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D Gordon

Publications and source records attributed to D Gordon.

At least 181 records · Page 10Linked to original sources
PubMed1997

Insect tolerance to a neurotoxic polypeptide: pharmacokinetic and pharmacodynamic aspects

Androctonus australis insect toxin (AaIT) is an insect-selective neurotoxic polypeptide from scorpion venom used to probe insect Na+ channels and to design insecticidal recombinant baculoviruses. When injected into susceptible insects (such as flies or cockroaches), nanogram doses of the toxin induce a rapid paralysis within seconds. More tolerant insects respond to microgram doses by developing either a slow progressive paralysis, as in lepidopterous larvae, or a rapid but reversible paralysis, as in Trachyderma philistina, a tenebrionid beetle. Using toxicity and binding assays, microscopy and chromatography, we show that the tolerance of insects to AaIT occurs at both the pharmacokinetic and pharmacodynamic levels. Pharmacokinetic effects occur in Trachyderma philistina in which the toxin undergoes a progressive process of degradation and elimination from the hemolymph, resulting in the loss of 95­97 % of toxin activity 6 h after injection. The pharmacodynamic aspect was demonstrated in studies of the kinetics of binding dissociation of [125I]AaIT from neuronal membranes of susceptible and tolerant insects. Stable binding is shown in susceptible insects such as cockroaches and locusts, which have a dissociation half-time of approximately 9 and 5 min, respectively. This contrasts strongly with the fast half-time of dissociation of 7 s for Spodoptera littoralis larvae and 9 s for Trachyderma philistina, which are both relatively tolerant to AaIT. These differences in binding kinetics may reflect a structural and functional diversity of Na+ channels in different insects that is responsible for their diverse susceptibility to neurotoxic polypeptides.

Journal Article↗
PubMed1997

Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population.

A population-based series of 54 male breast cancer cases from Southern California were analyzed for germ-line mutations in the inherited breast/ovarian cancer genes, BRCA1 and BRCA2. Nine (17%) of the patients had a family history of breast and/or ovarian cancer in at least one first-degree relative. A further seven (13%) of the patients reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. No germ-line BRCA1 mutations were found. Two male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene. Only one of the two male breast cancer patients carrying a BRCA2 mutation had a family history of cancer, with one case of ovarian cancer in a first-degree relative. The remaining eight cases (89%) of male breast cancer with a family history of breast/ovarian cancer in first-degree relatives remain unaccounted for by mutations in either the BRCA1 gene or the BRCA2 gene.

Aged↗
PubMed1997

Protective effects of L-2-oxothiazolidine-4-carboxylate treatment on cyclophosphamide-induced cystitis in rats.

PURPOSE: Hemorrhagic cystitis is a therapy-limiting side effect of cyclophosphamide (CP) treatment for cancer. The purpose of this study was to investigate the potential protective effect of L-2-oxothiazolidine-4-carboxylate (OTZ; Procysteine) on CP-induced cystitis in the rat. MATERIALS AND METHODS: Thirty-six rats were divided into 6 groups: Group 1--Untreated controls, Group 2--OTZ alone (100 mg./kg., p.o.), Group 3--CP alone (68 mg./kg., i.v.), Group 4--CP + OTZ (68 mg./kg., i.v. + 100 mg.,/kg., p.o.), Group 5--CP + OTZ (68 mg./kg., i.v. + 1.0 g./kg., i.v.), and Group 6--CP + OTZ (68 mg./kg.,i.v. + 1.0 gm./kg., i.p.). OTZ was given once a day to groups 2 and 4 on the day prior to and on the day of CP administration. OTZ was given twice a day to groups 5 and 6 on the day prior to, the day of, and the day after CP administration. On the day of CP administration, CP was given 30 minutes prior to OTZ. Blood and bladder samples were taken for evaluation two days after CP administration. RESULTS: Expected depression in blood cell parameters were identified in all groups receiving CP with no differences noted between the CP-treated groups. Histologic changes (cystitis) were identified in the bladders of all CP treated groups. The lesions in the CP + OTZ groups were found to be less severe than the groups that received CP alone, with higher dosages of OTZ resulting in a significant (p < 0.05) decrease in lesion incidence and severity. CONCLUSIONS: Under the conditions of this study, L-2-oxothiazolidine-4 carboxylate caused a reduction in the incidence and severity of cyclophosphamide-induced lesions in the urinary bladder of rats. Further studies are needed to investigate optimal dosage scheme, mechanism of action, and interference with anti-tumor activity and prevention of long-term side effects of cyclophosphamide.

Animals↗
PubMed1997

Case-control study of GP attendance rates by suicide cases with or without a psychiatric history.

BACKGROUND: Targets for reduction in suicide deaths have been set against a background of an increasing number of people committing suicide. It is often assumed that a reduction can be effected by increasing the detection in primary care of patients at risk. This presupposes that there are indicators that enable suicide risk to be detected reliably. AIM: To compare the characteristics of those who commit suicide with an age- and sex-matched control group in terms of level of general practitioner attendance, diagnosis and pharmacological treatment of mental illness, and to compare those suicides with and without a psychiatric history in terms of general practitioner attendance and history of pharmacological treatment. METHOD: From a total of 48 deaths attributed to suicide and undetermined causes in the Forth Valley in 1993, general practice case notes were located for 41. Live controls were matched to index cases by age, sex and practice. Information on consultations, referrals to secondary care, medication and diagnoses in the previous 10 years was extracted from general practice and, for suicides, psychiatric case notes. RESULTS: Over the 10-year period, suicide patients attended their general practitioner at a higher level than control subjects. However, the number of suicide patients who attended their general practitioner in the month before their death did not differ in comparison with control subjects over a similar period. Suicide cases, in comparison with control subjects, were more likely to have received a psychiatric diagnosis from their general practitioner, been prescribed psychotropic medication and received referral to specialist mental health services. Those suicide patients with a psychiatric history had a significantly higher number of general practitioner consultations than those without a psychiatric history in four out of the five years preceding death. Those suicide patients without a psychiatric history did not differ significantly from control subjects on any of the variables assessed. CONCLUSION: For those people committing suicide who do not have a psychiatric history and whose consultation patterns do not differ from the norm, it is difficult to suggest how general practitioners might improve their detection of relevant suicidal risk factors. For those patients with a psychiatric history who commit suicide, until we have more detailed information regarding the specific content of general practitioner's consultations before death and how these differed from other consultations of the deceased, then it is premature to assume that general practitioners are failing to identify indicators of impending suicide.

Adult↗
PubMed1997

Inhibition of vascular smooth muscle cell proliferation and intimal hyperplasia by gene transfer of beta-interferon.

BACKGROUND: Balloon injury of the arterial wall induces increased vascular smooth cell proliferation, enhanced elastic recoil, and abnormalities in thrombosis, each of which contribute to regrowth of intima and the lesion of restenosis. Several gene transfer approaches have been used to inhibit such intimal smooth muscle cell growth. In this report, adenoviral gene transfer of beta-interferon (beta-IFN) was analyzed in a porcine model of balloon injury to determine whether a secreted growth inhibitory protein might affect the regrowth of vascular smooth muscle cells in vitro and in arteries. MATERIALS AND METHODS: An adenoviral vector encoding beta-interferon (ADV-beta-IFN) was prepared and used to infect porcine vascular smooth muscle cells in a porcine balloon injury model. Its antiproliferative effect was analyzed in vitro and in vivo. RESULTS: Expression of recombinant porcine beta-IFN in vascular smooth muscle cells reduced cell proliferation significantly in vitro, and supernatants derived from the beta-IFN vector inhibited vascular smooth muscle cell proliferation relative to controls. When introduced into porcine arteries after balloon injury, a reduction in cell proliferation was observed 7 days after gene transfer measured by BrdC incorporation (ADV-delta E1 arteries 14.5 +/- 1.2%, ADV-beta IFN 6.8 +/- 0.8%, p < 0.05, unpaired, two-tailed t-test). The intima-to-media area ratio was also reduced (nontransfected arteries, 0.70 +/- 0.05; ADV-delta E1 infected arteries, 0.69 +/- 0.06; ADV-beta-IFN infected arteries, 0.53 +/- 0.03; p < 0.05, ANOVA with Dunnett t-test). No evidence of organ toxicity was observed, and regrowth of the endothelial cell surface was observed 3-6 weeks after balloon injury. CONCLUSIONS: Gene transfer of an adenoviral vector encoding beta-IFN into balloon-injured arteries reduced vascular smooth muscle proliferation and intimal formation. Expression of this gene product may have potential application for the treatment of vascular proliferative diseases.

Adenoviridae↗
PubMed1997

[Gene transfer of interferon beta inhibits vascular smooth muscle cell proliferation in vitro and in animal model of arterial injury].

Vascular hypertrophy may increase the blood pressure by its effect on vascular resistance. In this study, adenoviral gene transfer of IFN-beta was analysed in a porcine model of balloon injury to determine whether a secreted growth inhibitory protein might affect the regrowth of vascular smooth muscle cells (VSMC) in vitro and in arteries. An adenoviral vector encoding IFN-beta (ADV-IFN-beta) was constructed by homologous recombination between sub360 genomic DNA, an ADV 5 derivative with a deletion in the E3 region and a porcine IFN-beta expression plasmid. Its antiproliferative effect was analysed using cell proliferation assays, and used in a porcine model of balloon injury. After injury, arteries were immediately transfected with 7 x 10(9) plaques forming units of either ADV-IFN-beta or a control E1A deficient adenovirus that does not encode a recombinant protein, ADV-delta E1. The intima/media (I/M) area ratio was determined by quantitative morphometry 21 days after artery injury and gene transfer. Expression of recombinant porcine IFN-beta in VSMC reduced cell proliferation significantly in vitro, and supernatants derived from IFN-beta vector infected cells inhibited VSMC proliferation relative to controls. When introduced into porcine arteries after balloon injury, a reduction in I/M ratio of 30% was found. I/M ratio in the IFN-beta transduced arteries was 0.54 +/- 0.03 vs 0.69 +/- 0.06 in ADV-delta E1 transfected arteries and 0.702 +/- 0.05 in the non-transfected arteries. Gene transfer of an adenoviral vector encoding IFN-beta to VSMC and injured arteries reduced cell proliferation and vascular thickening. This approach is potentially applicable to vascular proliferative diseases.

Animals↗
PubMed1996

Immune response in human melanoma after transfer of an allogeneic class I major histocompatibility complex gene with DNA-liposome complexes.

Analysis of the antitumor immune response after gene transfer of a foreign major histocompatibility complex class I protein, HLA-B7, was performed. Ten HLA-B7-negative patients with stage IV melanoma were treated in an effort to stimulate local tumor immunity. Plasmid DNA was detected within treated tumor nodules, and RNA encoding recombinant HLA-B7 or HLA-B7 protein was demonstrated in 9 of 10 patients. T cell migration into treated lesions was observed and tumor-infiltrating lymphocyte reactivity was enhanced in six of seven and two of two patients analyzed, respectively. In contrast, the frequency of cytotoxic T lymphocyte against autologous tumor in circulating peripheral blood lymphocytes was not altered significantly, suggesting that peripheral blood lymphocyte reactivity is not indicative of local tumor responsiveness. Local inhibition of tumor growth was detected after gene transfer in two patients, one of whom showed a partial remission. This patient subsequently received treatment with tumor-infiltrating lymphocytes derived from gene-modified tumor, with a complete regression of residual disease. Thus, gene transfer with DNA-liposome complexes encoding an allogeneic major histocompatibility complex protein stimulated local antitumor immune responses that facilitated the generation of effector cells for immunotherapy of cancer.

Adult↗
PubMed1996

The Delta trial.

Explore the source record for details and available documents.

Antiviral Agents↗
PubMed1996

MDs' failure to use plain language can lead to the courtroom.

Two recent court cases in British Columbia reveal the importance of using plain, simple language to communicate with patients. This is particularly important because almost half of Canadians have low literacy levels. The CMA, which promotes the use of plain language in professional practice, is participating in the Canadian Public Health Association's National Literacy and Health Program. Resources are available to help physicians better serve patients.

British Columbia↗
PubMed1996

Systemic delivery of the interleukin-1 receptor antagonist protein using a new strategy of direct adenoviral-mediated gene transfer to skeletal muscle capillary endothelium in the isolated rat hindlimb.

Current gene therapy strategies using adenoviral vectors to target the lung or liver have been complicated by an acute inflammatory response that can result in loss of transgene expression as well as tissue injury and necrosis. Skeletal muscle comprises 40% of total body weight; it possesses a high density, accessible capillary network that is resistant to injury and thus may be a logical target for adenoviral vectors. We hypothesized that adenoviral transduction of the rat skeletal muscle capillary bed during vascular isolation would achieve efficient gene transfer sufficient to achieve systemic serum levels of a recombinant protein without significant tissue injury. During vascular isolation of the hindleg, a replication-incompetent adenovirus (Ad) encoding for either the marker gene, human placental alkaline phosphatase (hpAP), or interleukin-1 receptor antagonist (IL-1ra) was infused and subsequently flushed from the circulation after a 30-min dwell period. Gene transfer over a 10(9)-10(12) particle/ml range to the gastrocnemius capillary endothelium and muscle fibers was highly efficient and titer-dependent, reaching maximum transduction rates of 71 +/- 7% and 25 +/- 5%, respectively, 5 days after gene transfer (n = 3-8 rats/group, p < 0.05). hpAP transgene expression was barely detectable at 14 days. No significant tissue injury or necrosis of the skeletal muscle was observed at 5 and 14 days, and distant organ gene transfer was minimal or absent. Gastrocnemius muscle from rats (n = 4) given Ad-IL-1ra had 241 +/- 66 pg IL-1ra/mg protein at 5 days, while those given Ad-hpAP, negative control (n = 3) had 35 +/- 14 pg IL-1ra/mg protein (p < 0.05). Ad-IL-1ra rats (n = 4) had serum levels of 185 +/- 20 pg/ml IL-1ra at 5 days whereas Ad-hpAP control rats (n = 5) had no IL-1ra detectable (p < 0.0001). Athymic rats given Ad-IL-1ra (n = 6) had serum levels of 493 +/- 62 pg/ml IL-1ra 14 days after transduction, and IL-1ra was detected for up to 98 days. Sera from Ad-IL-1ra athymic rats significantly inhibited IL-1 beta-induced (1 ng/ml) prostaglandin E2 (PGE2) production from cultured endothelial cells by 82 +/- 2% (p < 0.001). Thus, this gene transfer strategy is the first to result in substantial transduction of both skeletal muscle capillary endothelium and fibers, sufficient to achieve pharmacologic levels of IL-1ra. Although no acute tissue injury or necrosis was observed, persistence of transgene expression in athymic rats suggests that loss of expression in normal rats was by an immune-mediated mechanism.

Adenoviridae↗
PubMed1996

A new cationic liposome DNA complex enhances the efficiency of arterial gene transfer in vivo.

An important goal of gene therapy for cardiovascular diseases and cancer is the development of effective vectors for catheter-based gene delivery. Although adenoviral vectors have proven effective for this purpose in animal models, the ability to achieve comparable gene transfer with nonviral vectors would provide potentially desirable safety and toxicity features for clinical studies. In this report, we describe the use of a new cationic DNA-liposome complex using an improved expression vector and lipid, N-(3-aminopropyl)-N, N-dimethyl-2,3-bis(dodecyloxy)-1-propaniminium bromide/dioleyl phosphatidylethanolamine (GAP-DL-RIE/DOPE) to optimize catheter-mediated gene transfer in porcine arteries. The efficiency of this vector was compared to DNA alone, DNA with a previously described cationic liposome complex, (+/-)-N-(2-hydroxyethyl)-N, N-dimethyl-2,3-bis(tetradecyloxy)-1-propanaminium bromide (DMRIE/DOPE), and a replication-defective adenoviral vector in a porcine artery gene transfer model. When used in optimal ratios, GAP-DL-RIE/DOPE liposomes provided a 15-fold higher level of gene expression in arteries compared to DNA alone or DMRIE/DOPE. Gene expression was observed in intimal and medial cells. However, when compared to adenoviral vectors (10(10) pfu/ml), gene expression following GAP-DLRIE/DOPE transfection was approximately 20-fold lower. Following intravenous injection of GAP-DLRIE/DOPE in mice, biochemical, hematological, and histopathological abnormalities were not observed. Significant improvements in the efficacy of arterial gene expression can be achieved by optimization of transfection condition with DNA-liposome complexes in vivo that may prove useful for arterial gene delivery in cardiovascular diseases and cancer.

Animals↗
PubMed1996

Functional expression and genetic alteration of an alpha scorpion neurotoxin.

The alpha neurotoxin Lqh alpha IT is toxic to both insects and mammals but exhibits a bioactivity ratio favoring insects (insect/mammal approximately 2). With the objective of increasing this ratio by genetic manipulation of the amino acid sequence, a cDNA clone encoding Lqh alpha IT was used to produce recombinant variants of the toxin in a high efficiency bacterial expression system. The unmodified recombinant toxin, isolated from inclusion bodies and renatured in vitro, exhibited chemical and biological properties indistinguishable from those of the authentic native toxin. Alteration of the toxin by site-directed mutagenesis led to a substantial reduction in anti-mammalian toxicity (mouse LD50 reduced 6.4-fold) but only a slight reduction (x 1.5) in the insect ED50 value for paralysis. The reduction in anti-mammalian toxicity was correlated with a approximately 2-fold reduction of its potency for slowing of sodium channel inactivation in mammalian neurons, while no change in mutant toxin binding affinity to insect neuronal receptors was registered. These results demonstrate for the first time expression of a recombinant sodium channel neurotoxin in Escherichia coli and the use of site-directed mutagenesis to improve phylogenetic selectivity. This recombinant approach provides a promising strategy for optimizing the selective toxicity of peptide neurotoxins.

Amino Acid Sequence↗
PubMed1996

Tetrodotoxin reverses brevetoxin allosteric inhibition of scorpion alpha-toxin binding on rat brain sodium channels.

Voltage-sensitive sodium channels are responsible for the initiation of action potentials in many excitable cells. Several neurotoxins bind to distinct receptor sites on sodium channels and reveal strong allosteric interactions among them. Scorpion alpha toxins, which inhibit sodium channel inactivation by binding to receptor site 3, have been very important tools to study sodium channel structure and function. Recently, we have shown that brevetoxin induce a strong negative allosteric modulation on scorpion alpha-toxin binding on rat brain sodium channels, in contrast to previously published studies. In this report we have examined the reasons for this discrepancy and found new, unexpected allosteric interactions between the tetrodotoxin and brevetoxin receptor sites, using scorpion alpha-toxin as sensitive probe for subtle conformational changes on sodium channels. Tetrodotoxin reverses the negative modulation induced by brevetoxin on scorpion alpha-toxin binding, revealing new dynamic interactions in sodium channel structure.

Allosteric Site↗