Aprotinin inhibits tissue plasminogen activator-mediated fibrinolysis during orthotopic liver transplantation.
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Aprotinin↗
Biomedical subjects
B Hunt
Publications and source records attributed to B Hunt.
Synergistic cytotoxicity using 2'-deoxy-5-azacytidine and cisplatin or 4-hydroperoxycyclophosphamide with human tumor cells.
The combined use of 2'-deoxy-5-azacytidine with cisplatin or 4-hydroperoxycyclophosphamide in vitro frequently resulted in synergistic cytotoxicity against a panel of six human cell lines. This enhanced cell killing occurred at drug concentrations that are clinically achievable. Synergy was also seen if the sequence of drug administration was altered, implying that a temporal overlap between the drugs was necessary, but that the actual biochemical lesions induced by each agent were probably unique, and interacted in an as yet undefined manner. Of further interest was the observation that at least one of the synergistic pairs was active against five of the six cell lines tested. 2'-Deoxy-5-azacytidine incorporation as assessed by the level of gross genomic DNA methylation did not appear to correlate with the synergistic cytotoxicity observed. Thus, we could not discern a clear relationship between the degree of DNA hypomethylation and the observed synergies, although DNA hypomethylation frequently occurred when synergy was demonstrated. The practical usefulness of these drug combinations has not yet been tested and awaits appropriate clinical trials both to assess the tumoricidal effects and possible increased toxicity.
Antineoplastic Agents↗
A comparison of AIDS and STD knowledge between sexually active alcohol consumers and abstainers.
Effective curricula should influence knowledge levels of all students, including high-risk populations. In this study, a modified version of the National Adolescent Student Health Survey was administered to a group of eighth and 10th grade students (N = 3,803) exposed to a curriculum designed to improve AIDS and STD knowledge levels. The analysis examined the influence of gender, ethnicity, alcohol use, and sexual activity as they related to AIDS and STD knowledge. Findings indicated poor knowledge scores on STD items, with no significant differences on group comparisons. Comparisons of AIDS knowledge scores indicated significant differences based on gender, ethnicity, and behavior. Females scored higher than males, whites scored higher than blacks, and abstainers from sexual activity and alcohol scored higher than their active counterparts. Results suggest current educational efforts are not equally effective. Future educational initiatives should be sensitive to group membership.
Acquired Immunodeficiency Syndrome↗
The entrainment of low frequency breathing periodicity.
It has been predicted by mathematical models of the respiratory control system that the delay between the lung and the respiratory controller may determine the cycle time found in periodic breathing. We examined cycle time of periodic breathing and circulation time in 11 patients known to have circulation delay due to heart failure. We did not find a significant relationship between the amount of periodic breathing and circulation delay, but found a very high correlation between circulation delay and the cycle time of periodic breathing (r2 = 0.825; p = 0.0001).
Blood Circulation↗
Genotypic and phenotypic evidence of clonal interactions in murine tumor cells.
The stability of mixed tumor cell populations has been described in terms of phenotypic characteristics such as metastatic potential, immunogenicity, and drug resistance. We have extended these analyses to the molecular level in a model that uses transfection of the hemagglutinin antigen (HA) gene of influenza virus into murine CT-26 colorectal carcinoma cells. Transfection was followed by fluorescence-activated cell sorting (FACS) to select a parent population with expression of high levels of HA. We characterized this population (FACS-3) and four derived clones (5, 6, 9, and 18) over time with regard to phenotypic characteristics: immunogenicity and cross-protection against tumor challenge, cell surface expression of HA, evidence of HA gene amplification, and levels of HA mRNA. During 6 months in culture, the FACS-3 parent cells remained stable, but the individual clones varied for all of the parameters assessed. Among the clones, all possible molecular variations occurred, including changes in HA gene copy number (increased in clone 5 and decreased in clone 18), gene rearrangement (clone 5), decrease in HA mRNA (clones 6, 9, and 18), increase in HA mRNA (clone 5), and an abnormality in translational control or a posttranslational error. In all cases, the molecular changes correlated with cell surface HA expression, immunogenicity, and cross-protective potential. We conclude that in vitro clonal interactions play a role in stabilizing heterogeneity in this system. These studies show that even in the absence of selection, clonal interactions may alter the phenotype of tumors by increasing malignant progression or impeding tumor growth.
Animals↗
Retention of immunogenicity after X-irradiation of mouse colon tumor cells expressing the transfected influenza virus hemagglutinin gene.
We have previously demonstrated that murine colon tumor cells transfected with the gene coding for the hemagglutination antigen (HA) of influenza virus acquire an inherent immunogenicity, fail to grow in syngeneic mice, and demonstrate an ability to cross-protect against a challenge with parental nontransfected cells. In the present study the immunogenic potential of HA-transfected cells correlated with cell-surface HA expression, as measured both by a fluorescence-activated cell sorter and by radio-labeled antibody binding. HA-transfected immunogenic cells had a median lethal dose (LD50) that was 10,000-fold greater than that of nontransfected cells. Most importantly this study demonstrated that HA-transfected cells retained their immunogenicity after X-irradiation with 12,000 rad. This characteristic makes their potential usefulness in treating human neoplasia more plausible.
Animals↗
Induction in a murine tumor of immunogenic tumor variants by transfection with a foreign gene.
Transfection of the undifferentiated murine colon carcinoma line CT-26 with the gene coding for the hemagglutination antigen (HA) of influenza virus resulted in the generation of highly immunogenic tumor cells. CT-26 cells transfected with HA not only failed to grow in syngeneic mice but also protected normal animals against a challenge with otherwise lethal doses of parental nontransfected cells. The immunogenicity of HA-transfected cells appeared to correlate with surface HA expression in that tumorigenic clones of HA-transfected CT-26 cells expressed little HA, while immunogenic clones were high expressers of HA. Irradiation of immunogenic HA clones did not abrogate their immunogenicity. These observations demonstrate that immune recognition of a poorly immunogenic tumor can be produced by immunization with tumor cells expressing a defined, foreign cell surface antigen.
Animals↗
The prevalence of ouabain-resistant variants after mutagen treatment. Lack of correlation between the frequency of variant expression and the metastatic phenotype.
In order to test the hypothesis that tumor cells with greater malignant potential should have an increased sensitivity to mutagens, four individual murine cell lines, each paired for their metastatic and nonmetastatic potentials, were compared with respect to the prevalence at which ouabain-resistant mutants could be obtained after treatment of the cells with the mutagen MNNG. No increase in the prevalence of induced mutation in metastatic cells was observed; and, in fact, in two cases (h-ras-transfected 3T3 and SP1 cells), nonmetastatic cells had a higher prevalence of mutations after MNNG treatment than did their metastatic counterparts. We suggest that the absolute level of genomic instability, measured by this means, is not critical to malignant potential and tumor progression.
Animals↗
Selection of metastatic variants with identifiable karyotypic changes from a nonmetastatic murine tumor after treatment with 2'-deoxy-5-azacytidine or hydroxyurea: implications for the mechanisms of tumor progression.
Experiments were undertaken to explore whether in vitro exposure of a nonmetastatic murine tumor to chemotherapeutic drugs would affect the ability of this tumor to metastasize spontaneously. The tumor chosen was an aneuploid (near-tetraploid) spontaneously arising intraductal mammary adenocarcinoma (CBA-SP1), which normally fails to give rise to microscopic or macroscopic metastases after s.c. inoculation of cells. The drugs tested were 5-aza-2'-deoxycytidine (5-aza-dCyd) and hydroxyurea. We found that the injection of 1 X 10(5) uncloned drug-treated cells s.c. resulted in the emergence of gross and/or microscopically detectable metastases in the lungs of CBA mice. Individual clones derived from hydroxyurea-treated cells all produced metastases in a manner similar to the bulk culture injections. Clones of 5-aza-dCyd-treated cells also produced metastases, but fewer of these produced macroscopic metastases. In addition, only 9 of 15 5-aza-dCyd-treated clones produced tumor takes because of the ability of 5-Aza-dCyd to engender Imm+ variants in CBA-SP1 cells. Lung metastases obtained after the injection of uncloned cells retained their metastatic phenotype for three generations, indicating that the phenotypic change was a heritable characteristic. Although the genetic or epigenetic mechanism for this change is unknown, we observed karyotypic changes of a similar nature in the drug-treated cell lines established from micrometastases. These involved the detection of extra copies of chromosome 8. It is possible that exposure of tumors to therapeutic agents may in some cases increase their aggressiveness through genetic or epigenetic mechanisms that lead to high frequency heritable phenotypic alterations associated with distinguishable chromosomal changes.
Animals↗
A cluster of patients with a chronic mononucleosis-like syndrome. Is Epstein-Barr virus the cause?
A cluster of 134 patients who had undergone Epstein-Barr virus (EBV) serological testing because of suspected chronic EBV syndrome was investigated in Nevada. Fifteen case-patients were identified who had severe, persistent fatigue of undetermined etiology for more than two months. When compared with the remaining 119 patients who had less severe illnesses and with 30 age-, sex-, and race-matched control-persons, these 15 patients had significantly higher antibody titers against various components of EBV and against cytomegalovirus and herpes simplex and measles viruses. Epstein-Barr virus serology could not reliably differentiate individual case-patients from the others, and the reproducibility of the tests within and among laboratories was poor. As a group, the case-patients appear to have had a syndrome that is characterized by chronic fatigue, fever, sore throat, and lymphadenopathy. The relationship of this fatigue syndrome to EBV is unclear; further studies are needed to determine its etiology.
Adolescent↗
Campylobacter gastroenteritis in fattening lambs.
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Animals↗
Trial of relaxation in reducing coronary risk: four year follow up.
On screening 192 men and women aged 35-64 were identified as having two or more of the following risk factors: blood pressure greater than or equal to 140/90 mm Hg, plasma cholesterol concentration greater than or equal to 6.3 mmol/l (243.6 mg/100 ml), and current smoking habit greater than or equal to 10 cigarettes a day. They were randomly allocated to a group for modification of behaviour or to serve as controls. Both groups were given health education leaflets containing advice to stop smoking, to reduce animal fats in the diet, and on the importance of reducing blood pressure. In addition, the treatment group had group sessions of one hour a week for eight weeks in which they were taught breathing exercises, relaxation, and meditation and about managing stress. It had previously been found that after eight weeks and eight months there was a significantly greater reduction in both systolic and diastolic blood pressures in the group taught to relax compared with the control group. After four years of follow up these differences in blood pressure were maintained. Plasma cholesterol concentration and the number of cigarettes smoked were lower in the treatment group at eight weeks and eight months but not at the four year follow up. At four years more subjects in the control group reported having had angina and treatment for hypertension and its complications. Incidence of ischaemic heart disease, fatal myocardial infarction, or electrocardiographic evidence of ischaemia was significantly greater in the control group. If the results of this study could be obtained in a larger study the financial and health care implications would be enormous.
Adult↗
Newly diagnosed cystic fibrosis in middle and later life.
Four patients with cystic fibrosis diagnosed in middle and later life are presented. All had chronic bronchopulmonary infection with a high sweat sodium concentration, and chest radiographic evidence of upper zone bronchiectasis. Two patients had pancreatic dysfunction. Sputum culture grew mucoid Pseudomonas aeruginosa in three patients and Haemophilus influenzae in one. Ages at diagnosis were 63, 42, 40, and 35 years. These patients confirm the possibility of occasional longevity in cystic fibrosis and emphasise the need to consider the diagnosis at all ages. They also provide encouragement for younger patients.
Adult↗
Medical conditions in patients with diabetic maculopathy.
Ninety-four patients with untreated diabetic maculopathy in at least one eye had their visual acuity and medical condition assessed and followed for 5 years. The mean patient age was 58 years (range 29 to 73 years) at the diagnosis of maculopathy, and they were predominantly non-insulin-dependent diabetics (NIDD). Thirty-two patients had maculopathy diagnosed at or within 2 years of the diagnosis of diabetes. Visual loss was severe, the mean final vision being 6/36 with 44 eyes blind. In addition to progression of the maculopathy, causes for loss of vision included complications of new vessels (vitreous haemorrhage and macular traction) often leading to complete blindness. Medical abnormalities were commoner than would be expected in a similarly aged normal population. Mean blood pressure was 163/90, 81 patients had degenerative vascular disease, 22 patients had nephropathy, and 35 had raised cholesterol levels. Twenty-six patients died during the study mainly from vascular disease and renal failure. No significant association was found between visual acuity loss and medical conditions, glucose control, type of therapy, age, diabetes duration, and mortality.
Adult↗
Fall in vital capacity with posture.
In a study of 147 subjects (50 normals, 50 with obstructive, and 47 with restrictive lung function), the mean reduction in forced vital capacity from standing to supine (delta FVC) was 7.5% (SD +/- 5.7), 11.2% (+/- 13.4), and 8.2% (+/- 7.7) respectively, with no significant difference between groups. The respective 95% upper confidence limits were 19%, 38% and 24%. We conclude that delta FVC greater than 25% associated with normal or restrictive lung function or greater than 35% associated with airways obstruction should be an indication for further study of diaphragm function.
Adult↗
Valvular endocarditis associated with Streptococcus suis type 2.
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Animals↗
Post-irradiation sensitization with the ADP-ribosyltransferase inhibitor 3-acetamidobenzamide.
In recent years several lines of evidence have indicated that nuclear ADP-ribosyltransferase (ADPRT) activity is involved in DNA repair, although the requirement of ADPRT activity for cell survival has only been demonstrated in certain cases. We have investigated further the possible role of ADP-ribosylation in the response of cells to ionizing radiation, using 3-acetamidobenzamide (3-AAB), a highly effective inhibitor of ADPRT. With this compound we have demonstrated that marked enhancement of cell killing is observed if ADP-ribosylation is inhibited to a sufficient extent during the post-irradiation repair period, using concentrations of 3-AAB which are not toxic towards unirradiated cells. The critical period within which the inhibitor was effective was the first 90 min post-irradiation, and the half life of the recoverable radiation damage involved was estimated as approximately 20 min. Treatment with 3-AAB slowed the rate at which DNA strand breaks were repaired but did not prevent the ultimate repair of breaks, within the limits of resolution of the alkaline unwinding method used to determine DNA strand breakage. Although the majority of breaks were ultimately repaired, the frequency of radiation-induced sister chromatid exchanges and chromosome aberrations was increased, indicating that more genomic rearrangement had taken place, possibly as a consequence of the persistence of breaks when ADPRT activity was inhibited by 3-AAB during the post-irradiation repair period. It is suggested that the increased frequency of transposition and recombination which these observations reflect is likely to be associated with an increased risk of lethal mutations, some possibly involving chromosomal aberrations.
Adenosine Diphosphate Ribose↗
Aspirin and prostacyclin treatment of diabetic dogs.
Spontaneously diabetic dogs were treated initially (the first 1/2 yr) with i.v. prostacyclin and oral aspirin and then for 1 yr with varying doses of aspirin alone. At this time cataracts prevented visualization of retinae, and one eye of each animal was removed for examination of the vasculature of the trypsin digested retinae. Studies of the blood during the course of treatment showed an elevation of plasma cyclic adenylic acid and marked lowering of inordinately high platelet count and platelet aggregation. Treatment was stopped and after an additional 1/2 year the animals were euthanized and the fellow eye removed for retinal study. Although just three diabetic animals survived for binocular retinal histology, there were no discernible differences in the retinal vasculature in the fellow eyes of a given animal, and in only one of these three animals were there clear signs of diabetic retinopathy. We must conclude, therefore, that in spite of relative normalization of platelet function in the parameters measured during the course of treatment, we cannot yet claim a salutary effect of treatment on the diabetic retina. Cataracts prevented us from having better information on diabetic retinae prior to treatment and a redesigned study would have to include unilateral histological retinal examination before any treatment is started to determine if, indeed, improved platelet physiology slows or reverses changes in the diabetic retina.
Animals↗