Actinomycin D, hepatic toxicity and Wilms' tumour--a mystery explained?
Explore the source record for details and available documents.
Antibiotics, Antineoplastic↗
Biomedical subjects
A Davidson
Publications and source records attributed to A Davidson.
Protection against developmental deficiencies by a lipophilic VIP analogue.
Stearyl-Nle-VIP (SNV) is a novel agonist of vasoactive intestinal peptide (VIP) exhibiting a 100-fold greater potency than the parent molecule and specificity for a receptor associated with neuronal survival. Here, the developmental and protective effects of SNV were investigated in vivo using two models of developmental retardation, hypoxia and cholinergic blockade. In both cases chronic administration of SNV during development provided protective effects. Water maze experiments on the weaned animals have demonstrated a prophylactic action for SNV and enhancement of spatial memory in animals exposed to a cholinotoxin. SNV may act by providing neuroprotection, thereby improving cognitive functions. This work is dedicated to Prof. R.J. Wurtman whose inspiration and leadership in the field of neuroscience and cognition is beyond comparison.
Aging↗
Assessment of intubating conditions in adults after induction with propofol and varying doses of remifentanil.
We have assessed intubating conditions in three groups of 60 ASA I or II patients after induction of anaesthesia with propofol 2 mg kg-1 and remifentanil 0.5, 1.0 or 2.0 micrograms kg-1. Tracheal intubation was graded according to ease of laryn-goscopy, position of the vocal cords, coughing, jaw relaxation and movement of the limbs. Intubation was successful in 80%, 90% and 100% of patients after remifentanil 0.5, 1.0 or 2.0 micrograms kg-1, respectively. Overall intubating conditions were regarded as acceptable in 20%, 50% and 80% of patients, respectively. All three groups had a decrease in arterial pressure after induction but there was no difference between groups. The decrease in arterial pressure was not regarded as clinically significant. Intubating conditions were best after induction with remifentanil 2 micrograms kg and propofol 2 mg kg-1.
Adult↗
Cytokine gene therapy or infusion as treatment for solid human cancer.
In the induction of tissue-directed immune responses, cytokines tend to be released within the affected tissues. We used two strategies to expose tumor tissues to continuous high levels of cytokines: First, a vaccinia interleukin (IL)2 recombinant was injected directly intratumorally 3-weekly at 10(7) pfus/dose in six patients with the solid tumor malignant mesothelioma (MM). No virus excretion was detectable. At each cycle vaccinia-IL-2 mRNA (SQ [semi-quantitative] reverse transcription polymerase chain reaction) was maximal 24-72 h following injection reduced at 8 days and faded by 21 days. No tumor regression occurred. Second, based on the success of granulocyte macrophage colony-stimulating factor (GM-CSF) in gene transfer experiments, we conducted a study using continuous intratumoral GM-CSF infusion in eight patients with MM using a portable pump at doses of 10 micro/cg/24 h over 8 weeks. Systemic neutrophil agglutination and local catheter-related difficulties occurred. Two patients demonstrated tumor necrosis, one of whom had a marked progressive mononuclear cell infiltration of the tumor associated with a partial response (>50% reduction in tumor area). Murine studies using our MM model in CBA and BALB/C mice have demonstrated that B7-1 and allo-class I transfections induce strong tumor-specific cytotoxic T lymphocyte responses: GM-CSF, IL-12, and IL-2 induced mixed nonspecific plus specific responses, whereas B7-2 and class II transfections were not effective. We conclude that increased intratumoral cytokine concentrations can be generated using both gene transfer and cytokine infusion approaches; however, both have their limitations and, at this stage, have not produced dramatic antitumor effects in humans.
Cytokines↗
Potential barriers to the removal of Norplant among family planning clinic patients.
OBJECTIVES: This study examined the prevalence and effects of potential barriers to removal of levonorgestrel implants (Norplant) among low-income women. METHODS: A sample of 687 women who received Norplant at hospital-based family planning clinics were interviewed before Norplant insertion and 6 months after Norplant insertion (or at Norplant removal if removal occurred earlier). Those who continued to use Norplant were reinterviewed at 2 years or at removal. RESULTS: In a multivariate analysis, only 1 of the 4 potential barriers--cost--significantly impeded Norplant discontinuation. CONCLUSIONS: Family planning clinics need to make clear that they follow a policy of Norplant removal on demand, regardless of the patient's ability to pay.
Adolescent↗
Activity-dependent neurotrophic factor: structure-activity relationships of femtomolar-acting peptides.
Activity-dependent neurotrophic factor (ADNF) is a glia-derived protein that is neuroprotective at femtomolar concentrations. A 14-amino acid peptide of ADNF (ADNF-14) has been reported that protects cultured neurons from multiple neurotoxins. Structure-activity relationships of peptides related to ADNF-14 now have been determined. A 9-amino acid core peptide (ADNF-9) has been identified that has greater potency and a broader effective concentration range (10(-16) to 10(-13) M) than ADNF or ADNF-14 in preventing cell death associated with tetrodotoxin treatment of cerebral cortical cultures. Deletions or conservative amino acid substitutions to ADNF-9 resulted in reduced potency, narrower effective concentration range and/or decreased efficacy. Removal of the N-terminal serine or the COOH-terminal isoleucine-proline-alanine from ADNF-9 produced a significant reduction in survival-promoting activity. Comparative studies of ADNF-9 action in mixed (glia plus neurons) vs. glia-depleted neuronal cultures indicated that ADNF-9 can act directly on neurons, although the potency of the peptide was 10,000-fold greater in mixed cultures. Kinetic studies showed that exposure to ADNF-9 for only 2 hr was sufficient to produce a 4-day protection against the cell-killing action of tetrodotoxin. Treatment with bafilomycin A1 (an inhibitor of receptor-mediated endocytosis) for 2 hr prevented the ADNF- and ADNF-9-mediated neuroprotection. ADNF-9, like ADNF-14, was neuroprotective against N-methyl-D-aspartate and the beta-amyloid peptide (amino acids 25-35), and had a much broader range of effective concentrations than ADNF-14. These studies identify ADNF-9 as an attractive lead compound for the development of therapeutic agents against neurodegenerative diseases.
Animals↗
Lupus-specific antibodies reveal an altered pattern of somatic mutation.
The F4 idiotype is a heavy chain determinant expressed almost exclusively on IgG immunoglobulins and is highly associated with specificity for double-stranded DNA. Since high-titered F4 expression is present predominantly in sera of patients with systemic lupus erythematosus (SLE), we thought F4+ IgG antibodies might constitute a useful subset of immunoglobulins in which to investigate lupus-specific alterations in variable (V) region gene expression or in the process of somatic mutation. This molecular analysis of F4+ B cell lines generated from lupus patients demonstrates that despite the strong association of F4 reactivity with specificity for native DNA, there is no apparent VH gene restriction. Furthermore, VH gene segments encoding these antibodies are also used in protective immune responses. An examination of the process of somatic mutation in F4+ antibodies showed no abnormality in frequency of somatic mutation nor in the distribution of mutations in complementarity-determining regions or framework regions. However, there was a decrease in targeting of mutations to putative mutational hot spots. This subtle difference in mutations present in these antibodies may reflect an intrinsic defect in mutational machinery or, more likely, altered state of B cell activation that affects the mutational process and perhaps also negative selection.
Amino Acid Sequence↗
S-nitrosohemoglobin in the fetal circulation may represent a cycle for blood pressure regulation.
It has recently been demonstrated, in rats, that hemoglobin transports nitric oxide (NO), as S-nitrosocysteine, from the lungs to the peripheral tissues. This cycle may be involved in the regulation of blood pressure and efficient delivery of oxygen in adult animals. We sought to determine whether this model was applicable to the human fetus. Umbilical cord blood was obtained from deliveries between 37 and 42 weeks of gestation (n = 19). NO, released from erythrocyte s-nitrosohemoglobin (SNO-Hb), was determined by the Saville reaction and total plasma NO was determined by the Greiss reaction. SNO-Hb levels were found to be higher in the umbilical vein, [SNO]/[Hb] = 2.19 +/- 1.22 (X10(-3)), than in the artery, [SNO]/[Hb] = 1.45 +/- 0.66 (X10(-3)) (P < 0.001, Wilcoxon Signed Rank test). This supports the hypothesis that fetal blood pressure may be regulated by erythrocytes acting via a hemoglobin-based mechanism.
Adult↗
Neuropeptides and neuronal survival: neuroprotective strategy for Alzheimer's disease.
Explore the source record for details and available documents.
Administration, Intranasal↗
Antiserum to activity-dependent neurotrophic factor produces neuronal cell death in CNS cultures: immunological and biological specificity.
Activity-dependent neurotrophic factor (ADNF) is a glia-derived protein that is neuroprotective at femtomolar concentrations. ADNF is released from astroglia after treatment with 0.1 nM vasoactive intestinal peptide (VIP). To further assess the biological role of ADNF, antiserum was produced following sequential injections of purified ADNF into mice. Anti-ADNF ascites fluid (1:10,000) decreased neuronal survival by 45-55% in comparison to untreated cultures or those treated with control ascites. The neuronal death after anti-ADNF treatment was observed in cultures derived from the spinal cord, hippocampus or cerebral cortex at similar IC50's. Using a terminal deoxynucleotidyl transferase in situ assay to estimate apoptosis in cerebral cortical cultures, anti-ADNF was shown to produce a 70% increase in the number of labeled cells in comparison to controls. In spinal cord cultures, anti-ADNF treatment produced a 20% decrease in choline acetyltransferase activity in comparison to controls. Neuronal cell death produced by the antiserum to ADNF was prevented in cultures co-treated with purified ADNF or ADNF-15, an active peptide derived from the parent ADNF. In vitro binding between the anti-ADNF and ADNF-15 was demonstrated with size exclusion chromatography. Comparative studies with other growth factors (insulin-like growth factor-1, platelet-derived growth factor, nerve growth factor, epidermal growth factor, ciliary neurotrophic growth factor, and neurotrophin-3) demonstrated that only ADNF prevented neuronal cell death associated with electrical blockade. These investigations indicated that an ADNF-like substance was present in cultures derived from multiple locations in the central nervous system and that ADNF-15 exhibited both neuroprotection and immunogenicity. ADNF appears to be both a regulator of activity-dependent neuronal survival and a neuroprotectant.
Amino Acid Sequence↗
Insertion of the adenoviral E3 region into a recombinant viral vector prevents antiviral humoral and cellular immune responses and permits long-term gene expression.
Recombinant adenoviruses (Ads) are highly efficient at transferring foreign genes to the liver in vivo; however, the duration of gene expression is limited by the host antiviral immune response, which prevents expression upon readministration of the virus. To test whether overexpression of the immunomodulatory products of the early Ad genome region 3 (E3) could prevent the antiviral immune response and prolong expression of foreign genes delivered by Ad vectors, we injected a recombinant Ad (Ad-E3-hBUGT), containing both E3 and the human bilirubin-uridine-diphosphoglucuronate-glucuronosyltransferase (BUGT) genes, into BUGT-deficient hyperbilirubinemic Gunn rats. Control Gunn rats received Ad-hBUGT, which expresses human BUGT alone. An initial injection of either virus resulted in hepatic expression of human BUGT as evidenced by excretion of bilirubin glucuronides in bile and a reduction of mean serum bilirubin levels from 7.0 mg/dl to 1.9-2.7 mg/dl within 7 days. In Ad-E3-hBUGT-injected rats, serum bilirubin levels increased to 4.5 mg/dl by 84 days after infection, but a second administration of the virus on that day resulted in a hypobilirubinemic response similar to that seen with the first injection. In contrast, rats receiving Ad-hBUGT had serum bilirubin levels of 7 mg/dl on day 84 after infection, but showed no reduction of serum bilirubin by reinjection of the virus on that day. In the rats injected with Ad-E3-hBUGT, but not in the ones injected with Ad-hBUGT, there was a marked inhibition of the antiviral antibody and Ad-specific cytotoxic T lymphocyte responses. This is the first demonstration that insertion of E3 genes in recombinant Ads facilitates readministration of a functional vector for long-term correction of an inherited metabolic disorder.
Adenoviridae↗
Oral tolerization to adenoviral antigens permits long-term gene expression using recombinant adenoviral vectors.
Recombinant adenoviruses (Ads) efficiently transfer foreign genes into hepatocytes in vivo, but the duration of transgene expression is limited by the host immune response which precludes gene expression upon readministration of the virus. To test if this immune response can be abrogated by oral tolerization, we instilled protein extracts of a recombinant adenovirus type-5 via gastroduodenostomy tubes into bilirubin-UDP-glucuronosyltransferase-1 (BUGT1)-deficient jaundiced Gunn rats. Control rats received BSA. Subsequent intravenous injection 5 x 10(9) pfu of a recombinant adenovirus-expressing human BUGT1 (Ad-hBUGT1) resulted in hepatic expression of human BUGT1 (hBUGT1) with reduction of serum bilirubin levels by 70%. After 2 mo serum bilirubin increased gradually. In orally tolerized rats, but not in controls, a second dose of the virus on day 98 markedly reduced serum bilirubin again. In the tolerized rats, the development of antiadenoviral neutralizing antibodies and cytotoxic lymphocytes were markedly inhibited, and transplantation of their splenocytes into naive Gunn rats adoptively transferred the tolerance, indicating a role for regulatory cells. Lymphocytes from the tolerized rats hyperexpressed TGFbeta1, IL2, and IL4 upon exposure to viral antigens, whereas IFNgamma expression became undetectable. Thus, oral tolerization with adenoviral antigens permits long-term gene expression by repeated injections of recombinant adenoviruses.
Adenoviridae↗
Protection against developmental retardation in apolipoprotein E-deficient mice by a fatty neuropeptide: implications for early treatment of Alzheimer's disease.
Stearyl-Nle17-VIP (SNV) is a novel agonist of vasoactive intestinal peptide (VIP) exhibiting a 100-fold greater potency than the parent molecule and specificity for a receptor associated with neuronal survival. Here, mice deficient in apolipoprotein E (ApoE), a molecule associated with the etiology of Alzheimer's disease, served as a model to investigate the developmental and protective effects of SNV. In comparison to control animals, the deficient mice exhibited (a) reduced amounts of VIP messenger RNA; (b) decreased cholinergic activity (c) significant retardation in the acquisition of developmental milestones: forelimb placing behavior and cliff avoidance behavior; and (d) learning and memory impairments. Daily injections of SNV to ApoE-deficient newborn pups resulted in increased cholinergic activity and marked improvements in the time of acquisition of behavioral milestones, with peptide-treated animals developing as fast as control animals and exhibiting improved cognitive functions after cessation of peptide treatment. Specificity was demonstrated in that treatment with a related peptide (PACAP), pituitary adenylate cyclase-activating peptide, produced only limited amelioration. As certain genotypes of ApoE increase the probability of Alzheimer's disease, early counseling and preventive treatments may now offer an important route for therapeutics design.
Alzheimer Disease↗
Transient immunosuppression with FK506 permits long-term expression of therapeutic genes introduced into the liver using recombinant adenoviruses in the rat.
The host immune response limits the duration of expression of adenovirally transduced genes and precludes long-term gene expression upon re-administration of the virus. In this study we wished to evaluate whether short-term immunosuppression of the host, at the time of recombinant virus administration, would allow expression of the therapeutic gene product upon virus reinjection. Gunn rats were used as recipients of recombinant adenoviruses expressing human BUGT (Ad-hBUGT) or E. coli beta-galactosidase (Ad-LacZ). Rats were treated with FK506 (1-1.5 mg/kg, per OS daily) for three days beginning 24 hours before each virus injection. Control groups did not receive any immunosuppressant. The serum bilirubin level was reduced from 7.1 +/- 0.75 mg/dL to 2.0 +/- 0.7 mg/dL within two days of viral injection in both FK506 treated and control groups, and then gradually increased in 6 weeks. FK506-treated rats had low or undetectable antibody titers against the recombinant adenovirus and minimal or no cytotoxic T lymphocyte (CTL) response against adenovirus-infected cells. The tolerized rats received two subsequent injections 42 and 98 days after the first injection, which reduced the bilirubin levels again to 2.0 +/- 0.56 and 2.2 +/- 0.61 mg/dL, respectively. In contrast, control rats developed high titer neutralizing antibodies and a CTL response, and their serum bilirubin levels were not reduced following subsequent injections. We conclude that short-term FK506 treatment around the time of virus administration prevents the host immune response, permitting long-term gene therapy by repeated administration of the recombinant virus.
Adenoviridae↗
Mechanisms of intrathymic tolerance induction to isolated rat hepatocyte allografts.
Intrathymic injection of alloantigen in young adult rats is capable of mediating long-lived transplantation tolerance. In this study, we use a well-defined model of isolated hepatocyte transplantation to define the mechanisms of intrathymic induced tolerance. The recipient rats are Nagase analbuminemic rats (NAR) that are deficient in albumin, to allow for following transplant acceptance using metabolic and genetic markers. Tolerance to allogeneic hepatocyte transplants could be mediated by intrathymic injection of live allogeneic splenocytes, lethally irradiated splenocytes, or isolated hepatocytes. Intrathymic injection of live allogeneic splenocytes, but not of hepatocytes or irradiated splenocytes, resulted in donor microchimerism in peripheral lymphoid organs, with preferential expansion of CD4-positive T cells in the recipient spleens. Tolerance could be adoptively transferred from tolerant animals to naive recipients, but only from those animals that had been inoculated with intrathymic donor splenocytes. We conclude that donor microchimerism is found after intrathymic inoculation of live splenocytes, but is not required for tolerance induction and that microchimerism is not an absolute requirement for the generation of regulatory cells.
Animals↗
Phase II study of 21 day schedule oral etoposide in children. New Agents Group of the United Kingdom Children's Cancer Study Group (UKCCSG).
We report a multicentre phase II study of orally administered prolonged schedule etoposide in children with refractory or relapsed malignancy. 83 children were entered into the study. The largest diagnostic groups were neuroblastoma (n = 20), rhabdomyosarcoma/soft tissue sarcoma (n = 16) and brain tumours (n = 16). Etoposide was administered twice daily at a dose of 50 mg/m2/day for 21 days using the intravenous preparation given orally. Disease reassessment was performed after the second course. Etoposide plasma concentrations were measured by HPLC, 2 and 6 h after administration of therapy on days 7 and 14 in 15 patients. 61 patients completed two courses and were evaluable for response. There was 1 complete response (CR), 5 partial responses (PR) 22 stable disease (SD) and 33 progressive disease (PD). Of the 6 with responses, 3 had a diagnosis of medulloblastoma/cerebral primitive neuroectodermal tumour. 24 of 26 patients with SD/PR/CR received further courses with excellent palliative effect. The main toxicity observed was myelosuppression, with 8% and 7% of evaluable courses complicated by grade III-IV neutropenia and thrombocytopenia, respectively. Severe infection (grade III-IV) was rare, complicating only 2/94 evaluable courses. Plasma etoposide median concentrations at 2 h after administration on day 7 of course 1 were 1.5 (range 0.6-2.4) micrograms/ml. Total course 1 area under the etoposide plasma concentration versus time curve (AUC) values were estimated using a limited sampling model. Grade > or = 2 leucopenia was only observed in patients with a day 72 h etoposide concentration of > 2 micrograms/ml or a course 1 AUC of > 35 mg/ml.min. It is concluded that given at a dose of 50 mg/m2/day in two doses for 21 day courses, oral etoposide is well tolerated in children. A correlation between drug concentrations and toxicity was observed. Overall, a low response rate was seen (approximately 10%), but disease stabilisation appears to occur, and useful palliative effect was frequently noted. The response in brain tumours was more encouraging (3/14 PR) and this group requires further evaluation.
Administration, Oral↗
Preferential sequestration in vitro of BCR/ABL negative hematopoietic progenitor cells among cytokine nonresponsive CML marrow CD34+ cells.
It is believed that long-term cultures of CML marrow cells favor the outgrowth of BCR/ABL negative hematopoietic progenitor cells (HPC) and that this phenomenon may be enhanced with negative hematopoietic regulators which can maintain primitive HPC in a quiescent state. Proliferation of CML marrow CD34+ cells in primary short-term cultures, maintained in the presence or absence of macrophage inhibitory protein-1 alpha (MIP-1 alpha), was tracked with the membrane dye PKH2. After 7 to 10 days it was possible to distinguish between cytokine responsive (CR) CD34+ cells (cells which had divided thus becoming PKH2dim) and cytokine nonresponsive (CNR) CD34+ cells (cells which had not divided and had therefore remained PKH2bright). CR and CNR CD34+ cells were isolated by flow cytometric cell sorting, seeded in secondary long-term cultures, and their progeny cells assayed weekly for their clonogenic progenitor cell content and expression of BCR/ABL by reverse transcriptase polymerase chain reaction (RT-PCR). Whereas CNR cells isolated from control primary cultures (control/CNR) sustained in vitro hematopoiesis, similar cells from cultures treated with MIP-1 alpha (MIP-1 alpha/CNR) supported a higher and, in some patients, a more extended production of clonogenic HPC, indicating that MIP-1 alpha was able to maintain primitive HPC in a quiescent state. Predominance of BCR/ABL negative progenitors in vitro was more evident in secondary cultures initiated with CNR cells than in those initiated with CR cells, especially those established with MIP-1 alpha/CNR cells. Of interest is the observed decline in the percentage of BCR/ABL+ progenitors in these cultures with time. Whereas up to 100% of progenitors were BCR/ABL+ on day 0, by day 14, only 46% of progenitors in MIP-1 alpha/CNR secondary cultures were BCR/ABL+ and by day 28 and beyond, the percentage of BCR/ABL+ progenitors dropped to below 20%. These results suggest that the quiescent nature of normal HPC present in CML marrow may favor their identification via cell tracking and, subsequently, their isolation from the more actively cycling leukemic cells. These studies also confirm the feasibility of employing negative hematopoietic regulators to augment the sequestration of normal HPC among the cytokine nonresponsive fraction of CD34+ cells, an approach that may be clinically feasible for autotransplantation.
Adult↗
The effectiveness of a needleless intravenous connection system: an assessment by injury rate and user satisfaction.
OBJECTIVE: To assess the impact of a needleless intravenous (i.v.) connection system on the rate of reported intravenous-connection-related (IVCR) percutaneous injuries, and to assess user satisfaction, frequency of use, and barriers to use. DESIGN: A pre-post intervention design, with injury incidence rates being compared 3 years before and 1 year after hospital wide device implementation; and a cross-sectional descriptive user satisfaction survey. SETTING: Two tertiary-care teaching hospitals, one general and one pediatric, located in a large metropolitan medical center. OUTCOME VARIABLE: All IVCR percutaneous injuries reported to the employee health services at both hospitals during the years from 1989 to 1991 and 1993. STUDY POPULATION: Survey participants were selected randomly from licensed nursing employees at both hospitals. INTERVENTION: i.v. connection system consisting of blunt plastic cannulas and compressed latex injection sites. RESULTS: After device implementation, the IVCR injury rate was reduced 62.4% (rate ratio [RR], 0.38; 95% confidence interval [CI95], 0.27-0.53) at the general hospital and 70.2% (RR, 0.30; CI95, 0.17-0.53) at the pediatric hospital. After adjusting for the reduction in injury rate due to factors other than device implementation, the IVCR injury rate was reduced 54.5% (adjusted RR, 0.46; CI95, 0.32-0.65) at the general hospital and 57.2% (adjusted RR, 0.43; CI95, 0.24-0.78) at the pediatric hospital. Approximately 94% of survey respondents (n = 478, response rate = 51%) were satisfied with the device and recommended continued use. However, needles still were being used for activities that could have been performed with the needleless system because of compatibility, accessibility, and other technical problems related to the device. CONCLUSIONS: The device was effective in reducing the rate of reported IVCR percutaneous injuries and users were satisfied with the device, but barriers to universal use were identified.
Cross-Sectional Studies↗