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Biomedical subjects

B Norris

Publications and source records attributed to B Norris.

At least 19 recordsLinked to original sources
PubMed2000

Phase III comparative study of vinorelbine combined with doxorubicin versus doxorubicin alone in disseminated metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group Study MA8.

PURPOSE: This phase III study was performed to determine the superiority of doxorubicin (DOX) and vinorelbine (VNB) (arm 1) versus DOX alone (arm 2) in metastatic breast cancer (MBC) for overall survival (OS), time to treatment failure (TTF), toxicity, and quality of life (QOL). PATIENTS AND METHODS: Three hundred three patients were randomized to DOX 50 mg/m(2) intravenously (IV) on day 1 and VNB 25 mg/m(2) IV on days 1 and 8 (arm 1) or DOX 70 mg/m(2) IV on day 1 (arm 2). Both regimens were given every 3 weeks until a cumulative DOX dose of 450 mg/m(2). After 16 of the first 65 randomized patients experienced febrile neutropenia (FN), the doses were reduced to DOX 40 mg/m(2) on day 1 and VNB 20 mg/m(2) on days 1 and 8 versus DOX 60 mg/m(2) on day 1. Eligible patients were vinca alkaloid and anthracycline naive. Chemotherapy was first-line or second-line for MBC. RESULTS: Three patients were ineligible. Thus, 300 patients were assessable for toxicity and to determine time to disease progression (TTP), TTF, and OS. Two hundred eighty-nine patients were assessable for response, and 99 responders were assessable for response duration (RD). The response rates, QOL, and median RD, TTP, and TTF were not significantly different between the arms. Median OS was 13.8 months for arm 1 versus 14.4 months for arm 2 (P =.4). Grade 3 or 4 granulocytopenia was equivalent in both arms but more grade 3/4 neurotoxicity, mild venous toxicity, and FN were seen on arm 1. CONCLUSION: The survival with DOX and VNB is not superior to DOX alone in MBC.

Adult↗
PubMed1999

Interactions of Al(acac)3 with cell membranes and model phospholipid bilayers.

Aluminum is a neurotoxic agent; however, little information has been obtained regarding its molecular cytotoxicity and the effects on the stability of biological membranes. This is mainly due to the ill-defined chemical speciation of the metal compounds. For this reason, the present study used aluminum acetylacetonate, (Al(acac)3), a neutral, chemically well-defined, hydrolytically stable and lipophilic compound. To understand the molecular mechanism of its interaction with cell membranes, Al(acac)3 was incubated with human erythrocytes, isolated toad skin and molecular models of biomembranes. The latter consisted of multilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoyphosphatidylethanolamine (DMPE), representative of phospholipid classes located in the outer and inner monolayers of the human erythrocyte membrane, respectively. The results showed that Al(acac)3 interacted with the erythrocyte membrane modifying its normal discoid morphology to both echinocytic and stomatocytic shapes. This finding indicates that the Al complex was inserted in both the outer and inner layers of the red cell membrane, a conclusion supported by X-ray diffraction analyses of DMPC and DMPE bilayers. Electrophysiological measurements performed on toad skin revealed a significant decrease in the potential difference and short-circuit current responses after application of Al(acac)3, effects interpreted to reflect inhibition of the active transport of ions. Al(acac)3 was active on both surfaces of the skin suggesting that the membrane was permeated by the metal complex. It is concluded that Al(acac)3 both alters the molecular structure of the lipid bilayer, thereby modifying the biophysical properties of the cell membrane, and changes its physiological properties.

Animals↗
PubMed1999

Abdominal surgery in the older Crohn's population.

BACKGROUND: The surgical literature perceives that the elderly cohort of Crohn's patients may have increased risk with surgery. METHODS: A retrospective review and prospective database analysis of all patients with histologically proven Crohn' s disease who had a laparotomy at a single Sydney teaching hospital were performed. The last laparotomy of each patient was included in the analysis for morbidity and mortality to assess whether an older cohort was at an increased risk. RESULTS: A total of 156 patients had 298 laparotomies for histopathologically proven Crohn's disease. The frequency distribution of age at last laparotomy was bimodal, and the statistically determined cut-off age between younger and older cohorts was 55 years. Thirty-three patients were older than 55 years. There was no difference in duration of symptoms before first diagnosis (older, 17 months vs younger, 25 months), previous number of Crohn's operations (42.4 vs 39.8%), or duration of known Crohn's disease. Isolated large bowel disease was more common in the elderly cohort (42.4 vs 18.7%, chi2 = 8.09, P < 0.01). Small bowel and ileocaecal resections were more common in the younger cohort (72.4 vs 51.6%, chi2 = 5.19, P < 0.025). There was one death in each cohort (overall mortality 1.3%) and anastomotic leak rates (defined as the number of leaks per number of patients with anastomoses), were 4.3% (older) vs 5.3% (younger) despite frank sepsis present in 21.2% of all subjects at the time of surgery. The older group had more cardiac (18.2 vs 0.8%, P < 0.001) and respiratory complications (18.2 vs 2.4%; P = 0.0003) and a longer mean but not median postoperative hospital admission. CONCLUSIONS: In conclusion, clinical features and presentation are similar in the older and younger Crohn's patients having a laparotomy. However, in the older patient there is a greater likelihood of large bowel disease, ileocaecal resection is done less commonly, there is a higher risk of minor cardiopulmonary postoperative complications, but with similar mortality and anastomotic leak rates to the younger patient.

Abdomen↗
PubMed1998

Safety pictograms: are they getting the message across?

This study set out to investigate the role of pictograms in conveying consumer safety information. The experimental work was carried out in two parts. The first part investigated UK comprehension levels of 13 product related pictograms. A new method of judging levels of comprehension of the pictograms was developed. In general the pictograms surveyed were found to be poorly understood, particularly those which were abstract in nature. The second part of the research investigated the effect of different warning styles on noticeability and intended compliance. This was tested using the new European Standard pictogram developed to convey the small parts warning on toys. The effect on parents' intended purchase decisions of different pictograms and or text messages was investigated. Results indicated that parents' decisions on toy suitability were influenced by the perceived hazardousness of the product rather than warnings, regardless of their design. The paper discusses the advantages and limitations of pictograms as a method for conveying consumer information and makes recommendations for their effective use.

Consumer Product Safety↗
PubMed1998

The organochlorine herbicide chloridazon interacts with cell membranes.

Chloridazon is a widely used organochlorine herbicide. In order to evaluate its perturbing effect on cell membranes it was made to interact with human erythrocytes, frog adrenergic neuroepithelial synapse and molecular models. These consisted in multilayers of dimyristoylphosphatidylethanolamine (DMPE) and of dimyristoylphosphatidyltidylcholine (DMPC), representative of phospholipid classes located in the inner and outer monolayers of the erythrocyte membrane, respectively. X-ray diffraction showed that chloridazon interacted preferentially with DMPC multilayers. Scanning electron microscopy revealed that 0.1 mM chloridazon induced erythrocyte crenation. According to the bilayer couple hypothesis, this is due to the preferential insertion of chloridazon in the phosphatidylcholine-rich external moiety of the red cell membrane. Electrophysiological measurements showed that nerve stimulation was followed immediately by a transient increase in short-circuit current (SCC) and in the potential difference (PD) of the neuroepithelial synapse. Increasing concentrations of chloridazon caused a dose-dependent and reversible decrease of the responses of both parameters to 76% of their control values. The pesticide induced a similar (28%) significant time-dependent decrease in the basal values of the SCC and of PD. These results are in accordance with a perturbing effect of chloridazon on the phospholipid moiety of the nerve fibre membrane leading to interference with total ion transport across the nerve skin junction.

Animals↗
PubMed1997

Decrease of tolerance to, and physical dependence on morphine by, glutamate receptor antagonists.

The effects of the non-competitive antagonists of the glutamate complex receptor, dizocilpine (MK 801) and ketamine and of the competitive antagonist CGP 39551 were examined on the induction of tolerance to morphine, the development of physical dependence and the expression of the abstinence syndrome to the opiate in mice. Morphine was administered in a single dose (300 mg/kg) of a slow release preparation. Dizocilpine (0.005 or 0.01 mg/kg given at 3, 12 and 24 h after the priming dose of morphine), ketamine (2, 4 or 8 mg/kg, 30 min before and 3, 6, 9 and 24 h after the priming dose) and DL-(E)-2-amino-4-methyl-5-phosphonopentanoate carboxy-ethylester (CGP 39551) (1.5 or 3 mg/kg, but not 6 or 12 mg/kg 30 min before and 12 and 24 h after the priming dose) reduced the intensity of tolerance to, and physical dependence on morphine. The drugs also reduced the intensity of the abstinence behaviour when given in a single dose, 30 min before (s.c.) naloxone (4 mg/kg)-precipitated withdrawal syndrome in mice chronically treated with morphine. Thus, the results of this study indicate that competitive and non-competitive NMDA receptor antagonists prevent morphine tolerance and decrease the development of physical dependence on the opiate in mice.

2-Amino-5-phosphonovalerate↗
PubMed1997

Influence of opiate tolerance and calcium channel antagonists on the antinociceptive effects of L-arginine and NG-nitro L-arginine.

1. The antinociceptive effects induced by L-arginine (L-Arg 300-600 mg sc) or NG-nitro-L-arginine (NOArg 20-70 mg sc) in mice were assessed by the hot-plate test. 2. The antinociception induced by both agents was antagonized by naloxone. L-Arg significantly reduced the effects of the largest doses of morphine (3, 5, and 10 mg/kg) or pentazocine (7.5, 15, and 30 mg/kg). 3. Morphine antagonized L-Arg-induced antinociception but did not change the responses to NOArg. 4. Diltiazem (10 mg/kg) or verapamil (10 mg/kg) decreased L-Arg antinociceptive responses, whereas the effects of NOArg were enhanced. 5. The antinociceptive effects of L-Arg and NOArg were also tested in mice rendered tolerant to morphine or pentazocine. Whereas the effect of L-Arg were lower in tolerant animals, the responses to NOArg were unchanged. 6. The results suggest the involvement of opiate mechanisms and NO synthesis in L-ARG-induced antinociception and a lesser influence of opiate mechanisms in the antinociception induced by NOArg.

Analgesia↗
PubMed1997

Detection of a soluble form of the leukocyte surface antigen CD48 in plasma and its elevation in patients with lymphoid leukemias and arthritis.

Proteins with glycosylphosphatidylinositol (GPI) anchors exhibit a range of activities and some of these proteins exist in both a membrane-associated and a soluble form. CD48 is a 47-kd GPI-linked glycoprotein which is expressed on T and B lymphocytes, monocytes, and many lymphoid malignancies. The biological function of CD48 is unknown. We describe the detection of a soluble form of CD48 in plasma and serum. Its level was quantified by an immunoenzymometric assay (IEMA) specific for soluble CD48. While soluble CD48 was detected in the plasma of healthy individuals (median = 29 ng/ml; range, 15-48 ng/ml), elevated levels were detected in some patients with lymphoproliferative disease (median = 41 ng/ml; range, 9-213 ng/ml, arthritis (median = 42 ng/ml; range, 13-67 ng/ml), and acute EBV infection (174 ng/ml). Soluble CD48 was also detectable in tissue culture supernatants from the Raji lymphoid cell line. The mechanism of CD48 release from cells is unclear. The finding of significant levels of soluble CD48 in plasma and the development of a sensitive IEMA for its measurement will facilitate further studies on its normal function and its role in disease.

Adult↗
PubMed1996

Influence of nitric oxide on transepithelial transport in toad skin: effects of cholinergic agents and morphine.

The effects induced by L-arginine (L-Arg) on the short-circuit current and potential difference of Pleurodema thaul skin were investigated. L-Arg, but not D-Arg significantly increased the short-circuit current and potential difference when applied to the serosal surface. The effects of L-Arg were antagonized by amiloride, NG-nitro-methyl-L-arginine (L-NAME) and by methylene blue. Carbachol and acetylcholine induced significant increases of both electrical parameters of the toad skin. These effects of the muscarinic cholinergic drugs were potentiated by a low concentration of L-Arg and antagonized by L-NAME or methylene blue. Carbachol and acetylcholine induced significant increases of both electrical parameters of the toad skin. These effects of the muscarinic cholinergic drugs were potentiated by a low concentration of L-Arg and antagonized by L-NAME or methylene blue. Addition of dibutyryl cyclic guanosyl monophosphate (db cGMP) or dibutyryl cyclic adenosine monophosphate (db cAMP) increased short-circuit current and potential difference. The effects of db cGMP, but not those of db cAMP were antagonized by L-NAME. The consecutive application of db cGMP and db cAMP induced additive effects. These results suggest that L-Arg increases transport in toad skin presumably acting through the formation of nitric oxide, which then stimulates cytoplasmic guanylate cyclase and leads to increased Na+ and K+ transport. The effects of L-Arg and carbachol were antagonized by acute application of morphine; however, a rebound response was observed when carbachol or noradrenaline were given after prolonged exposure of the skin to morphine, which suggests an adaptive response of the skin involving both cGMP and cAMP. Responses to both nucleotides were unchanged by morphine.

Acetylcholine↗
PubMed1996

Phase II study of the progesterone antagonist mifepristone in patients with untreated metastatic breast carcinoma: a National Cancer Institute of Canada Clinical Trials Group study.

PURPOSE: Mifepristone (RU486) is a progesterone receptor (PgR) antagonist that has been shown to be active in some preclinical hormone-dependent breast cancer tumor models and to produce a few responses in patients with pretreated metastatic disease in two small trials. This trial was designed to assess the response rate and toxic effects of mifepristone in a favorable group of women with PgR-positive recurrent breast cancer who had received no prior therapy. METHODS: Postmenopausal patients with PgR-positive, bidimensionally measurable disease were eligible provided they had received no other therapy for recurrence. Prior adjuvant hormonal treatment was permitted if a disease-free interval of at least 24 months had been observed. Mifepristone 200 mg was given daily and disease was reassessed every 4 weeks. Standard criteria for tumor response and toxic effects were used. RESULTS: A total of 28 patients were registered in the trial: all were eligible and assessable. Three partial responses were noted for an overall response rate of 10.7% (95% confidence interval [CI], 2% to 28%). Toxic effects were generally mild to moderate and consisted primarily of nausea, lethargy, anorexia, and hot flashes. CONCLUSION: Mifepristone had minimal activity in this optimal group of patients. While there may be reason to conduct some clinical studies with it in combination with antiestrogens on the basis of some preclinical work, our data do not support its use as a single agent in the management of breast cancer.

Aged↗
PubMed1996

An amino-terminal truncated progesterone receptor isoform, PRc, enhances progestin-induced transcriptional activity.

Previously we reported the identification of two unique progesterone receptor (PR) messenger RNA transcripts that encode a smaller PR isoform, termed the C-receptor (PRc). These two PR transcripts encode a protein that is N-terminally truncated, so that it lacks the first zinc finger of the DNA binding domain, but still contains a complete hormone binding region with sequences for dimerization and nuclear localization. We also have demonstrated the existence of a 60-kDa progestin-specific binding protein in progestin target cells using a monoclonal antibody directed to the C-terminus of PRs, suggesting that these two novel transcripts generate a truncated form of PR. In this paper, we address the hypothesis that the C-receptor arises from the initiation of translation of a methionine C-terminal to the methionine start sites that generate the larger 94-kDa A and 116-kDa B human PR isoforms. The studies shown here support the postulate that another downstream in-frame methionine within the PR-coding region can serve as a translation initiation site for the generation of a third PR protein. A partial PR complementary DNA, lacking the translation start sites for B- and A-receptors was translated in vitro. The synthetic protein product bound [3H]progestins and unlabeled progestins. The antiprogestin RU486 also competed for this binding. Transfection of this partial PR complementary DNA into PR-negative HeLa cells resulted in progestin-specific binding activity. Because the third PR isoform lacks the first zinc finger of the DNA binding domain, but contains sequences for dimerization, we reasoned that the C-receptor isoform would be transcriptionally in-active and not bind DNA directly. Surprisingly, however, in the presence of A- and/or B-receptors, we found that C-receptors can modulate the transcriptional activity of A- and/or B-receptors using a reporter gene. These studies emphasize that multiple receptor isoforms may have distinct biological properties, and that the truncated C-receptor may play a role in explaining some of the pleiotropic effects of progestins.

Antineoplastic Agents↗
PubMed1995

Diazepam induces tolerance in the isolated skin of Pleurodema thaul.

The effects of the long-term administration of diazepam on the potential difference and short-circuit current of the isolated skin of the toad Pleurodema thaul (P. thaul) were investigated. Diazepam applied in a concentration range of 4.6 x 10(-6) to 5.2 x 10(-5) M decreased both electrical parameters. This response was unaffected by flumazenil indicating that the action of diazepam is not induced through benzodiazepine receptors. Induction of tolerance to diazepam on its observed effects on potential difference and short-circuit current was obtained by the administration of a single dose of the drug in a slow release preparation. Skins tolerant to diazepam were also tolerant to the acute effects of verapamil on both electric parameters. Tolerance to diazepam effects was partly reversed by increasing Ca2+ concentration in the inner bathing solution. The results are consistent with a Ca2+ channel blocking effect of diazepam in the P. thaul skin.

Animals↗
PubMed1995

Diazepam decreases the response to the electrical stimulation of the nerve-skin preparation of the toad Caudiverbera caudiverbera.

1. The effect of diazepam was examined in the nerve skin preparation of the toad Caudiverbera caudiverbera. 2. Nerve stimulation was followed immediately by a transient increase in short-circuit current (SCC) and in the potential difference (PD), which consisted of a rapid and then a slow component. 3. Diazepam concentrations from 5.0 x 10(-5)M to 5.1 x 10(-4)M caused a dose-dependent block of both components to a 30% of their control values and also reduced the stimulatory responses to noradrenaline in this preparation. 4. Diazepam antagonized the potassium blocking effect of barium. 5. These results, based on electrophysiological and pharmacological evidence, are consistent with a calcium and sodium blocking effect of diazepam on the nerve skin junction of C. caudiverbera.

Adrenergic alpha-Agonists↗
PubMed1993

Pentachlorophenol (PCP) inhibits ion transport in the isolated toad cornea.

1. Active chloride transport from the stroma to the epithelial surface (tear side) accounts for 80% of the amphibian cornea short-circuit current (SCC). 2. The effect of pentachlorophenol (PCP, a wood preservative) on the bioelectric parameters of the toad Caudiverbera caudiverbera isolated cornea was studied. 3. PCP applied to the epithelial surface in the concentration range 0.3-4.3 microM caused a dose-dependent inhibition of the PD and of the SCC in 7 corneas. This inhibition was irreversible at all concentrations after several washouts. The agent had no effect when applied to the endothelial surface. 4. In 4 experiments the inhibitory effect was partly reversed by the addition of 1 microM calcium ionophore A-23187 to the epithelial surface. 5. It is concluded that PCP is an inhibitor of corneal active chloride transport and that this structure shows greater sensitivity to this agent than other tissues.

Animals↗
PubMed1993

Calcium channel blockers apparently decrease noradrenaline release from nerve-skin terminals in Caudiverbera caudiverbera.

1. The effects of three calcium channel blockers, verapamil, diltiazem and nifedipine were examined on the response of the skin neuroepithelial synapse of the toad Caudiverbera caudiverbera to electrical stimulation. 2. The stimulus induced a significant rise in potential difference (PD) and short-circuit current (SCC). The three calcium antagonists reduced the responses in a dose-dependent manner. The greatest reduction was induced by verapamil followed by diltiazem and nifedipine. 3. Amiloride treatment did not affect the responses to electrical stimulation, indicating that the response to nerve stimulation is not due to current flowing through sodium channels. 4. When the preparation was blocked by either of the three antagonists, the skin response to noradrenaline was not affected. 5. It may be concluded that verapamil, diltiazem or nifedipine reduce the release of noradrenaline at the neuroepithelial synapse of C. caudiverbera.

Amiloride↗