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Biomedical subjects

W Sheridan

Publications and source records attributed to W Sheridan.

At least 37 records · Page 2Linked to original sources
PubMed1989

Clinical experience with recombinant human granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor.

Bacterially synthesized human granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) have been studied to determine if they could prevent or reduce the neutropenia caused by chemotherapy. Our studies suggest that 10 micrograms/kg/day of G-CSF administered as a continuous subcutaneous infusion abrogates the neutropenia associated with a standard dose of melphalan. G-CSF produced a rapid increase of neutrophil levels, was well-tolerated, and was associated with only one frequent adverse effect: bone pain. GM-CSF, administered in doses ranging from 3 to 15 micrograms/kg/day subcutaneously, appeared to be useful in abrogating the neutropenia associated with chemotherapy, producing elevations in neutrophils, eosinophils, and monocytes. Although GM-CSF was relatively well-tolerated, several adverse effects, including bone pain, rashes, and fluid retention, were observed. The initial dose of GM-CSF in some patients produced a reaction that was characterized by hypoxia.

Clinical Trials as Topic↗
PubMed1989

Empiric single agent or combination antibiotic therapy for febrile episodes in neutropenic patients: an overview.

Febrile episodes during chemotherapy-induced neutropenia are a frequent cause of morbidity and mortality in cancer patients. Empiric antibiotic therapy commencing at the onset of fever is selected according to three principles: intravenous therapy is used to rapidly achieve bactericidal serum levels, antibiotics with appropriate antibacterial spectra are required, and combinations of antibiotics have been preferred for their synergistic activity. Initial empiric monotherapy with single antibiotics such as imipenem which have a sufficiently broad antibacterial spectrum in their own right are potentially as efficacious as conventional combination therapies. Granulocytopenic periods complicated by fever are significantly longer in patients receiving chemotherapy for leukaemia than in patients undergoing treatment for lymphoma and solid tumours. However, defervescence of fever following commencement of antibiotic therapy occurs equally rapidly in these three groups. The persistent granulocytopenia leaves leukaemic patients at greatest risk of breakthrough or second infections. These patients therefore appear to be the most likely to benefit from the clinical use of haemopoietic growth factors such as granulocyte and granulocyte-macrophage colony-stimulating factor.

Agranulocytosis↗
PubMed1989

Preclinical studies on deoxycoformycin and deoxyadenosine as pharmacologic T cell purging tools.

Deoxycoformycin (dCf) is a potent toxin to T lymphocytes in human peripheral blood and bone marrow. In the presence of deoxyadenosine (dAdo), dCf inhibits T cell function as measured by DNA synthesis induced by stimuli in the rank order of mixed lymphocyte culture greater than murine monoclonal antibody OKT3 greater than phytohemagglutinin. Approximately two logs of human bone marrow T cells were removed by 24 h of incubation with dCf and dAdo at doses that preserved colony-forming ability of the treated marrow. A semi-closed system of isolating mononuclear cells in large volumes using density gradient centrifugation was developed. Using this system, it was found that dCf and dAdo could remove about two logs of T lymphocytes after 24 h of incubation when the cells were incubated in large volumes at a relatively high concentration (10(7) cells/ml). This system appears well suited for purging T lymphocytes from human bone marrow before clinical transplantation.

Adenosine Deaminase Inhibitors↗
PubMed1988

Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy.

A phase I/II study of granulocyte colony stimulating factor (G-CSF) was undertaken in patients with advanced malignancy receiving melphalan to determine the granulocyte response, side-effects, and pharmacokinetics. Patients received doses of 1-60 micrograms/kg intravenously. There were 3 patients at each dose level. Before chemotherapy the immediate effect of G-CSF was a transient depression in circulating neutrophils followed by a dose-dependent rise. Neutrophil counts up to 80 X 10(9)/l were achieved. G-CSF administration following melphalan reduced the period of neutropenia caused by melphalan. G-CSF was well tolerated and the only clinical observation that appeared related to G-CSF administration was slight bone pain during some infusions. G-CSF was rapidly cleared from the blood with a mean half-life of 110 min for the second phase. Reductions in the number of days of neutropenia following cytotoxic chemotherapy may reduce the morbidity and mortality of chemotherapy.

Aged↗
PubMed1988

Leukemia of non-T lineage natural killer cells.

An unusual case of an aggressive leukemia of natural killer (NK) cells occurred in a 65-year-old male. Clinical characteristics of this case included hepatosplenomegaly, ascites, marrow infiltrate with leukemic cells, and a WBC up to 82.8 X 10(9) before therapy. One year before his presentation he had been noted to have a WBC of 12.1 X 10(9) with 78% lymphocytes, and 6 months before had noted intermittent fever and weight loss. He and his brother had well documented hereditary cold urticaria. The patient was treated with a modification of ProMACE CYTABOM regimen and had prompt regression of the leukemia with associated acute tumor lysis. Renal, hepatic, and marrow failure predominated during a terminal course that ended 22 days after therapy was commenced, and at autopsy there was no evidence for leukemic cell infiltrate in the liver, spleen or marrow. The leukemic cells were large granular lymphocytes by light and electron microscopic criteria, and had the following immunophenotype: CD2+, DR+, Leu7+, NKH1+, CD11+, CD3-, CD5-, CD4-, CD8-, CD16-. The cells displayed high antibody-dependent cell-mediated cytotoxicity (ADCC) and NK activity, and had a high rate of spontaneous proliferation in vitro that was not augmented by phytohemagglutinin (PHA), concanavalin A (Con A), or pokeweed mitogen (PWM). Southern analysis of DNA from leukemic cells revealed normal germline arrangements for the beta and gamma chains of the T cell antigen receptor and immunoglobulin heavy chain genes. The majority of metaphases were clonally abnormal revealing consistent rearrangements involving extra material attached to the long arms of chromosomes 5 and 11.

Aged↗
PubMed1985

Post-transfusion purpura.

We report two cases of purpura characterised by severe immune thrombocytopenia which appeared one to two weeks after blood transfusion during elective surgery. Both patients had antibodies to the platelet P1A1 antigen and displayed high levels of platelet-bindable IgG and IgM in their serum; they were treated with glucocorticoids and recovered after four weeks. One case relapsed following a further transfusion of packed red cells. Theories of pathogenesis, methods of diagnosis, and alternative forms of therapy are reviewed.

Aged↗
PubMed1981

The mouse specific-locus test with agents other than radiations: interpretation of data and recommendations for future work.

The mouse specific-locus test with visible markers (SLT) has been the only extensively used method for detecting and quantifying the induction of heritable point mutations (intragenic changes and small deficiencies) in mammals. Mutations are detected in first-generation offspring; and scoring is simple, objective, and rapid. Different germ-cell stages can be sampled, including those of greatest pertinence for genetic risk assessment. The differential probability of involving the various loci of the marked set makes the method capable of detecting qualitative (as well as quantitative) differences between the actions of mutagens. Control SLT frequencies for males reported by 4 sets of investigators are in excellent agreement and were summed as a "historical control" (801406 observations) for use in our calculations. Experimental results were classified as positive, negative, or inconclusive based upon a multiple-decision procedure produced by the testing of the following 2 hypotheses: (1) the mutation frequency (induced + spontaneous) of treated mice is not higher than the spontaneous mutation frequency, and (2) the induced mutation frequency of treated mice is no less than 4 times the historical-control mutation frequency. Each hypothesis was tested at the 5% significance level. Because of the low mutation frequency in a very large control, the SLT is capable of yielding positive results in relatively small samples. We reviewed 58 publications, SLT results have been reported for 25 chemical agents, of which 17 (representing 21 chemical classes) gave results that were positive or negative by our criteria. The frequency of positive agents was 6 of 14, 5 of 5, and 0 of 1 conclusively tested, respectively, in spermatogonia, post-spermatogonial stages, and unspecified male germ cells. Depending on the chemical used, post-spermatogonial stages can be of greater, less, or equal sensitivity relative to spermatogonia. The SLT was strongly positive for some chemicals that are not mutagenic (or only weakly so) in lower systems, and there are several examples of the reverse situation. Factors which presumably operated to cause these differences (e.g., metabolism, transport, repair in germ cells) are likely also to operate for transmitted point mutations in man.

Animals↗
PubMed1981

Use of the mouse spot test in chemical mutagenesis: interpretation of past data and recommendations for future work.

The mouse spot test, developed 23 years ago, is an in vivo assay capable of detecting genetic effects of several kinds, including intragenic mutations, minute deficiencies, deletions (through breakage or nondisjunction) of various amounts of chromosomal material, and somatic crossing-over. The method involves exposing embryos that are heterozygous for a number of coat-color markers to the test agent, and, 3 weeks later, looking for clones of mutant cells, i.e., spots of color expressing the recessive marker in an otherwise black fur. Spots having other causes may also be induced, specifically white midventral spots due to cytotoxic effects, and certain spots resulting from misdifferentiation. Spot-test results have, to date, been reported from 7 laboratories. Because the control results for any one cross and solvent were found to be reasonably consistent between the laboratories, we pooled these to develop a "historical" control with which experimental results for the same cross and solvent were compared. Experimental results were classified as positive, negative, or inconclusive on the basis of a multiple-decision procedure produced by the testing of the following 2 hypotheses: (1) the mutation frequency (induced + spontaneous) in treated mice is not higher than the mutation frequency in the appropriate pooled control, and (2) the induced mutation frequency of the treated mice is no less than 4 times as high as the observed mutation frequency in the appropriate pooled control. Each hypothesis was tested at the 5% significance level. To date, 30 substances have been employed in the spot test, including 3 that are solvents for some of the others. Of the remaining 27 (26 compounds and 1 mixture), 16 were positive, 6 negative, and 5 inconclusive. The 26 compounds fell into 27 chemical classifications (using a system provided for use by the GENE-TOX program). The inadequacies in the design and reporting of some past experiments indicate a need for a carefully specified protocol. When properly done, the spot test will fulfill a useful role in mutagenicity testing programs because (1) it is an in vivo mammalian assay, (2) it detects genetic effects of many kinds, and (3) it is relatively rapid. Since the test appears well suited to the identification of potent mutagens, its main value should be in screening large numbers of substances and singling out the potentially worst offenders to be further studied in germ-line mutagenesis tests.

Animals↗
PubMed1979

Induction of lethal mutations in female mice by 9 generations of gamma-irradiation during foetal development.

Female CBA mice were chronically gamma-irradiated in utero during either of two periods, the 10th to 14th days or the 14th to 18th days of gestation. The doses administered were 34 rad/generation in the earlier group and 160 rad/generation in the latter with dose rates of 0.3 rad/h and 1.7 rad/h, respectively. The doses were given through 9 generations. The effect of the irradiation was expressed as an increased frequency in the rate of recessive lethal equivalents by just above 4%. This corresponds to a mutation rate of 1.5 X 10(-4) mutation/rad/genome in the animals irradiated during the 10th to 14th gestational days and 0.3 X 10(-4) mutation/rad/genome in the 14th to 18th day group. As in earlier investigations, neither dominant mutations nor dominance effects of induced recessive lethal equivalents were found.

Animals↗
PubMed1979

Increased frequencies of aberrant sperm as indicators of mutagenic damage in mice.

We have tested the effects of TEM in 3 strains of mice using the sperm morphology assay. In addition, we have made an attempt to evaluate this test system with respect to experimental design, statistical problems and possible interlaboratory differences. Treatment with TEM results in significant increases in the percent of abnormally shaped sperm. These increases are readily detectable in sperm treated as spermatocytes and spermatogonial stages. Our data indicate possible problems associated with inter-laboratory variation in slide analysis. We have found that despite the introduction of such sources of variation, our data were consistent with respect to the effects of TEM. Another area of concern in the sperm morphology test is the presence of "outlier" animals. In our study, such animals comprised 4% of the total number of animals considered. Statistical analysis of the slides from these animals have shown that this problem can be dealt with and that when recognized as such, "outliers" do not effect the outcome of the sperm morphology assay.

Animals↗
PubMed1978

Expression of TEM-induced damage to postmeiotic stages of spermatogenesis of the mouse during early embryogenesis. II. Cytological investigations.

After treatment of postmeiotic stages of spermatogenesis of the mouse with TEM (0.2 or 0.4 mg/kg), dose- and stage-of-spermatogenesis-dependent frequencies of cytogenetic aberrations can be observed in early embryos. The frequencies of first-cleavage metaphases exhibiting structural aberrations (all of the chromosome type), the frequencies of 2 cell embryos and of 4--8 cell embryos containing nuclei accompanied by micronuclei or nuclei connected by bridges show a close correlation to frequencies of preimplantation loss of embryos recorded in a dominant lethal test. The frequencies of morulae/blastulae exhibiting blastomeres with micronuclei show a close correlation to the frequencies of total (pre- and post-implantation) loss of embryos. This indicates delayed expression of TEM-induced chromosomal damage which could persist undetected in very early stages of embryogenesis.

Animals↗
PubMed1978

Expression of TEM-induced damage to postmeiotic stages of spermatogenesis of the mouse during early embryogenesis. I. Investigations with in vitro embryo culture.

After treatment of postmeiotic stages of spermatogenesis of the mouse with TEM, dose and stage of spermatogenesis-dependent disturbances of the early embryonic development can be observed both in vivo and after in vitro culture of the embryos. The observations in both systems can be correlated. The embryo-culture system thereby enables analysis of the expression of mutagen-induced damage more accurately than the in vivo dominant lethal test. With the doses used (0.2 and 0.4 mg/kg) TEM-treatment of the fathers did not affect the rate of fertilized and cleaving eggs during the first three weeks post-treatment but severely disturbed the further development of the embryos at all stages up to implantation, exhibiting a maximum effect on morulae.

Animals↗
PubMed1977

Triethylenemelamine induced dominant lethals in mice--comparisons of oral versus intraperitoneal injection.

We have compared the relative effectiveness of oral and i.p. injections of triethylenemelamine (TEM) in inducing dominant lethality in male mice. The standard dominant lethal protocol was used in these experiments. TEM, when injected i.p. resulted in significant increased in fetal mortality during the first three weeks post-treatment. Decreases in the number of implants per pregnant female were noted during this same period, with only minor decreases in fertility. In contrast, oral injections of TEM resulted in only fluctuations in the percent of fetal mortality. In addition, oral injections of TEM did not result in significant differences in either total implants or percent fertility. Possible causes of the observed differences between these two routes of administration are discussed.

Administration, Oral↗
PubMed1977

Postoperative physiotherapy device for mandibular hypomobility.

The most difficult problem in the treatment of ankylosis of the temporomandibular joint is to maintain the immediate jaw mobility gained by surgery over a long period of time. This article describes a spring-loaded device for physiotherapy which provides an active opening force from the mandibular splint, distributed against a splint on the maxillary teeth and hard palate. Because the force is continuous and broadly distributed, patients have been able to exercise with minimal discomfort, and they have been able to maintain their initial postoperative mobility.

Ankylosis↗
PubMed1975

Lack of induction of dominant lethals in mice by orally administered AF-2.

In a series of toxicity tests, male mice of three inbred strains were exposed to several doses of orally administered furylfuramide (AF-2). Subsequent to these test the effects of AF-2, as measured by induced dominant lethals, were tested in strain DBA/2J mice. AF-2 at the doses used in this study was relatively non-toxic to the strains of mice tested. No indication of AF-2 induced dominant lethality was observed.

Acrylamides↗
PubMed1975

Genetic effects of acute and chronic irradiation with 14 MeV neutrons.

Male CBA mice were exposed to 14.5 MeV neutron, either in an acute (150 or 250 rad) or a chronic dose (250 rad) and the genetic effects of the irradiations were compared. No detectable difference in the rate of mutations existed between acute and chronic exposure, with these neutrons.

Animals↗