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Biomedical subjects

M Lynch

Publications and source records attributed to M Lynch.

At least 271 records · Page 15Linked to original sources
PubMed1981

Mice, men, mustard and methylated xanthines: the potential role of caffeine and related drugs in the sensitization of human tumours to alkylating agents.

The relationships between DNA damage from UV radiation, alkylating drugs and the methylated xanthines (MX) have been studied in normal and malignant rodent and human cells. A comparison of the level of DNA excision repair (repair replication and unscheduled DNA synthesis) confirms that some forms of alkylating-agent damage (probably mono-filar DNA adducts) are less completely removed by both normal and malignant rodent cells than by their human counterparts, rendering rodent cells more susceptible to the toxic potential of unexcised lesions. The toxicity of alkylating agents can be increased by the presence of several MXs during the period of DNA replication which follows infliction of the damage. Human cells appear capable of excising more DNA damage, rendering them somewhat less susceptible to enhancement of cytotoxicity by MX. This resistance of human cells is only quantitative, however, since 2 human cancer cell lines (HeLa and HT-29) could be sensitized to a variety of alkylating agents by appropriate concentrations of MX. Trimethylxanthine (caffeine) and the 2 clinically useful dimethylxanthines (theophylline and theobromine) appeared equally effective in sensitizing cells. The sensitization was dependent upon a slightly cytotoxic concentration of the MX and a suitably prolonged period of post-damage MX exposure. Of these 3 classic MXs, only theobromine might be clinically useful. The levels required for alkylating-agent sensitization exceed the clinically tolerable level of theophylline, and probably approach the tolerance of man to caffeine. The most likely mechanism by which MX sensitization is achieved is reversal of the inhibition of DNA replicon initiation which follows the infliction of significant DNA damage. Through the selection of suitable clinically useful alkylating agents (those dependent on active cellular transport for cell penetration) and appropriate MX scheduling, an enhanced therapeutic ratio might be achieved, potentially increasing the clinical usefulness of these alkylating agents. MX would thus form a useful class of agents adjuvant to conventional anti-cancer drugs.

Alkylating Agents↗
PubMed1981

Translation of phenylalanine hydroxylase-specific mRNA in vitro: evidence for pretranslational control by glucocorticoids.

We have found that the induction of phenylalanine hydroxylase by hydrocortisone and serum in confluent cultures of H4-II-E-C3 rat hepatoma cells is accompanied by an increase in polysomal mRNA specific for phenylalanine hydroxylase, as measured by translation in a cell-free protein-synthesizing system. Thus, the induction is mediated largely, if not entirely, by a pretranslational mechanism, possibly by stimulation of the transcription of the phenylalanine hydroxylase gene.

Animals↗
PubMed1981

A chronic dose-ranging study of the pharmacokinetics of phenylbutazone in rheumatoid arthritic patients.

Phenylbutazone in doses of 200, 300 and 400 mg/day was administered chronically to six rheumatoid arthritic patients. At each steady-state the plasma levels of phenylbutazone, oxyphenbutazone and gamma-hydroxyphenylbutazone as well as the extents of binding of phenylbutazone and oxyphenbutazone to plasma proteins were measured. 2 Plasma concentrations of phenylbutazone did not increase proportionally with dose but when corrected for protein binding unbound concentrations of phenylbutazone did show a proportional increase with dose. 3 Plasma concentrations of oxyphenbutazone decreased with an increase in phenylbutazone dose suggesting either that the elimination of oxyphenbutazone is stimulated or its formation inhibited after chronic administration of phenylbutazone. 4 Binding studies with human serum albumin demonstrated the ability of phenylbutazone and oxyphenbutazone to mutually displace one another. Neither saturation of the protein binding sites nor displacement interactions could account for the changes in binding shown by phenylbutazone with increased dose. 5 gamma-hydroxyphenylbutazone concentrations increased proportionally with phenylbutazone dose reaching 68% of the phenylbutazone concentration in one patient. There was a large inter-subject variation in the gamma-hydroxyphenylbutazone concentrations.

Aged↗
PubMed1978

Secretory immunity and immunodeficiency.

1) Certain selective IgA-deficient subjects are capable of synthesizing functional secretory antibodies (s-IgM or s-IgA class) to indigenous oral microorganisms. 2) The presence or absence of these secretory antibodies in saliva can be correlated with the extent of caries involvement. 3) Lysozyme activity is significantly increased in saliva from immune deficient subjects though no correlation can be made with caries experience.

Agammaglobulinemia↗
PubMed1978

Abolition and modification of reentry within the His-Purkinje system by procainamide in man.

The effects of intravenous procainamide infusion of 10--14 mg/kg body weight (i.e., 750 mg) of procainamide (PA) on reentry within the His-Purkinje system (HPS) were studied in 13 patients using His bundle electrograms and ventricular extrastimulus method. PA abolished reentry in eight patients (group 1) and decreased the width of reentry zone in the remaining five (group 2). At comparable S1S2 intervals, the S2H2 intervals after PA were longer than control in all patients. In group 1 patients, after PA, reentry did not occur even at S2H2 intervals that were significantly longer than control critical S2H2 intervals. In two of eight patients in group 1, PA abolished reentry by converting unidirectional block into bidirectional block in the antegrade limb (right bundle) of the reentry circuit. In the remaining six patients reentry was abolished because of consistent retrograde block of S2 impulse at some point between the site of stimulation and the His bundle recording site. In group 2, reentry was initiated after PA at approximately the same S1S2 intervals as in control, but required significantly longer S2H2 intervals; in these patients the zone of reentry was shortened due to increase in effective refractory period of the ventricular muscle. PA significantly increased the functional refractory period of HPS and the effective refractory period of ventricular muscle. The results of this study differ from the previously reported effects of lower concentrations of PA which facilitated reentry within the same circuit. We conclude that the effects of PA on reentry are dose-related and can both facilitate and suppress reentry, depending on critical changes in conduction and refractoriness of the HPS.

Adult↗
PubMed1977

Cellular effects of combined adriamycin and x-irradiation in human tumor cells.

The effects on cell survival in tissue culture of Adriamycin, of various Adriamycin derivatives and of the parent compound, daunomycin, have been studied. Adriamycin and three of its C-14 derivatives show similar toxicities towards cells chronically exposed in culture. Acute (30 min) exposures are significantly less toxic than exposures to the drug throughout the period of colony formation. Daunomycin, the parent compound, is significantly more toxic than any Adriamycin compound. Both high-dose, pulsed exposures and low-dose, chronic exposures result in shoulders on the cell survival curves. Split-dose experiments show little evidence for a significant acute repair of Ad damage. Ad toxicity is additive to X-rays at high levels of cell survival and synergistic at low levels of cell survival. Both excision repair-competent and excision-deficient cells show sensitization to X-irradiation when significantly cytotoxic levels of Ad are used. No evidence for an induction of Ad resistance by previous irradiation was found. Ad does not appear to inhibit the repair of sub-lethal X-ray damage. Since Ad produces molecular lesions similar to those induced by X-rays it is hypothesized that both radiation "enhancement" and the recall of latent X-ray injuries result from the induction of Ad of DNA damage similar to that occurring following X-ray exposure. The implications of these findings with respect to clinical drug and X-ray scheduling is discussed.

Cell Line↗
PubMed1975

Family unit in a children's psychiatric hospital.

The need for effective management of disorders of parent/child relationships is repeatedly stressed. Despite the bulk of theoretical work on the subject there is little information on the practical management of the clinical problems that arise. We describe a unit designed and staffed for the management of such disorders. In our view it meets a need in a way that could be difficult or impossible for most paediatric, psychiatric, and social services as they are at present organized.

Child↗