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Biomedical subjects

R Leonard

Publications and source records attributed to R Leonard.

At least 37 records · Page 2Linked to original sources
PubMed1998

Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate.

PURPOSE: To compare two doses of letrozole and megestrol acetate (MA) as second-line therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens. PATIENTS AND METHODS: Five hundred fifty-one patients with locally advanced, locoregionally recurrent or metastatic breast cancer were randomly assigned to receive letrozole 2.5 mg (n = 174), letrozole 0.5 mg (n = 188), or MA 160 mg (n = 189) once daily in a double-blind, multicenter trial. Data were analyzed for tumor response and safety variables up to 33 months of follow-up evaluation and for survival up to 45 months. RESULTS: Letrozole 2.5 mg produced a significantly higher overall objective response rate (24%) compared with MA (16%; logistic regression, P = .04) or letrozole 0.5 mg (13%; P = .004). Duration of objective response was significantly longer for letrozole 2.5 mg compared with MA (Cox regression, P = .02). Letrozole 2.5 mg was significantly superior to MA and letrozole 0.5 mg in time to treatment failure (P = .04 and P = .002, respectively). For time to progression, letrozole 2.5 mg was superior to letrozole 0.5 mg (P = .02), but not to MA (P = .07). There was a significant dose effect in overall survival in favor of letrozole 2.5 mg (P = .03) compared with letrozole 0.5 mg. Letrozole was significantly better tolerated than MA with respect to serious adverse experiences, discontinuation due to poor tolerability, cardiovascular side effects, and weight gain. CONCLUSION: The data show letrozole 2.5 mg once daily to be more effective and better tolerated than MA in the treatment of postmenopausal women with advanced breast cancer previously treated with antiestrogens.

Administration, Oral↗
PubMed1997

Initial frequency of alleles for resistance to Bacillus thuringiensis toxins in field populations of Heliothis virescens.

The risk of rapid pest adaptation to an insecticide is highly dependent on the initial frequency of resistance alleles in field populations. Because we have lacked empirical estimates of these frequencies, population-genetic models of resistance evolution have relied on a wide range of theoretical estimates. The recent commercialization of genetically engineered cotton that constitutively produces an insecticidal protein derived from the biocontrol agent, Bacillus thuringiensis (Bt) has raised concern that we lack data needed to quantify the risk of insect pests such as Heliothis virescens rapidly adapting to this ecologically valuable class of toxins. By individually mating over 2,000 male H. virescens moths collected in four states to females of a Bt toxin-resistant laboratory strain, and screening F1 and F2 offspring for tolerance of the toxic protein, we were able to directly estimate the field frequency of alleles for resistance as 1.5 x 10(-3). This high initial frequency underscores the need for caution in deploying transgenic cotton to control insect pests. Our single-pair mating technique greatly increases the efficiency of detecting recessive resistance alleles. Because alleles that decrease target site sensitivity to Bt toxins and other insecticides are often recessive, this technique could be useful in estimating resistance allele frequencies in other insects exposed to transgenic insecticidal crops or conventional insecticides.

Journal Article↗
PubMed1996

Discomfort associated with regional anesthetic placement in obstetrics: does alkalinization help?

Lidocaine is commonly used prior to intravenous catheter insertion as well as before instituting a regional anesthetic[ but it often causes a burning discomfort during injection. We undertook this study to determine if the addition of bicarbonate to lidocaine would decrease the discomfort associated with the initiation of regional anesthesia in obstetrics. Forty patients who were scheduled for elective cesarean section or who were in active labor were selected. Lidocaine was prepared before infiltration using 9 ml of preservative-free 1% lidocaine with either 1 ml of preservative-free normal saline or 1 ml of sodium bicarbonate (1 mEq.ml(-1)). A skin wheal was raised with 0.5 ml of the solution; the remainder (1.5 ml) was injected into the deep tissues. Pain was assessed using visual analog scales on three occasions, immediately after lidocaine placement, following introducer needle insertion (in the spinal group) or following epidural needle insertion (in the epidural group), and following the successful placement of the local anesthetic (in the spinal group) or the epidural catheter (in the epidural group). There was no difference in the visual analog scale scores at any of the assessment periods. We found no benefit from adding sodium bicarbonate to lidocaine used for infiltration before needle placement when initiating an obstetrical regional anesthetic.

Journal Article↗
PubMed1996

High-dose chemotherapy supported by peripheral blood progenitor cells in poor prognosis metastatic breast cancer--phase I/II study. Edinburgh Breast Group.

Current treatments for metastatic breast cancer are not associated with significant survival benefits despite response rates of over 50%. High-dose therapy with autologous bone marrow transplantation (ABMT) has been investigated, particularly in North America, and prolonged survival in up to 25% of women has been reported, but with a significant treatment-related mortality. However, in patients with haematological malignancies undergoing autologous transplantation, haematopoietic reconstruction is significantly quicker and mortality lower than with ABMT, when peripheral blood progenitor cells (PBPCs) are used. In 32 women with metastatic breast cancer, we investigated the feasibility of PBPC mobilisation with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) after 12 weeks' infusional induction chemotherapy and the subsequent efficacy of the haematopoietic reconstitution after conditioning with melphalan and either etoposide or thiotepa. PBPC mobilisation was successful in 28/32 (88%) patients, and there was a rapid post-transplantation haematopoietic recovery: median time to neutrophils > 0.5 x 10(9) l-1 was 14 days and to platelets > 20 x 10(9) l-1 was 10 days. There was no procedure-related mortality, and the major morbidity was mucositis (WHO grade 3-4) in 18/32 patients (56%). In a patient group of which the majority had very poor prognostic features, the median survival from start of induction chemotherapy was 15 months. Thus, PBPC mobilisation and support of high-dose chemotherapy is feasible after infusional induction chemotherapy for patients with metastatic breast cancer, although the optimum drug combination has not yet been determined.

Adult↗
PubMed1996

Adhesion of calcium oxalate monohydrate crystals to anionic sites on the surface of renal epithelial cells.

Adhesion of microcrystals to the apical surface of renal tubular cells could be a critical step in the formation of kidney stones. The role of membrane surface charge as a determinant of the interaction between renal epithelial cells (BSC-1 line) and the most common crystal in kidney stones, calcium oxalate monohydrate (COM), was studied in a tissue culture model system. Adhesion of COM crystals to cells was blocked by cationized ferritin. Other cations that bind to cells including cetylpyridinium chloride and polylysine, as well as cationic dyes such as Alcian blue, also inhibited adhesion of COM crystals, but not all polycations shared this effect. Specific lectins including Triticum vulgaris (wheat germ agglutinin) blocked crystal binding to the cells. Furthermore, treatment of cells with neuraminidase inhibited binding of crystals. Therefore, anionic cell surface sialic acid residues appear to function as COM crystal receptors that can be blocked by specific cations or lectins. In vivo, alterations in the structure, function, quantity, or availability of these anionic cell surface molecules could lead to crystal retention and formation of renal calculi.

3T3 Cells↗
PubMed1996

Modulation of pulsatile GH release through a novel receptor in hypothalamus and pituitary gland.

Hormone replacement should provide a serum hormone profile similar to that found in normal physiology. This is generally impractical because hormones are usually released episodically and therefore require frequent administration. However, rather than replacing the hormone directly, in theory, one could administer a mimic or amplifier of the pulse generator that controls pulsatile release of the particular hormone. Using growth hormone (GH) as a paradigm we sought such a mimetic that would provide episodic GH release when administered by the oral route. A GH secretagogue MK0677, is described that has these ideal properties; following oral administration MK0677 amplifies episodic GH release. Mechanistically, it synergizes with growth hormone releasing hormone (GHRH) through a receptor and signal transduction pathway distinct from that of GHRH and is a functional antagonist of somatostatin (SRIF). MK0677 also acts on the arcuate nucleus and appears to stimulate GHRH release. By using 35S-MK0677, a new G-protein coupled receptor for MK0677 was characterized in the plasma membrane fraction of pituitary and hypothalamic tissue. The receptor is present in very low abundance and couples to phospholipase C. Other ligands selective for this receptor also cause synchronization of well-defined pathways leading to GH release. Repeated oral treatment of dogs once daily with MK0677 initiates amplified pulsatile GH release accompanied by increases in IGF-1 that are sustained. The unique biological properties of MK0677 and other synthetic ligands that bind to the same receptor force us to predict that these ligands mimic a naturally occurring hormone that regulates pulsatile GH release. Understanding the regulatory mechanisms involved in this paradigm has broad implications for the control of pulsatile rhythms in the endocrine system.

Amino Acid Sequence↗
PubMed1995

Effects of chronic ozone (O3) exposure on vocal-fold mucosa in bonnet monkeys.

Effects of ambient ozone (O3) on the respiratory tract have been frequently reported. However, little is known regarding possible effects of chronic exposure to O3 on the larynx or on vocal-fold mucosa. In this study, six bonnet monkeys were exposed to 1 ppm O3 8 h per day, 5 days per week, for 3 months. Three of the monkeys' larynges were examined 4 h after exposure, and three were examined 9 months after exposure. Tissues were subjected to histological staining and morphometric quantification. Results revealed increased thickness of epithelial and connective tissue components of vocal-fold mucosa in the 4-h group and connective tissue changes that persisted in mucosa examined 9 months after exposure. Additional changes indicative of hyperplasia and disorganization of epithelial and connective tissue, as well as disruption of glands and vessels, were also noted in tissues examined at both postexposure intervals. Implications of the data for the larynx and voice quality in humans exposed to similar environmental toxins are discussed.

Animals↗
PubMed1995

Volunteers or victims: patients' views of randomised cancer clinical trials.

Randomised clinical trials are essential for the objective evaluation of different treatment strategies in cancer. However, in the field of oncology, very few of the eligible patients are entered into trials, and most treatments have only been tested on a small percentage of patients. For doctors, a major deterrent to participating in trials is the lack of resources--particularly time, but often also the local facilities. This report suggests that patients themselves are willing to take part in clinical research, and are attracted by being treated by a doctor with a specialist interest in the disease and encouraged by the possibility that their progress will be monitored closely. With the recent NHS changes, it is timely for the Department of Health and other national health departments to consider carefully what can be done to ensure that no new treatments are adopted without effective evaluation. This will require departments of health to identify and implement ways to facilitate accrual of appropriate numbers of patients onto research protocols (whether non-randomised phase I or phase II studies or large, multicentre phase III trials) over short time periods.

Adolescent↗
PubMed1995

Adhesion of calcium oxalate monohydrate crystals to renal epithelial cells is inhibited by specific anions.

Adhesion of urinary crystals to the apical surface of renal tubular cells could be a critical step in the formation of kidney stones. The interaction between renal epithelial cells (BSC-1 line) and the most common crystal in kidney stones, calcium oxalate monohydrate (COM), was studied in a tissue culture model system. COM crystals bound to the cell surface within seconds in a concentration-dependent manner to a far greater extent than did brushite, another calcium-containing crystal found in urine. Adhesion of COM crystals to cells was blocked by the polyanion, heparin. Other glycosaminoglycans including chondroitin sulfate A or B, heparan sulfate, and hyaluronic acid, but not chondroitin sulfate C, prevented binding of COM crystals. Two nonsulfated polyanions, polyglutamic acid and polyaspartic acid, also blocked adherence of COM crystals. Three molecules found in urine, nephrocalcin, uropontin, and citrate, each inhibited binding of COM crystals, whereas Tamm-Horsfall glycoprotein (THP) did not. Prior exposure of crystals but not cells to inhibitory molecules blocked adhesion, suggesting that these agents exert their effect at the crystal surface. Inhibition of crystal binding followed a linear Langmuir adsorption isotherm for each inhibitor identified, suggesting that these molecules bind to a single class of sites on the crystal that are important for adhesion to the cell surface. Inhibition of crystal adhesion by heparin was rapidly overcome by the polycation protamine, suggesting that the glycosaminoglycan regulates cell-crystal interactions in a potentially reversible manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Inhibition of activity of the protease from bovine leukemia virus.

In view of the close similarity between bovine leukemia virus (BLV) and human T-cell leukemia virus type I (HTLV-I) we investigated the possibility of developing specific inhibitors of the proteases of these retroviruses using the purified enzyme from BLV. We tested the ability of this protease to specifically cleave various short oligopeptide substrates containing cleavage sites of BLV and HTLV-I proteases, as well as a recombinant BLV Gag precursor. The best substrate, a synthetic decapeptide bearing the natural cleavage site between the matrix and the capsid proteins of BLV Gag precursor polyprotein, was used to develop an inhibition assay. We determined the relative inhibitory effect of synthetic Gag precursor-like peptides in which the cleavable site was replaced by a non-hydrolyzable moiety. The encouraging inhibitory effect of these compounds indicates that potent non-peptidic inhibitors for retroviral proteases are not unattainable.

Amino Acid Sequence↗
PubMed1994

Psychiatric morbidity in primary health care in Santiago, Chile. Preliminary findings.

BACKGROUND: The aims were to determine the prevalence of psychiatric morbidity among primary care attenders in a poor suburb of Santiago and to study the relationship with health service use. METHOD: A cross-sectional survey was made of 163 consecutive attenders to a primary care clinic. RESULTS: Eleven per cent of the sample gave a psychological reason for consultation and the prevalence of psychiatric morbidity was 53%, defined using the revised Clinical Interview Schedule. Women and those of lower socio-economic status were at higher risk. Physicians recognised 14% of the psychiatric morbidity. Attenders with psychiatric morbidity consulted more frequently. CONCLUSIONS: There is a need to improve the recognition and management of psychiatric morbidity in primary care in Chile and other less developed countries. This could lead to the more efficient use of scarce health care resources in primary care.

Adult↗
PubMed1992

CASSPERT--an expert system to guide choice and strategy in coronary angioplasty.

Coronary angioplasty is a technique widely used in the treatment of coronary artery disease. The success of coronary angioplasty depends on patient selection, the use of an appropriate technique, and to a large extent a carefully considered choice of angioplasty equipment. The authors have developed an expert system which can assist in this decision making process. CASSPERT was developed using the expert system shell 'Leonardo' running on a standard Personal Computer. The user interacts with CASSPERT to build up a detailed profile of clinical, investigational and angiographic features of the patient. This information, together with technical data stored within Leonardo's own object orientated database, is used to infer a suitable choice of equipment. To make the expert system useful in clinical practise, it was interfaced within a functional, readily accessible, data acquisition and storage environment which could be used within the day to day running of the department.

Angioplasty, Balloon, Coronary↗
PubMed1992

Early loss of heterozygosity on 17q in ovarian cancer. The Abe Ovarian Cancer Genetics Group.

We have studied 146 ovarian tumours (94 carcinomas, 22 tumours of low malignant potential and 30 benign tumours) for evidence of allele loss on chromosome 17p and 17q sufficient to imply the proximity of a tumour-suppressor gene. We have examined two polymorphic loci (YNZ22.2 and BHP53) on 17p13 and one on chromosome 17q (17q23-qter). Loss of heterozygosity (LOH) was detected in 34/63 (54%) informative malignant tumours at YNZ22.2 and 22/47 (47%) at BHP53; on 17q, 45/64 (70%) had LOH. Allele loss was detected in a small number of benign and borderline tumours. There was a statistically significant difference between the patterns of allele loss in serous and endometrioid groups of tumours, and allele loss occurred with significantly greater frequency on 17q than on 17p. Comparison of all malignant tumours presenting with either localized (FIGO stage I/II) or widespread (FIGO stage III/IV) disease showed that, particularly on 17q, allele loss increases in the more advanced stages. The p53 tumour-suppressor gene is implicated in ovarian carcinogenesis, and our findings suggest that an important tumour-suppressor gene may be located in the region 17q23-qter. Loss of function in this gene may be responsible for the frequently observed rapid progression of serous-type adenocarcinomas to an advanced stage.

Alleles↗
PubMed1989

Herpes simplex virus, Candida albicans and mouth ulcers in neutropenic patients with non-haematological malignancy.

Mouth ulcers are a frequent cause of morbidity in patients rendered neutropenic as a result of chemotherapy. We report here a series of 28 such patients from whom swabs were taken for viral isolation and mycological culture. In 13 patients, herpes simplex virus (type I) was isolated and in 17 patients Candida albicans was cultured. Both organisms were isolated in 9 patients. Our results suggest that both a viral and fungal element may be important in the aetiology of oral ulceration and that antiviral and antifungal agents may each have a role in the prophylaxis and treatment of such patients.

Agranulocytosis↗
PubMed1989

SC-41930: an inhibitor of leukotriene B4-stimulated human neutrophil functions.

SC-41930 was evaluated for effects on human neutrophil chemotaxis and degranulation. At concentrations up to 100 microM, SC-41930 alone exhibited no effect on neutrophil migration, but dose-dependently inhibited neutrophil chemotaxis induced by leukotriene B4 (LTB4) in a modified Boyden chamber. Concentrations of SC-41930 from 0.3 microM to 3 microM competitively inhibited LTB4-induced chemotaxis with a pA2 value of 6.35. While inactive at 10 microM against C5a-induced chemotaxis, SC-41930 inhibited N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced chemotaxis, with 10 times less potency than against LTB4-induced chemotaxis. SC-41930 inhibited [3H]LTB4 and [3H]fMLP binding to their receptor sites on human neutrophils with KD values of 0.2 microM and 2 microM, respectively. SC-41930 also inhibited neutrophil chemotaxis induced by 20-OH LTB or 12(R)-HETE. At concentrations up to 10 microM, SC-41930 alone did not cause neutrophil degranulation, but inhibited LTB4-induced degranulation in a noncompetitive manner. SC-41930 also inhibited fMLP- or C5a-induced degranulation, but was about 8 and 10 times less effective for fMLP and C5a, respectively. The results indicate that SC-41930 is a human neutrophil LTB4 receptor antagonist with greater specificity for LTB4 than for fMLP or C5a receptors.

Benzopyrans↗
PubMed1989

Differential effects of 20-trifluoromethyl leukotriene B4 on human neutrophil functions.

A leukotriene B4 (LTB4) analog, 20-trifluoromethyl LTB4 (20CF3-LTB4), has been synthesized and evaluated with human neutrophils for effects on chemotaxis and degranulation. 20CF3-LTB4 was equipotent to LTB4 as a chemoattractant (EC50, 3 nM), produced 50% of maximal activity of LTB4, and competed with [H] LTB4 for binding to intact human neutrophil LTB4 receptors. In contrast to chemotactic activity, 20CF3-LTB4 in nanomolar concentrations exhibited antagonist activity without agonist activity up to 10 microM on LTB4-induced degranulation. The analog had no significant effect on degranulation induced by the chemoattractant peptide, N-formyl-methionyl-leucyl-phenylalanine (fMLP). Like LTB4, 20CF3-LTB4 induced neutrophil desensitization to degranulation by LTB4. The results indicate that hydrogen atoms at C-20 of LTB4 are critical for its intrinsic chemotactic and degranulation activities. The fact that 20CF3-LTB4 is a partial agonist for chemotaxis and an antagonist for degranulation suggests that different LTB4 receptor subtypes are coupled to these neutrophil functions. Desensitization of the neutrophil degranulation response to LTB4 can result from receptor occupancy by an antagonist, and therefore, the desensitization is not specific for an agonist.

Binding, Competitive↗
PubMed1988

A group specific anamnestic immune reaction against HIV-1 induced by a candidate vaccine against AIDS.

The first experimental immunization of humans against the AIDS retrovirus, HIV-1, was started in a series of HIV seronegative, healthy volunteers in November 1986. For the primary vaccination recombinant vaccinia virus (V25) expressing the complete gp160 env protein of the HTLV-IIIB strain of HIV-1 was introduced by scarification. This elicited a weak primary response which we subsequently attempted to enhance by additional immunizations (boosting), using four different immunization protocols. We report here that intravenous injection of paraformaldehyde-fixed autologous cells infected in vitro with V25 (individual D.Z.) gave the best results. This individual received second and third boosts of intramuscular gp160 derived from an HTLV-IIIB clone using the hybrid vaccinia virus/bacteriophage T7 expression system. An anamnestic humoral and cellular immune reaction was achieved for over one year after the original vaccination, with high levels of antibodies to the viral envelope, and neutralizing antibodies against divergent HIV-1 strains such as HTLV-IIIB and HTLV-IIIRF (also called HTLV-III HAT) after the first boost. In addition, group-specific cell-mediated immunity and cell-mediated cytotoxicity against infected T4 cells were obtained after the primary vaccine and enhanced by the boosts. Finally, skin tests showed both immediate and delayed hypersensitivity to gp160 in vivo. Although this protocol is not practical for a large scale vaccine trial, our results show for the first time that an immune state against HIV can be obtained in man.

Acquired Immunodeficiency Syndrome↗