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Biomedical subjects

D E Williams

Publications and source records attributed to D E Williams.

At least 145 records · Page 8Linked to original sources
PubMed1993

Altered metabolism of mast-cell growth factor (c-kit ligand) in cutaneous mastocytosis.

BACKGROUND AND METHODS: The lesions of cutaneous mastocytosis are characterized by dermal infiltrates of mast cells and may appear hyperpigmented because of the presence of increased levels of epidermal melanin. Mast-cell growth factor, the ligand for the product of the c-kit proto-oncogene, stimulates the proliferation of mast cells and increases the production of melanin by melanocytes. We therefore looked for the expression of the mast-cell growth factor gene in the skin of patients with cutaneous mastocytosis using immunohistochemical techniques and the polymerase chain reaction. RESULTS: In the skin of normal subjects and those with unrelated diseases, immunoreactive mast-cell growth factor was associated with keratinocytes and scattered dermal cells, a pattern consistent with cell-bound mast-cell growth factor. In skin samples containing lesions and in clinically normal skin from patients with mastocytosis, however, mast-cell growth factor was also found free in the dermis and in the extracellular spaces between keratinocytes, suggesting the presence of a soluble form of this protein. Messenger RNA (mRNA) that can encode soluble mast-cell growth factor was present in the skin of patients as well as in that of normal control subjects. No sequence abnormalities were detected in mRNA for mast-cell growth factor from one patient. CONCLUSIONS: The altered distribution of mast-cell growth factor in the skin of patients with cutaneous mastocytosis is consistent with abnormal production of the soluble form of this factor. This abnormality is probably due to increased proteolytic processing, since it was not explained by differences in the splicing or sequence of mast-cell growth factor mRNA in the patients. Soluble mast-cell growth factor may cause the characteristic accumulation of mast cells and the hyperpigmentation of skin found in cutaneous mastocytosis. These findings suggest that some forms of mastocytosis represent reactive hyperplasia rather than mast-cell neoplasia.

Adult↗
PubMed1993

Protective effects of recombinant human interleukin-1 alpha in doxorubicin-treated normal and tumor-bearing mice.

Experiments were performed to determine whether treatment with recombinant human IL-1 alpha (rhuIL-1 alpha) would protect C3H mice from the toxic effects of the widely used chemotherapeutic agent, doxorubicin (DXR). Pretreatment of mice with rhuIL-1 alpha was found to protect 85-90% of mice tested from the acute toxic effects of a lethal dose of doxorubicin (25 mg/kg). Late deaths (> 20 days post-DXR) were observed in a substantial proportion (40-45%) of rhuIL-1 alpha-pretreated mice. However, the data clearly demonstrate a beneficial effect of rhuIL-1 alpha pretreatment on the overall survival of mice challenged with DXR, since both the median survival (32 days) and proportion (53%) of surviving mice were significantly increased (P < 0.0001) compared to the control group (8 days and 14%, respectively). The beneficial effects mediated by rhuIL-1 alpha treatment were both dose- and schedule-dependent and were associated with decreases in the level and duration of DXR-induced neutropenia, and amelioration of the suppressive effects of DXR on myeloid progenitor cells (granulocyte/monocyte colony forming units) as evidenced by milder depressions in marrow cellularity and enhanced recovery of granulocyte/monocyte colony forming unit activity. Finally, pretreatment of mice bearing a solid tumor with rhuIL-1 alpha permitted effective dose escalation with DXR that resulted in decreased tumor growth rates and increased survival (90%) as compared to non-rhuIL-1 alpha-treated groups (20% survival). Thus, effective chemotherapeutic dose escalation is made feasible by rhuIL-1 alpha pretreatment of mice, but may ultimately be limited by nonhematological toxicities associated with DXR.

Animals↗
PubMed1993

Induction of flavin-containing monooxygenase (FMO B) in rabbit lung and kidney by sex steroids and glucocorticoids.

Modulation of lung and kidney levels of flavin-containing monooxygenase (FMO) isoform B following sc administration of dexamethasone, progesterone, beta-estradiol, aldosterone, or beta-estradiol plus progesterone was examined in male rabbits. Both dexamethasone and progesterone increased FMO B protein levels in lung. N-Oxygenation of N,N'-dimethylaniline (DMA) was significantly induced in lung microsomes from rabbits treated with progesterone. In kidney, only dexamethasone was effective in inducing FMO B protein levels and DMA N-oxygenation. Surgical implantation of osmotic pumps containing beta-estradiol or progesterone into non-pregnant female rabbits resulted in elevated plasma levels of these steroids after 4-5 days at which point the lung levels of FMO B were induced by 35 and 82% for beta-estradiol and progesterone, respectively. The responsiveness of FMO B in lung to both progesterone and glucocorticoids and in kidney to only the latter is consistent with the developmental pattern of both maternal FMO B and peak plasma levels of these steroids during pregnancy.

Aldosterone↗
PubMed1993

Mast cell growth factor (C-kit ligand) in combination with granulocyte-macrophage colony-stimulating factor and interleukin-3: in vivo hemopoietic effects in irradiated mice compared to in vitro effects.

In the presence of hemopoietic cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), mast cell growth factor (MGF; also known as steel factor, stem cell factor, and c-kit ligand) has proven to be a potent hemopoietic regulator in vitro. In these studies, we examined the in vivo effects of MGF in combination with GM-CSF or GM-CSF plus IL-3. Effects were based on the ability of these cytokines to stimulate recovery from radiation-induced hemopoietic aplasia. Female B6D2F1 mice were exposed to a sublethal 7.75-Gy dose of 60Co radiation followed by subcutaneous administration of either saline, recombinant murine (rm) MGF (100 micrograms/kg/day), rmGM-CSF (100 micrograms/kg/day), rmIL-3 (100 micrograms/kg/day), or combinations of these cytokines on days 1-17 postirradiation. Recoveries of bone marrow and splenic spleen colony-forming units (CFU-s), granulocyte macrophage colony-forming cells (GM-CFC), and peripheral white blood cells (WBC), red blood cells (RBC) and platelets (PLT) were determined on days 14 and 17 during the postirradiation recovery period. MGF administered in combination with GM-CSF or in combination with GM-CSF plus IL-3 either produced no greater response than GM-CSF alone or down-regulated the GM-CSF-induced recovery. These results sharply contrasted results of in vitro studies evaluating the effects of these cytokines on induction of GM-CFC colony formation from bone marrow cells obtained from normal or irradiated B6D2F1 mice, in which MGF synergized with GM-CSF or GM-CSF plus IL-3 to increase both GM-CFC colony numbers and colony size. These studies demonstrate a dichotomy between MGF-induced effects in vivo and in vitro and emphasize that caution should be taken in attempting to predict cytokine interactions in vivo in hemopoietically injured animals based on in vitro cytokine effects.

Animals↗
PubMed1993

Chemical and biological evidence links microcystins to salmon 'netpen liver disease'.

Evidence is presented that links microcystins to a severe liver disease that occurs in Atlantic salmon that are netpen-reared in coastal British Columbia. Liquid chromatography-linked protein phosphatase bioassay analysis of extracts of liver tissue taken from Atlantic salmon afflicted with netpen liver disease showed the presence of an inhibitor of protein phosphatase that was chromatographically indistinguishable from microcystin-LR. Analysis of liver tissue from healthy control fish showed a complete absence of microcystin-LR. Intraperitoneal injection of microcystin-LR into healthy Atlantic salmon re-created the pathologic changes of netpen liver disease, including diffuse necrosis and hepatic megalocytosis.

Animals↗
PubMed1993

Hepatocarcinogenic potency of mixed and pure enantiomers of trans-7,8-dihydrobenzo[a]pyrene-7,8-diol in trout.

The hepatocarcinogenic potency of pure and racemic trans-7,8-dihydrobenzo[a]pyrene-7,8-diol was investigated in embryos and sac-fry rainbow trout. Embryos microinjected with (+/-)-trans-7,8-dihydrobenzo[a]pyrene-7,8-diol ((+/-) BP-7,8-DHD) developed liver tumors 9 months after hatching. However, this exposure protocol resulted in high mortalities. Microinjection of newly hatched sac-fry with 0.01-1.0 microgram of (+/-) BP-7,8-DHD resulted in a dose-dependent production of liver tumors (0-13%) similar to the results with embryos but without the problem of high mortalities. Co-injection of sac-fry with (+/-) BP-7,8-DHD and either beta-naphthoflavone or carbon tetrachloride significantly enhanced the tumor response (approx. 3-fold). The relative carcinogenic potencies of the pure (+) and (-) enantiomers of BP-7,8-DHD were evaluated by microinjection into sac-fry at doses of 0.5-5.0 micrograms. The results demonstrated that the (-) enantiomer was 4-18 times more potent than the (+). Mixed carcinomas were the most prevalent liver tumors observed. These results demonstrate that trout embryos and sac-fry are both responsive to hepatocarcinogenesis initiation by injection with BP-7,8-DHD. The marked enhancement seen with co-injection of sac-fry with beta-naphthoflavone or carbon tetrachloride suggests that both cytochrome P-450-dependent and lipid peroxidation-dependent pathways could be involved in bioactivation of this compound, presumably through epoxidation at the 9,10-position. As is the case with mammals, the (-) enantiomer of BP-7,8-DHD is a more potent carcinogen than the (+) enantiomer.

Animals↗
PubMed1993

The etiology of lung cancer.

The association between tobacco smoking and lung cancer has been noted for more than 50 years and continues to dominate the etiologic milieu of this malignant disease. Other agents, many discovered in the occupational setting, have also been substantiated as lung carcinogens. Inherent predisposition to the disease has long been suspected, and recent investigations suggest several potential mechanisms and a possible mode of inheritance. Considerable progress has been made in deciphiring the molecular defects present in lung cancer cells. These recent findings have been incorporated into two well-known models of lung carcinogenesis. As the details of the carcinogenic process are unraveled, one goal is to identify intermediate (preneoplastic) markers of exposure and inherent predisposition that will help assess the risk of lung cancer for individuals as well as for groups.

Causality↗
PubMed1993

Factor structure of the Motivation Assessment Scale.

The Motivation Assessment Scale (MAS) was developed to provide clinical information on four hypothesized functions that may control problem behaviour in persons with developmental disabilities. The original four-factor structure of the MAS was based on face validity, with the items being grouped in terms of each of the hypothesized functions. Validation of the scale was provided in terms of correlations between teacher ratings of eight children on the MAS and ranking of the controlling variables from functional analogue tests. In this study, staff in residential facilities rated 60 residents and teachers in schools rated 96 students on the MAS. The target behaviour rated for both samples was self-injury, with the institutional sample engaging in the behaviour more than 15 times an hour and the school sample, less than 15 times an hour. The results of factor analyses, with varimax rotation, provided a conceptually meaningful factor structure with the institutional sample, but not with the school sample. The 16 MAS items resolved into four factors that were conceptually related to four conditions that may maintain problem behaviour (i.e. sensory, escape, attention and tangible). The results suggested that the original MAS has a robust factor structure and may be clinically useful in predicting the controlling functions of problem behaviours, if the target behaviours occur at a rate no less than 15 responses per hour.

Adult↗
PubMed1993

Psychophysiological and MMPI personality assessment of headaches: an integrative approach.

Multiple psychophysiological measures and personality assessment techniques were combined to facilitate the diagnosis of headache type and improve upon existing methodology. Twenty-four migraine, 24 chronic tension headache patients, and 24 normal age- and gender-matched controls were assessed with bilateral measures of frontalis and occipitalis EMG and blood volume pulse. All subjects completed the MMPI. Results suggest that headache subjects could be differentiated on baseline heart rates and MMPI scales 1,2,3, and 7. Only one physiological measure served as an index of psychological distress, suggesting issues of an interaction between psychophysiological and personality variables, as well as the chronicity of the headache.

Adult↗
PubMed1993

Mycobacterium avium-intracellulare complex: evaluation with CT.

Pulmonary Mycobacterium avium-intracellulare (MAI) complex has been reported with increasing frequency, but computed tomographic (CT) evaluation of pulmonary MAI complex has been seldom reported. The authors retrospectively reviewed chest CT examinations performed in 62 patients with positive MAI cultures within 1 month of CT. Of the 62 patients, 40 had bronchiectasis and 60 had infiltrates, usually of the nodular variety (39 patients). All 35 patients with small nodular infiltrates had bronchiectasis. These 35 patients did not have concurrent malignancy or clinical evidence of immunocompromise, and 29 (83%) of them were women (mean age, 66 years). Of the 27 patients without small nodular infiltrates and bronchiectasis, 25 had underlying malignancy or immunocompromise. The predominance of older women without underlying malignancy or immunocompromise but with findings of small nodular infiltrates and bronchiectasis at chest CT may indicate such patients to be a subtype of patients with pulmonary MAI complex.

Adult↗
PubMed1993

Biology and behavior. A set-point hypothesis of psychological functioning.

This article provides a broad overview of an exploratory thesis designed to enhance an understanding of perturbations and rigidities of psychological functioning--a set-point hypothesis of psychological functioning. Historical precedents and parallels with Keesey's set-point theory of obesity are offered. Basic tenets of the hypothesis are detailed, and relevance to clinical behavioral theory is outlined. It is concluded that the set-point hypothesis may provide a framework for conceptualizing clinical cases and optimizing interventions. The thesis appears to be testable; however, the articulation of specific methodologies and research designs must be undertaken before the ultimate usefulness of the set-point hypothesis can be determined.

Adaptation, Psychological↗
PubMed1993

Cerebral flavin-containing monooxygenase-mediated metabolism of antidepressants in brain: immunochemical properties and immunocytochemical localization.

Flavin-containing monooxygenase (FMO)-mediated oxidation of the model substrates N,N-dimethylaniline and methimazole, and the antidepressants imipramine and fluoxetine, was determined in rat brain microsomes. No sex-related difference was observed in the activity of the FMO-mediated metabolism of the four substrates examined. The Km values for flavin-containing monooxygenase-mediated metabolism of N,N-dimethylaniline and methimazole were 2.8 and 0.8 mM, respectively, and the Km values for the oxidation of the antidepressants imipramine and fluoxetine were 20.9 and 9.8 microM, respectively. The Vmax values for oxidation of N,N-dimethylaniline, methimazole, imipramine and fluoxetine were 340, 31, 182 and 470 nmol nicotinamide adenine dinucleotide phosphate oxidized/min/mg protein, respectively. Western immunoblot analysis using antisera to purified porcine liver FMO did not reveal any immunological cross-reactivity with male or female brain microsomal protein. Antibody to rabbit lung flavin-containing monooxygenase cross-reacted with brain microsomes as examined by Western immunoblot studies. Addition of the antibody raised against rabbit lung FMO resulted in inhibition (43% inhibition) of the FMO-mediated metabolism of imipramine. Immunocytochemical examination of rat brain sections using the above antibody revealed the preferential localization of flavin-containing monooxygenase in the neuronal cell body. The flavin-containing monooxygenase-mediated metabolism of antidepressant drugs by brain microsomes is of profound pharmacological significance.

Animals↗
PubMed1992

Thymus reconstitution by c-kit-expressing hematopoietic stem cells purified from adult mouse bone marrow.

The introduction of clonal assays and long-term culture systems has resulted in considerable progress in the understanding of the early events that control self-renewal and commitment to differentiation of pluripotent hematopoietic stem cells (PHSC). Relatively little is known about the factors that control the commitment of PHSC to the lymphoid lineages, especially the T cell lineage. In the present study, the expression of the proto-oncogene c-kit was used to isolate and study the capacity of highly purified day 14 colony-forming units-spleen (CFU-S) to reconstitute the thymus of sublethally irradiated Thy-1 congenic recipient mice. We demonstrate here that one c-kit positive (c-kitpos) stem cell upon intrathymic transfer can effectively reconstitute the thymus of a sublethally irradiated recipient. After a lag phase of 15 d, high levels of donor-derived thymocytes (Thy-1.1pos) could be detected until 65 d after transplantation in Thy-1.2pos host mice. Donor-derived cells were only detected in the lobe of the thymus in which cells were previously injected and not in the noninjected lobe. These data suggest that c-kitpos stem cells do not migrate from one lobe to another and that they do not re-seed the thymus after having migrated to the bone marrow. The level and duration of reconstitution was found to be cell dose dependent, suggesting that, over time, endogenous stem cells compete with donor stem cells for available sites in the thymus microenvironment. The data presented in this paper demonstrate that commitment of purified adult bone marrow-derived c-kitpos stem cells to the T cell differentiation pathway can occur in the thymus and does not have to happen in the bone marrow.

Animals↗
PubMed1992

Influence of recombinant human interleukin (IL)-7 on disease progression in mice infected with Friend virus complex.

Recombinant human (rhu) IL-7 was evaluated for its influence on disease progression in mice infected with the polycythemia-inducing strain of the Friend virus complex (FVC). DBA/2 mice were injected i.v. with FVC, and then treated s.c. with rhuIL-7. IL-7 significantly prolonged survival time and decreased spleen focus-forming virus (SFFV) levels, expression of SFFV mRNA and SFFV protein production in FVC-infected mice. IL-7 did not appear to directly inactivate SFFV. Although both splenic weight and cellularity in FVC-infected mice treated with IL-7 were higher than those of normal mice, they were respectively 58% and 66% lower than those of the untreated FVC-infected mice. NK-cell activity was substantially lower in FVC-infected mice than in normal mice, while IL-7 restored NK-cell activity to normal levels. IL-6 and IFN-gamma levels were markedly reduced in FVC-infected mice compared to normal mice, but treatment of FVC-infected mice with IL-7 restored these cytokine levels. While the actual mechanisms of these effects are not yet known, the results suggest the potential therapeutic efficacy of IL-7 for certain hematopoietic and viral disorders, possibly mediated through an action on accessory cells and cytokine production.

Animals↗
PubMed1992

Effect of mast cell growth factor (c-kit ligand) on clonogenic leukemic precursor cells.

Mast cell growth factor (MGF), the ligand for the c-kit receptor, has been shown to be a hematopoietic growth factor that preferentially stimulates the proliferation of immature hematopoietic progenitor cells (HPC). We studied the effect of MGF on the in vitro growth of clonogenic leukemic precursor cells in the presence or absence of interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and/or erythropoietin (EPO). Leukemic blood and bone marrow cells from patients with various types of acute myeloid leukemia (AML), chronic myeloid leukemia (CML) in chronic phase, as well as bone marrow samples from patients with myelodysplastic syndromes (MDS) were studied. MGF as a single factor did not induce significant colony formation by clonogenic leukemic precursor cells. In the presence of IL-3 and/or GM-CSF, MGF weakly stimulated the colony formation by clonogenic precursor cells from patients with AML. In contrast, in the presence of IL-3 and/or GM-CSF, MGF strongly induced both size and number of leukemic colonies from patients with CML in chronic phase. Furthermore, in the presence of EPO, MGF strongly stimulated erythroid colony formation by CML precursor cells. Cytogenetic analysis of the colonies showed that all metaphases after 1 week of culture were derived from the leukemic clone. In patients with MDS, MGF strongly stimulated myeloid colony formation in the presence of IL-3 and/or GM-CSF (up to fourfold), and erythroid colony formation in the presence of EPO (up to eightfold). Not only the number, but also the size of the colonies increased. In the presence of MGF, the percentage of normal metaphases increased in three patients tested after 1 week of culture compared with the initial suspension, suggesting that the normal HPC were preferentially stimulated compared with the preleukemic precursor cells. In the absence of exogenous EPO and in the presence of 10% human AB serum, MGF in the presence of IL-3 and/or GM-CSF induced erythroid colony formation from normal bone marrow and patients with MDS or CML, illustrating that MGF greatly diminished the EPO requirement for erythroid differentiation. These results indicate that MGF may be a candidate as a hematopoietic growth factor to stimulate normal hematopoiesis in patients with acute myeloid leukemia, or with myelodysplastic syndromes.

Acute Disease↗
PubMed1992

Influence of steel factor on hemoglobin synthesis in sickle cell disease.

A new hematopoietic growth factor (Steel factor) has been identified which stimulates erythroid proliferation both in vitro and in vivo. We evaluated the influence of recombinant Steel factor on hemoglobin synthesis in peripheral blood (PB) BFU-E-derived cells from normal donors by radioimmunoassay (RIA) and compared it with stimulation with GM-CSF and interleukin-3 (IL-3). Only Steel factor stimulated a significant increase in BFU-E-derived colony size and a significant increase in fetal hemoglobin (HbF) in BFU-E-derived erythroblasts from 0.49% +/- 0.27% to 6.33% +/- 1.11% in serum-deprived media and from 1.88% +/- 0.24% to 11.17% +/- 0.91% in serum. To determine whether this influence on hemoglobinization also occurred in sickle cell disease, we studied 13 patients with sickle cell disease. In serum-deprived conditions, there was a significant increase in the number and size of BFU-E-derived colonies with Steel factor that was dose-dependent. In addition, the proportion of HbF in progenitor-derived cells increased by 66% from 4.1% +/- 0.6% to 6.8% +/- 1.2% with Steel factor. In serum-containing conditions studied in 12 patients, the increase in percentage of HbF was even greater, from 10.7% +/- 0.9% in control cultures to 22.5% +/- 2.6% with Steel factor. These increases in percentage of HbF were significant and dose-dependent. An increase in percentage of HbF was observed in erythroblasts harvested on day 11, 14, and 18 of culture. A decrease in mean picograms of total Hb per cell after coculture with Steel factor was noted, suggesting that growth kinetics influenced complete hemoglobinization. In serum-deprived conditions, picograms of HbF per cell was not affected by Steel factor, and in serum-containing conditions that augment in vitro HbF production it was enhanced. Thus, Steel factor stimulated a significant increase in percentage of HbF in erythroid cells from normal donors and patients with SCA in vitro.

Anemia, Sickle Cell↗