Search PubMed⌕ Search

Biomedical subjects

C Hardy

Publications and source records attributed to C Hardy.

At least 73 records · Page 4Linked to original sources
PubMed1985

Relationship between mediator release from human lung mast cells in vitro and in vivo.

There is now compelling evidence to incriminate bronchial mast cells in the pathogenesis of bronchoconstriction of allergic asthma. Human mast cells isolated from lung tissue or bronchoalveolar lavage release histamine and generate eicosanoids upon IgE-dependent activation. In this paper we present data that raise doubts about the significance of phospholipid methylation in IgE-dependent activation-secretion coupling and provide evidence that drugs such as 3-deazaadenosine inhibit mediator secretion by inhibiting phosphodiesterase, in addition to inhibiting putative methylation pathways. Activation of human mast cells and basophils also stimulates adenylate cyclase to increase levels of cyclic AMP, which, on the basis of pharmacological manipulation with purine nucleosides, we believe is involved in the progression of the secretory response. Human lung cells also generate both cyclo- and lipoxygenase products of arachidonate upon Ca++-dependent stimulation with complex interactions occurring between these pathways in the presence of the leukotriene inhibitor, Piriprost. The role of mast cells in the immediate airway response to inhaled allergens in asthma was demonstrated by showing an interaction between nonspecific bronchial reactivity and mast cell reactivity in predicting the airway response upon antigen inhalation. Further confirmation of this concept was obtained by showing an inverse relationship between the release of histamine and neutrophil chemotactic factor (NCF) into the circulation induced by antigen challenge, and nonspecific airway reactivity. The identification of significant increases in circulating mediators following antigen provocation of patients with seasonal asthma enabled the effects of drugs used in the treatment of asthma to be compared on airway calibre and mast cell mediator release. Sodium cromoglycate partially inhibited the airway and plasma histamine responses with antigen, but totally inhibited the increases in NCF. Salbutamol completely inhibited all responses, while ipratropium bromide, which produced the same bronchoconstriction as achieved with salbutamol, had no effect. The potent H1-antagonist astemizole partially inhibited bronchoconstriction without affecting histamine release. Antigen provocation produced a significant increase in circulating levels of the 13,14-dihydro-15-keto metabolite of PGF2 alpha which could originate from mast cell-derived PGD2. In both retrospective and prospective studies, a close relationship was shown between nonspecific bronchial reactivity and resting airway calibre in asthma.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Airway and cardiovascular responses to inhaled prostacyclin in normal and asthmatic subjects.

Prostacyclin (PGI2) is one of several prostanoids released after antigen challenge of human lung fragments. To define its activity on human airways, we studied the effect of inhaled PGI2 in 10 normal and 8 asthmatic subjects. In random order, PGI2, 1 mg/ml, its hydrolysis product, 6-oxo-PGF1 alpha, 1 mg/ml, and glycine vehicle were given on separate occasions by nebulizer. Measurements of specific airway conductance (SGaw), blood pressure (BP), heart rate (HR), plasma 6-oxo-PGF1 alpha, and cyclic AMP levels were made at frequent intervals for as long as 45 min after nebulization. Prostacyclin and 6-oxo-PGF1 alpha caused cough and retrosternal discomfort. None of the drugs had any significant effect on SGaw in either the normal or asthmatic subjects, though 2 asthmatics showed consistent bronchodilatation with prostacyclin. Prostacyclin caused a marked fall in diastolic blood pressure (mean 20 +/- 3 mmHg) and increase in heart rate (29 +/- 3 beats X min-1) with a small late fall in systolic blood pressure (8 +/- 2 mmHg). This was associated with a 12- to 15-fold increase in plasma 6-oxo-PGF1 alpha levels maximal at 1 min, and in normal subjects only, a later twofold increase in plasma levels of cyclic AMP maximal at 5 min. Thus, inhaled PGI2 at concentrations that had pronounced cardiovascular activity produced no consistent effect on airway caliber in normal or asthmatic subjects.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Transformation mediated by the SV40 T antigens: separation of the overlapping SV40 early genes with a retroviral vector.

A murine retroviral vector has been used to separate physically the overlapping genes encoded by SV40. This minimal retroviral vector contains LTRs and other cis-acting signals required for infectious RNA virus propagation. We placed the SV40 early region within this DNA and after transfection of cells producing helper Moloney murine leukemia virus, SV40 retroviruses (MV40) could be rescued. Cytoplasmic spliced large T and small t transcripts, as well as unspliced transcripts, are packaged into virions with equal efficiency. Pure SV40 large T retroviruses can be cloned from these heterogeneous virus stocks by secondary transformation of rodent cells. The large T retrovirus stocks morphologically transform primary or established mouse and rat lines with high efficiency. There is little difference in transformation either by agar assay or focus formation between retroviruses carrying both SV40 genes or large T alone. We present quantitative data that demonstrate that abortive transformation of rodent cells by SV40, transient expression of the transformed phenotype after infection, is not manifested by MV40. Thus abortive transformation is not the result of a weakly dominant transforming gene, but rather of the normally inefficient mode of integration and early gene expression of SV40 upon infection of rodent cells.

Antigens, Viral, Tumor↗
PubMed1984

Thiol reactive nitroimidazoles: radiosensitization studies in vitro and in vivo.

Using Chinese hamster V79 cells in vitro a study has been made of the radiosensitizing properties of 4- or 5-nitroimidazoles substituted in the 2, 5 or 4 position with various halo, sulphur ether, sulphonamide, sulphonate, ether or nitro groups. Values of E17 (the one-electron reduction potential measured versus the normal hydrogen electrode at pH7) vary in the range -178 to -565 mV. All the compounds, with one exception, are more efficient radiosensitizers than would be predicted from their redox potentials, and the factor, C1.6/C1.6, by which a compound is more efficient has been calculated. The second-order rate constants, k2, for reaction of these nitroimidazoles with glutathione and/or dithiothreitol were determined. Within each class of nitroimidazole there is a trend for k2 to increase with increasing redox potential. However, there is no clear trend between k2 and C1.6/C1.6. The concentration required to cause a 50 per cent depletion of intracellular glutathione was determined for selected compounds, as was the ability of glutathione-S-transferase to catalyse reaction with thiols. These observations suggested that the relative thiol reactivity measured under chemically controlled conditions does not necessarily indicate thiol reactivity intracellularly. Studies using the MT tumour in mice showed that the high levels of radiosensitization seen in vitro could not be duplicated in vivo. This was attributed to thiol reactivity, resulting in low metabolic stability and rapid depletion of sensitizer in vivo.

Animals↗
PubMed1984

Pure red blood cell aplasia associated with paraproteinemia: in vitro studies of erythropoiesis.

Pure red cell aplasia (PRCA) and monoclonal gammopathy were detected simultaneously in a 57 year old man with severe anemia. While erythroid burst forming units (BFU-E) were absent from blood, his bone marrow contained a high normal number of BFU-E in the absence of morphologically recognizable erythroid precursors. Serum from the patient did not inhibit the growth of BFU-E from normal blood suggesting that his PRCA was not antibody mediated. These studies suggest that in the patient the inability to produce erythrocytes was due to a block in the maturation of BFU-E; however, they do not indicate an etiology for this block. The absence of blood BFU-E and their abundance in the marrow may result from selective trapping of these cells by the marrow-blood barrier.

Blood Transfusion↗
PubMed1984

Objective evaluation of clinical performance and correlation with knowledge.

In certifying competence of anesthesiologists who have finished residency training, knowledge and judgment are evaluated objectively using written and oral examinations. Clinical motor skills, however, are not routinely assessed by objective techniques. This implicitly assumes that knowledge and judgment correlate with performance of motor skills. This study was designed to evaluate whether performance of a particular motor skill correlates with performance on a knowledge test related to that skill. To do this, we developed a criterion-referenced Spinal Anesthesia Skill Test and a knowledge test using multiple-choice questions related to spinal anesthesia. Both the skill and knowledge tests were administered to 44 residents at various levels of training at five major anesthesia teaching programs. Scores on the skill test were significantly higher than in the knowledge test, suggesting that proficiency in this essential motor skill is achieved earlier in training. There was no correlation between scores on the skill test and knowledge test. There were institution-linked differences in the scores on the skill test, suggesting that teaching of motor skills is not uniform. The advantages of developing criteria of performance of motor skills is discussed.

Anesthesia, Spinal↗
PubMed1983

Abnormal radiosensitizing and cytotoxic properties of ortho-substituted nitroimidazoles.

Various 5-substituted 4-nitroimidazoles have been shown to be much more efficient radiosensitizers and much more toxic than would have been predicted from their electron affinities, as measured by values of one-electron reduction potential, E17. Using Chinese hamster V79 cells in vitro, a comparison has been made with some isomeric 4-substituted 5-nitroimidazoles. These compounds have E17 values some 64mV greater than the 4-nitroimidazoles, yet show much lower sensitizing efficiency and also lower toxicity. Neither series of compounds shows the greater toxicity towards hypoxic cells usually associated with nitroaromatic and nitroheterocyclic compounds. The second-order rate constants, k2, for reaction of these isomeric nitroimidazoles with glutathione and dithiothreitol were determined. Within each series the value of k2 increased with increasing electron affinity, however, the 4-nitroimidazoles were always more reactive than their corresponding 5-nitro isomers. The sensitizing and toxic properties of these compounds may involve depletion of intracellular thiols; this possibility is discussed.

Animals↗
PubMed1983

High proliferation of granulocyte-macrophage progenitors in tumor-bearing mice.

Cancer may affect hemopoiesis by altering the proliferative status of hemopoietic progenitor cells. In Lewis lung carcinoma (LLC), the proliferative rate of the granulocyte-macrophage colony-forming unit (culture) (GM-CFUc) was studied using in vivo hydroxyurea techniques. The disposal of mature elements to the periphery was also monitored during tumor growth. Neutrophilia, anemia, and splenic hypertrophy developed during the course of the disease. By Day 6 post-tumor implant, myeloid hyperplasia of the marrow was evident, but the content of GM-CFUc in LLC mice was similar to that of control. However, by Day 11, the marrow of LLC mice displayed an increased concentration of GM-CFUc, which tripled by Day 19. There was an increased percentage of proliferating GM-CFUc in LLC mice by Day 6 which was highest by Day 11 and thereafter declined. The level of colony-stimulating activity was higher in the serum of tumor bearers than in that of controls. The early increase in proliferative rate of these early hemopoietic precursors can account for the later accumulation of GM-CFUc and myeloid elements in the marrow. Increased cycling of hemopoietic stem cells raises questions concerning the potential for early exhaustion of hemopoietic progenitor cells in these animals.

Animals↗
PubMed1981

Cytotoxic properties of a 4-nitroimidazole (NSC 38087): a radiosensitizer of hypoxic cells in vitro.

5-Phenoxysulphonyl-1-methyl-4-nitroimidazole (NSC 38087) can act as a sensitizer of hypoxic mammalian cells to radiation in vitro. The degree of sensitization achieved is greater than would be predicted from the drug's electron affinity. Cytotoxicity studies have shown that 5 microM NSC 38087 can reduce the surviving fraction of log-phase V79 cells in air at 37 degrees C to 10(-2) after 2 h exposure. This toxicity is considerably increased by small rises in temperature. In contrast to other nitro-heterocyclic radiosensitizers, NSC 38087 and related 5-substituted 4-nitroimidazoles show greater toxicity towards aerobic than to hypoxic cells. Log-phase cells show the highest sensitivity to the toxic action of NSC 38087, with plateau-phase cells, cells with a history of chronic hypoxia, and thermotolerant cells showing greater resistance. These toxicity data are compared to those for the 2-nitroimidazole hypoxic-cell sensitizer misonidazole.

Animals↗
PubMed1981

Radiosensitization of hypoxic mammalian cells in vitro by some 5-substituted-4-nitroimidazoles.

The efficiencies of various 5-substituted-4-nitroimidazoles as radiation sensitizers have been determined in hypoxic Chinese hamster cells irradiated in vitro. Compared with published data on the sensitizing properties of substituted 2-nitro- and 5-nitroimidazoles, some of the 4-nitro derivatives show unusually high sensitizing efficiencies defined as the concentrations required to give an enhancement ratio of 1.6. The equilibrium one-electron reduction potentials of the compounds (E17) were measured by a pulse radiolysis technique and the results show that although sensitizing efficiencies are unexpectedly high, based on considerations of electron affinity, they still increase with increasing values of E17. Enhancement ratios were determined in two V79 cell lines for combinations of one of these compounds (a 4-nitroimidazole containing the group SO2.O.phenyl in the 5-position, NSC 38087) with various concentrations of misonidazole. The sensitization observed suggests that the two compounds may be operating by different mechanisms.

Animals↗