients who had a CD4+ lymphocyte count of 200-500 x 10(6)/l and had received combination treatment with lamivudine 150 mg twice a day plus zidovudine 600 mg a day (divided into two or three doses) for > or = 16 weeks prior to study entry. METHODS: Patients were randomly assigned to receive lamivudine 150 mg twice a day or lamivudine 300 mg twice a day for 14 days, with at least a 48-h washout period between treatments. Serial blood samples were collected over 36 h for determination of lamivudine serum concentrations using liquid chromatography/mass spectrometry and intracellular phosphate PBMC concentrations using high performance liquid chromatography/radioimmunoassay methods. Pharmacokinetic parameters were calculated based on lamivudine and lamivudine anabolite concentration-time data. RESULTS: Intracellular pharmacokinetic parameters were highly variable between patients (coefficient of variations approximately 50%). The two regimens produced lamivudine-total phosphate (totP) values of a similar magnitude. Although the 300-mg regimen tended to produce higher lamivudine-monophosphate (MP) and -triphosphate (TP) values, differences from values produced by the 150-mg regimen were not statistically significant. As lamivudine diphosphate (DP) was the predominant anabolite, accounting for 50-55% of lamivudine-totP (compared with 30-35% for lamivudine-MP and 15-20% for lamivudine-TP), the conversion of lamivudine-DP to lamivudine-TP can be regarded as the rate-limiting step. The median lamivudine-TP intracellular half-life (t1/2) for the 150-mg and 300-mg regimens did not differ significantly (15.3 and 16.1 h, respectively). Serum lamivudine pharmacokinetic parameters were consistent with those observed in previous studies in HIV-1-infected patients. No apparent linear relationships were observed between lamivudine intracellular anabolite and serum data. CONCLUSIONS: The intracellular pharmacokinetics of lamivudine phosphorylation in PBMC from asymptomatic HIV-1-infected patients are highly variable and do not differ statistically between the 150- and 300-mg twice a day regimens. The variations in intracellular lamivudine-TP concentrations following these two lamivudine dosage regimens are unlikely to result in differences in clinical effect. This was confirmed by the results of a large phase III study in HIV-1-infected patients which showed no differences in HIV-1 RNA or CD4+ lymphocyte counts between the 150- and 300-mg lamivudine regimens in combination with zidovudine.

Anti-HIV Agents↗

PubMed1999

Effects of tamoxifen on telomerase activity in breast carcinoma cell lines.

BACKGROUND: The authors tested the effects of the antiestrogenic agent tamoxifen on telomerase activity and cell proliferation in MCF-7 and MDA-MB-231 breast carcinoma cell lines. MCF-7 cells belong to a known estrogen receptor positive cell line, whereas MDA-MB-231 cells, previously thought to be estrogen receptor negative, are now shown to contain estrogen receptor-beta. METHODS: Both cell lines were grown in the presence of tamoxifen 10(-6), 10(-7), 10(-8), and 10(-9) M for 10 days. Cells in separate flasks were harvested daily for determination of total cell number, protein was extracted for determination of telomerase activity, and RNA was extracted for reverse transcriptase-polymerase chain reaction analysis to measure expression levels of the telomerase components (the RNA component and the catalytic subunit) and estrogen receptors. RESULTS: Total cell counts and telomerase activity levels of both cell lines with 10(-8) M tamoxifen treatment were lower than control cells and other tamoxifen treatments. Changes in the expression of individual telomerase components correlated with telomerase activity. Estrogen receptor status did not correlate with telomerase activity. CONCLUSIONS: Tamoxifen strongly affected both cell count and telomerase activity within the 10(-8) M concentration of both cell lines. Cells were able to overcome drug inhibition at all other doses after 4 days. Telomerase activity and cell proliferation were correlated in both cell lines and depended on drug concentration. Tamoxifen showed long term effects on cell proliferation of the MCF-7 cells.

Breast Neoplasms↗

PubMed1999

Calculating the direct costs of urinary incontinence: a new test instrument.

OBJECTIVES: To develop a universally applicable test instrument to measure the total direct costs of urinary incontinence, including personal costs and treatment costs, i.e. the Dowell-Bryant Incontinence Cost Index (DBICI), and to study the construct validity and test-retest reliability of the instrument. PATIENTS AND METHODS: In a prospective observational study, 100 consecutive community-dwelling ambulatory women who presented with stress, urge or mixed incontinence were asked to complete the DBICI questionnaire on two occasions, 7 days apart, before any treatment. The construct validity of the DBICI was ascertained by correlation with other standard measures of urinary incontinence severity; (i) a visual analogue scale (VAS) to assess the impact of leakage upon lifestyle; (ii) frequency-volume charts (voids/24 h, leaks/week); (iii) urine loss during a standard 1 h pad test; and (iv) two disease-specific quality of life questionnaires. The test-retest reliability was measured by comparing the two test results and the construct validity of the individual subsets (personal and treatment) of the DBICI similarly assessed. RESULTS: Ninety-seven women completed the baseline assessment and 84 completed the re-test. The median (interquartile range) total direct incontinence cost (in Au$) was 12. 89 (5.26-22.67) per week, which comprised the median personal costs of 5.61 (1.68-10.36) and the median treatment costs of 4.96 (1.22-13. 37). The total direct incontinence cost was significantly correlated with the severity of urinary leakage on a 1 h pad test (Kendall's rank correlation, P=0.01), with the VAS impact score (P<0.001) and with the number of leaks/week (P=0.005). The correlation between the personal cost subset and other quantitative measures was also highly significant. Test-retest analysis of the personal costs subset revealed that this subset was robust and satisfied the statistical criteria of repeatability. CONCLUSIONS: The DBICI gives a detailed measure of the direct economic costs of urinary incontinence in ambulatory home-dwelling women, with the construct validity confirmed by the significant correlation with other quantitative measures of incontinence. By substituting local prices into the test format, the index should be useful in other countries. In the current climate of economic rationalization, such an index should be a part of future urinary incontinence research.

Adult↗

PubMed1999

An open study of the bladder neck support prosthesis in genuine stress incontinence.

OBJECTIVE: To determine the proportion of unselected women with genuine stress incontinence in whom a bladder neck support prosthesis could be fitted successfully by three gynaecologists with no prior knowledge of the device, and to measure efficacy of the device. DESIGN: Prospective interventional study. SETTING: Two metropolitan urodynamic units. SAMPLE: Eighty women with genuine stress incontinence. MAIN OUTCOME MEASURES: Average number of leaks per day on a frequency volume chart, average number of pads worn per day, urine loss on a one-hour pad test, and urine flow rate. RESULTS: Of the 80 recruits, 11 had exclusion criteria and four could not be fitted at the first visit. Of 65 participants, 39 (58%) withdrew from the study before week four. In 20 of 39 women (51%) post-surgical scarring made fitting difficult, and six (15%) withdrew for unrelated personal or medical reasons. In five women (13%) the device was never effective; six withdrew because of adverse events and two required devices that were larger or smaller than those presently available. Thus 38 of 65 participants (58%) could be fitted by the three gynaecologists. Of 26 women who wore the device for four weeks, median leaks per day fell from 2.5 (interquartile range (IQR) 1.9-4.6) to 1.0 (IQR 0-2); median number of pads per day fell from 1.5 (IQR 0.5-3) to 0 (IQR 0-1); and median pad test loss fell from 19 g/h (IQR 8-49) to 2 g/h (IQR 0-8). Sixteen of these 26 patients (62%) achieved objective success, six (23%) were socially continent, one failed to respond and three declined to complete all outcome measures. Urine flow rates revealed no evidence of outflow obstruction. At the sixth month, 18 of 26 patients (69%) were wearing the device successfully; 15 of these women continued to the 12th month, and all but one were objectively dry. CONCLUSIONS: The bladder neck support prosthesis is a useful addition to the range of treatments available for the management of genuine stress incontinence, but may be difficult to fit in women who are oestrogen-deprived or have undergone multiple surgical procedures. The demands of the trial protocol were found to be onerous by frail elderly women.

Aged↗