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C S Johnson

Publications and source records attributed to C S Johnson.

At least 91 records · Page 5Linked to original sources
PubMed1990

The effect of adrenalectomy and dexamethasone on interleukin-1 alpha induced responses in RIF-1 tumours.

In the present studies the effect of bilateral adrenalectomy on the pathophysiologic responses to recombinant human interleukin-1 alpha (rHIL-1 alpha) was determined in RIF-1 tumour models. Acute vascular injury and haemorrhagic responses were quantitated by the intra-tumour accumulation of 59Fe radiolabelled erythrocytes. In vivo clonogenic tumour cell kill was determined by an excision assay. A single, intraperitoneal rHIL-1 alpha treatment (6.25 x 10(7) D10 units kg-1, 25 micrograms kg-1) resulted in acute tumour haemorrhage and approximately 55% clonogenic tumour cell kill (24 h). Bilateral adrenalectomy, 24 h before rHIL-1 alpha, significantly increased haemorrhagic responses, but haemodynamic toxicity was severe. This toxicity could be ameliorated by giving dexamethasone (5 mg kg-1) before or up to 3 h after rHIL-1 alpha. The effect of dexamethasone on rHIL-1 alpha induced tumour responses in adrenalectomised mice was sequence dependent. Given before rHIL-1 alpha, dexamethasone inhibited tumour haemorrhage. When dexamethasone was given up to 3 h after rHIL-1 alpha, tumour haemorrhage was directly related to sequence interval. Although adrenalectomy and dexamethasone alone had little effect on RIF-1 tumours, adrenalectomy increased rHIL-1 alpha mediated clonogenic tumour cell kill. The surviving fraction 24 h after rHIL-1 alpha (6.25 x 10(7) D10 units kg-1, 25 micrograms kg-1) and dexamethasone (5 mg kg-1, 2 h after rHIL-1 alpha) was 1.3 +/- 0.4%. The surviving fraction after this combination in intact mice (36.7 +/- 1.4%) was approximately 30-fold higher than that seen in adrenalectomised mice. The results indicate that adrenal responses secondary to rHIL-1 alpha treatment exert a negative feedback on rHIL-1 alpha mediated responses in solid tumours.

Adrenalectomy↗
PubMed1990

Transient stress lymphocytosis during crisis of sickle cell anemia and emergency trauma and medical conditions. An immunophenotyping study.

Transient absolute lymphocytosis of peripheral blood has been described in "stress"-related emergency trauma and medical conditions. There are no reports of this phenomenon in patients with sickle cell anemia with vaso-occlusive crisis. We studied initial and follow-up immunophenotypic characteristics of 10 adult patients with sickle cell anemia in crisis and 15 adult patients with emergency conditions who presented with absolute lymphocytosis. On admission, both groups demonstrated increases in the numbers of CD20+ B cells and T cells of the CD2, CD4, CD8, and CD56 (NKH-1) phenotypes compared with control values. Findings in both groups of patients mimicked the results of parenteral epinephrine administration: a pan-B and -T lymphocytosis with marked increase in CD56 (fourfold to fivefold) and CD8 cells (threefold to fourfold) as well as moderate increases in CD20 and CD4 cells (twofold), resulting in a decrease in the CD4/CD8 ratio compared with control values. In patients with sickle cell anemia, there was an expected increase in the CD56 and CD4 populations; however, CD8 cells only doubled at the time of crisis. Therefore, the CD4/CD8 ratio was normal compared with control values. CD20+ B cell numbers exceeded those seen in the patients with medical and trauma emergencies. Elevated corticosteroid levels have been measured after injury in previous studies. Parenterally administered cortisol produces a lymphocytopenia after 4 to 6 hours that selectively decreases T cells. At 10 to 38 hours after admission, there was a marked reduction in the number of T cells in both groups of "stressed" patients, probably reflecting at least partial effects of endogenous corticosteroids. In contrast to the patients with medical and trauma emergencies, the mean lymphocyte count in the patients with sickle cell anemia remained elevated in the "high normal" range and consisted of increased numbers of B cells and CD4 cells. This finding persisted in the patients with sickle cell anemia for up to 3 months after presentation. The lymphocyte responses in both groups probably reflect interactions between adrenergic and steroidal factors.

Acute Disease↗
PubMed1990

In vivo suppression of erythropoiesis by tumor necrosis factor-alpha (TNF-alpha): reversal with exogenous erythropoietin (EPO).

Tumor necrosis factor-alpha (TNF-alpha) selectively kills tumor cells in vitro and in vivo and is being tested as a cancer therapeutic agent. We have shown that TNF-alpha significantly suppresses late-stage erythropoiesis, leading to anemia in chronically treated mice. These erythropoietic effects could limit the clinical use of TNF-alpha. Therefore, we have examined whether erythropoietin (EPO) could be used to prevent TNF-alpha-induced erythroid suppression. Normal mice were treated with a single dose of recombinant murine TNF-alpha (10(5) U/mouse, i.p.) with and without various concentrations of recombinant human EPO. After 3 days, effects on late-stage erythropoiesis were measured by determining the number of mature erythroid colony-forming cells (CFU-E) in the spleen and bone marrow. Simultaneous treatment with EPO abrogated the suppressive effect of TNF-alpha in a dose-dependent manner. EPO treatment also prevented the decrease in peripheral blood-hematocrit that was observed with chronic (5 x 10(4) U/mouse/day for 5 days) administration of TNF-alpha. TNF-alpha-induced hemorrhagic necrosis of tumors and stimulation of macrophage (CFU-M) progenitors were unaffected by EPO treatment. These results demonstrate that simultaneous injection of EPO can abrogate the TNF-alpha-induced suppressive effects on erythropoiesis.

Anemia↗
PubMed1989

31P-nuclear magnetic resonance studies of the effect of recombinant human interleukin 1 alpha on the bioenergetics of RIF-1 tumors.

The effect of a single injection of human recombinant interleukin 1 alpha (IL-1 alpha) on s.c. RIF-1 tumors in mice was studied by in vivo 31P nuclear magnetic resonance spectroscopy. Spectra were obtained before and up to 24 h after IL-1 alpha. At 2, 4, 6, and 8 h after IL-1 alpha injection, RIF-1 tumors exhibited a reduction in bioenergetic status compared to untreated controls. The Pi to beta-nucleoside triphosphate and the phosphomonoester to beta-nucleoside triphosphate ratios increased, while the phosphocreatine to Pi and phosphodiester to phosphomonoester ratios decreased. Tumor blood flow, estimated by 86RbCl uptake, decreased within 30 min after IL-1 alpha treatment. Minimum perfusion was detected at 4 h, with recovery between 6 and 12 h after IL-1 alpha treatment. Histological sections of the RIF-1 tumors revealed intravascular congestion by 2 h, extravascular hemorrhage by 4 h, and necrosis by 12 h after treatment with IL-1 alpha. The time course of bioenergetic changes in RIF-1 tumors determined by 31P-NMR spectroscopy was found to parallel the reduction and subsequent recovery of tumor blood flow.

Animals↗
PubMed1989

In vivo hematopoietic effects of recombinant interleukin-1 alpha in mice: stimulation of granulocytic, monocytic, megakaryocytic, and early erythroid progenitors, suppression of late-stage erythropoiesis, and reversal of erythroid suppression with erythropoietin.

Interleukin-1 alpha (IL-1 alpha) is a macrophage-derived, multifunctional cytokine that broadly potentiates myelopoiesis and induces the synthesis of hematopoietic colony-stimulating factors (CSF) in vitro and in vivo. To evaluate the possibility for use of IL-1 alpha in ameliorating in vivo bone marrow suppression induced by drugs or radiation, we examined the in vivo effects of the cytokine on erythropoietic and other hematopoietic progenitor cells. Normal mice were treated with a single intraperitoneal (IP) injection of recombinant human IL-1 alpha at varying doses and were assayed at various times post-treatment. By six hours postinjection, a significant suppression of mature erythroid progenitors (CFU-E) was observed in animals treated with IL-1 alpha (0.5 micrograms/mouse), with maximum suppression of CFU-E and peripheral blood reticulocyte counts occurring at 24 hours. Decreases in peripheral blood hematocrit did not occur after a single IL-1 alpha injection but were observed after multiple injections of the cytokine. The suppressive effects of IL-1 alpha on late-stage erythropoiesis were abrogated by simultaneous administration of erythropoietin (EPO). At 48 hours post-treatment, a marked stimulation was observed in the numbers of spleen and marrow immature erythroid (BFU-E), macrophage (CFU-M), granulocyte (CFU-G), granulocyte-macrophage (CFU-GM), and megakaryocyte (CFU-meg) progenitor cells. These results demonstrate the potential use of IL-1 alpha as a generalized stimulator of hematopoiesis and show that the cytokine-induced suppression of late-stage erythropoiesis can be prevented by EPO.

Animals↗
PubMed1989

Multivariate outcome research in arthritis. Implications for sample sizes.

Planning appropriate sample sizes prior to data collection is critical to the overall success of a research project. However, the investigator often encounters practical limitations regarding the number of subjects available. While the literature discusses the various options of analysis of clinical trial data, there is little discussion as to the sample size implications of the statistical method chosen. Since the analysis technique employed affects the required sample size, the investigator should select the analysis that is most appropriate for the data and has the most efficient sample size requirement. This paper addresses the sample size implications of three commonly used methods for comparing two populations when there are two or more outcome measures (multivariate outcome). The concepts and methods are illustrated using a Pain Management Study that was conducted using people with rheumatoid arthritis as subjects.

Arthritis↗
PubMed1989

Effects of inhibitors and activators of protein kinase C on late erythroid progenitor (CFU-e) colony formation in vitro.

Protein kinase C (PKC) plays a central role in external signal transduction for many cell types. To examine the involvement of PKC in the control of erythropoiesis, we tested the effects of PKC inhibitors on in vitro colony formation by late erythroid progenitors (CFU-e) from normal and Friend virus-infected mice. Inhibitors of PKC and other kinases (H-7 and H-8) inhibited CFU-e at concentrations which inhibit PKC. HA1004, an inhibitor of the cyclic nucleotide-dependent kinases and a weak inhibitor of PKC, had little effect on CFU-e. In the absence of erythropoietin, a combination of phorbol ester and Ca++ ionophore significantly increased normal CFU-e. These results suggest PKC plays a role in the transduction of regulatory signals for the growth of CFU-e.

Animals↗
PubMed1989

Pharmacological modification of oxygen affinity improves deformability of deoxygenated sickle erythrocytes: a possible therapeutic approach to sickle cell disease.

1. The formation of polymerized haemoglobin S in sickle cells is critically dependent on the concentration of deoxygenated haemoglobin so that compounds which increase the oxygen affinity of haemoglobin S are potential anti-sickling agents. 2. BW12C [5-(2-formyl-3-hydroxyphenoxy)pentanoic acid] and BWA589C [4-(2-formyl-3-hydroxyphenoxymethyl)benzoic acid] are aromatic benzaldehydes that cause a dose-dependent left-shift of the oxygen saturation curve of haemoglobin S by stabilization of its oxy-(R)-conformation. 3. A 5 micron pore filtration method, which is highly sensitive to polymerization of haemoglobin S, was used to demonstrate a significant improvement in the deformability of deoxygenated sickle erythrocytes at concentrations (0.75-1.5 mmol/l] of BW12C and BWA589C that are achievable in vivo. Both compounds may therefore be of value for the treatment of sickle cell disease. 4. Filtration of sickle cells through pores of 5 microns diameter is a sensitive technique for evaluating the rheological effects of potential anti-sickling compounds.

Anemia, Sickle Cell↗
PubMed1989

Effect of polymerization tendency on haematological, rheological and clinical parameters in sickle cell anaemia.

The polymerization tendency of sickle haemoglobin was estimated as a function of oxygen saturation in 30 patients with homozygous sickle cell anaemia. The deformability of their erythrocytes was also measured, by initial-flow-rate filtration at 37 degrees C through pores of 5 microns diameter, and clinical severity was assessed using a visual analogue scale. By means of partial correlation analysis, it was found that correlations between haematological, rheological, and clinical parameters in sickle cell anaemia could be explained on the basis of an association of each variable with polymerization tendency. Patients with the greatest tendency to form polymer had the least deformable erythrocytes and perceived their disease to be more severe as judged by the visual analogue scale. Polymer formation also appeared to be a determinant of the number of dense cells which, in turn, determine haemolytic rate and erythrocyte deformability.

Anemia, Sickle Cell↗
PubMed1989

Masked tonal hearing thresholds in the beluga whale.

Masked tonal thresholds were measured for a beluga whale at one noise level and 32 frequencies between 40 Hz and 115 kHz. Critical ratios were estimated and compared with those previously measured for the bottlenose dolphin. Beluga whale critical ratios were found to be about 3 dB lower than those of the bottlenose dolphin. Absolute tonal thresholds were extended below previous measurements to 40 Hz.

Acoustic Stimulation↗
PubMed1989

Lymphokine-activated killer cell plus recombinant interleukin-2 therapy of erythroleukemia in mice.

The antileukemic effects of lymphokine-activated killer (LAK) cells plus recombinant interleukin-2 (rIL-2) therapy were assessed in mice with Friend virus (FV)-induced erythroleukemia. LAK cells were generated by incubating normal spleen cells for 72 hr in the presence of rIL-2 (1000 units/ml). At the time of injection, the LAK cells were cytotoxic in vitro against FV-infected fibroblasts and NK-sensitive and -resistant tumor targets but not normal controls. To determine in vivo activity, fully leukemic mice (spleen weight greater than 0.75 g) were injected with either PBS or LAK cells (10(8) cells/mouse IV at 14 and 17 days post virus) and rIL-2 (10,000 units/mouse IP every 8 hr on days 14 through 18 post virus). More than 70% of the progressively leukemic mice experienced permanent leukemia regressions (disease-free for greater than 100 days) following LAK cell plus rIL-2 therapy. Regressions were characterized by return of spleen and liver weights to normal and elimination of virus-infected erythroid (CFU-E) and macrophage (CFU-C) progenitor cells from spleen and marrow. Leukemic animals treated with either LAK cells alone or IL-2 alone experienced only transient leukemia regressions. These results demonstrate that LAK cell plus rIL-2 treatment can induce permanent regressions in progressively leukemic mice and provide a responsive and manipulable model system to elucidate the mechanisms involved in this form of immunotherapy.

Animals↗
PubMed1988

Antitumor effects of recombinant human interleukin 1 alpha in RIF-1 and Panc02 solid tumors.

The antitumor effects of recombinant human interleukin 1 alpha (IL-1) were determined in RIF-1 and Panc02 murine solid tumors. Acute tumor hemorrhage was observed in both models as early as 3 h after a single 25 micrograms/kg IL-1 treatment and was quantitated by the intratumor accumulation of 59Fe-labeled erythrocytes (RBC). The IL-1-mediated hemorrhagic response was maximal 6-12 h after treatment and greater in Panc02 tumors than in RIF-1 tumors. Hemorrhagic responses to RIF-1 tumors growing in athymic nude mice were similar to those seen for RIF-1 tumors in C3H/HeJ mice. This acute vascular injury was accompanied by progressive edema in tumors but not in skin or muscle. In RIF-1 tumors, the extracell water volume at 12 h after IL-1 (395 microI/g) was nearly twice that in untreated controls (215 microI/g). IL-1 also produced marked reductions in tumor blood flow as early as 1 h after treatment. Maximal blood flow restriction was seen at 6 h after IL-1. Although restricted blood flow was observed in tumors for up to 48 h, IL-1 effects on muscle, liver, and skin blood flow were transient with recovery by 12 h after treatment. IL-1 (up to 0.4 ng/ml for 72 h) was not toxic to RIF-1 tissue culture cells in vitro, but 0.2 ng/ml IL-1, for 20 h, reduced the clonogenicity of RIF-1 cells in primary explant cultures by approximately 50%. In vivo, the clonogenic cellularity of RIF-1 tumors was reduced by 70%, 24 h after a single 25 micrograms/kg treatment. Increased clonogenic cell proliferation was observed at 24 h, and rapid repopulation of the clonogenic cell population was seen by 48 h. Although IL-1 transiently slowed the growth of RIF-1 tumors, no significant regrowth delay was observed. In Panc02 tumors, cell proliferation was also inhibited after IL-1. Recovery, however, was delayed and occurred more slowly than in RIF-1 tumors. Significant growth inhibition and regrowth delay (5 days) was observed in Panc02 tumors after a single IL-1 treatment. The results of these studies show that IL-1 has significant effects on the pathophysiology of both RIF-1 and Panc02 tumors in vivo. Further, our results indicate that these effects may be mediated through the activation of a non T-cell, adherent cell population residing in the tumor at the time of IL-1 treatment.

Animals↗
PubMed1988

Association of microinjected myosin and its subfragments with myofibrils in living muscle cells.

Purified skeletal muscle myosin was labeled with iodoacetamidofluorescein and microinjected into cultured chick myotubes. The fluorescent myosin analogue became incorporated within 10-15 min after injection, into either periodic (mean periodicity = 2.23 +/- 0.02 micron) bands or apparently continuous fibrillar structures. Comparison of rhodamine-labeled alpha-actinin with coinjected fluorescein-labeled myosin suggested that myosin fluorescence was localized at the A-bands of myofibrils. In addition, close examination of the fluorescent myosin bands indicated that they were composed of two fluorescent bars separated by a nonfluorescent line that corresponded to the H-zone. Once incorporated, the myosin underwent a relatively slow exchange along myofibrils as indicated by fluorescence recovery after photobleaching. Glycerinated myofibrils were able to bind fluorescent myosin in a similar pattern in the presence or absence of MgATP, indicating that actin-myosin interactions had little effect on this process. Fluorescent heavy meromyosin did not incorporate into myofibrillar structures after injection. Light meromyosin, however, associated with A-bands as did whole myosin. These results suggest that microinjected myosin, even with its relatively low solubility under the cytoplasmic ionic condition, is capable of association with physiological structures in living muscle cells. Additionally, the light meromyosin portion of the molecule appears to be mainly responsible for the incorporation.

Adenosine Triphosphate↗
PubMed1988

In vivo hematopoietic effects of tumor necrosis factor-alpha in normal and erythroleukemic mice: characterization and therapeutic applications.

The effects of recombinant, macrophage-derived, murine tumor necrosis factor-alpha (TNF-alpha) on hematopoiesis in vivo has been examined in normal mice and in Friend virus (FV)-induced erythroleukemic mice. Intravenous (IV) administration of a single dose of recombinant murine TNF-alpha (10(5) U per mouse) significantly suppressed normal and leukemic late-stage erythropoiesis as measured by numbers of mature erythroid colony forming cells (CFU-E) in the bone marrow and spleen and by peripheral blood reticulocyte counts. In normal animals, the immature erythroid (BFU-E), macrophage (CFU-M), and granulocyte-macrophage (CFU-GM) compartments were significantly stimulated by TNF-alpha in both the bone marrow and the spleen. In the bone marrow of leukemic mice, the BFU-E, CFU-GM, and CFU-M progenitor cell compartments were also stimulated by treatment with the monokine. In the spleens of leukemic mice (the primary site of FV leukemia cell accumulation), relative numbers of BFU-E and CFU-GM were increased by TNF-alpha, while those of CFU-M were suppressed. TNF-alpha caused a rapid decrease in the markedly elevated spleen weights of progressively leukemic mice, and in multiple doses it caused complete clinical disease regression in a significant percentage of leukemic animals. The combination of TNF-alpha with interferon-gamma (IFN-gamma) increased the incidence of leukemia regression, compared with TNF-alpha alone. These results show that TNF-alpha exerts a suppressive influence on late-stage erythropoiesis in vivo and suggest that this effect might be exploited in the treatment of acute erythroleukemia, erythroid hyperplasias, and related diseases.

Animals↗
PubMed1988

Rheologic impairment of sickle RBCs induced by repetitive cycles of deoxygenation-reoxygenation.

The transformation of less-dense, discoidal homozygous sickle cells (HbSS) RBCs into dehydrated, rheologically impaired cells is believed to be an important factor in the pathophysiology of sickle cell disease. We investigated this process by subjecting the less-dense fraction of HbSS RBCs, which contains a low percentage of irreversibly sickled cells (ISCs), to cyclic deoxygenation-reoxygenation for 15 hours at 37 degrees C. This incubation procedure caused cell shrinkage, shifts in intracellular Na and K content, and formation of ISCs that closely resembled endogenous ISCs found in sickle blood. The viscoelasticity of the treated cells was tested using micropipette techniques to measure the membrane shear elastic modulus (mu) and the time constant for extensional shape recovery (tc); mu represents the "static rigidity" of the cells, and the product mu.tc was taken as a measure of their "dynamic rigidity". Density separation of the incubated cells showed that their rheologic impairment (ie, elevation of both static and dynamic rigidities) paralleled cellular dehydration and that the newly formed dense cells had viscoelastic characteristics very similar to those of endogenous dense cells. Rehydration by osmotic swelling tended to normalize the dynamic rigidities of dense cells but had no significant effect on their static rigidities. Thus, cellular dehydration contributes to the observed changes of viscoelasticity, although an irreversible alteration of membrane structure also appears to be involved. Dense ISCs could be formed without added calcium, implying that entry of external calcium is not an essential requirement for cellular dehydration; ISCs formed without calcium tended to be less rigid (ie, to have lower static and dynamic rigidities) than those formed with calcium. Our results indicate that the cyclic incubation procedure closely mimics RBC rheologic deterioration in vivo and thus suggest its usefulness as a model for investigating this phenomenon.

Anemia, Sickle Cell↗
PubMed1987

Iron deficiency occurs frequently in patients with pernicious anemia.

We assessed iron status in patients with pernicious anemia. Iron deficiency coexisted as a presenting finding in 25 (20.7%) of 121 patients for whom data could be evaluated. Another 27 patients (22.3%) developed iron deficiency one month to 14 years later (median, two years). It was impossible to predict such a development in these 27 patients from any of their initial findings. The cause of the iron deficiency was identified in 17 of the 52 iron-deficient patients and suspected in another four. These findings show that patients with pernicious anemia are at high risk for iron deficiency, both at initial presentation and subsequently. Although the cause of the iron deficiency is often not identifiable, clinically important entities are detected often enough to warrant routine investigation for iron deficiency in such patients.

Adult↗
PubMed1987

Rheology of the sickle cell disorders.

The sickling process causes secondary changes in cell shape, size, cation and water content, and membrane structure that contribute to the impairment of intrinsic cell deformability (Figure 2). This rheological defect is partially compensated by a low haematocrit, which moderates the rise in whole-blood viscosity, and by a rise in cardiac output which increases capillary flow velocity (Berger and King, 1982). A delicate balance exists between these mechanisms and any local disturbance of this balance by pathological changes in factors extrinsic to the sickle cell (Figure 2) can precipitate vaso-occlusion. There is still considerable controversy over the site (arteriolar, capillary, or venular) of vaso-occlusion, the type of sickle cell (reversibly sickled or irreversibly sickled) that is primarily involved, and the relative importance of extra-erythrocytic precipitating factors such as stasis, hypoxia, hyperosmolality, acidosis, alteration in temperature, acute-phase rise in plasma proteins and leukocytes, prothrombotic changes in coagulation factors and platelets, and adhesion of blood cells to vascular endothelium (Figure 2). A low-grade hypercoagulable state has been described in patients with SS (Leichtman and Brewer, 1978; Richardson et al, 1979) which may be related to the procoagulant effect of the shift of phosphatidyl serine to the outer lipid bilayer of the sickle cell (Chiu et al, 1981; Franck et al, 1985). Platelets appear to accumulate at sites of vaso-occlusion (Siegel et al, 1985) and their migration to the vessel wall may be enhanced by the presence of poorly deformable erythrocytes (Aarts et al, 1984). Endothelial cell damage in the arterial or venous circulation may also contribute (Klug et al, 1982). Thus vaso-occlusion appears to result from a complex interaction between blood cells, plasma proteins and endothelium and any one of several precipitating factors may disturb the fragile steady state and cause a painful crisis. The study of sickle cells by rheological methods has considerable potential for investigating the pathophysiology of vaso-occlusive episodes in the SCD and for monitoring, both in vitro and ex vivo, the efficacy of antisickling compounds. Because of the multiple intrinsic and extrinsic factors that contribute to the rheological defect, it is not yet known which of these should be the primary target for an antisickling agent. In-vitro rheological studies in which different metabolic stresses can be applied to intact sickle cells in the presence of a putative antisickling drug should help to answer this question.(ABSTRACT TRUNCATED AT 400 WORDS)

Anemia, Sickle Cell↗