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Biomedical subjects

S Nelson

Publications and source records attributed to S Nelson.

At least 19 recordsLinked to original sources
PubMed1992

In vivo metabolic response of hepatic nonparenchymal cells and leukocytes to granulocyte-macrophage colony-stimulating factor.

This study investigates the in vivo glucose utilization of various immune-competent cells after an intra-arterial injection of a nonlethal dose (30 micrograms/kg body weight) of murine recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF). Injection of GM-CSF resulted in a rapid but transient reduction in the number of circulating neutrophils. After 20 min the number of neutrophils returned to normal values, and by 4 h it was about 80% greater than in time-matched saline-injected controls. One hour after the treatment, neutrophils were accumulated in the livers of GM-CSF-injected animals but not in control livers. In vivo glucose utilization by circulating neutrophils and mononuclear cells and various liver cell types was investigated by combining the 2-deoxyglucose tracer technique with cell isolation procedures. GM-CSF increased the in vivo glucose utilization of circulating and infiltrating neutrophils by more than 200%. Glucose utilization by circulating mononuclear cells was also doubled. After GM-CSF injection, glucose utilization by Kupffer cells was increased by 130% and by hepatic endothelial cells was increased by 60%. Indomethacin pretreatment blunted the hyperglycemia caused by GM-CSF injection; however, it did not inhibit the increased glucose utilization by immune-competent cells. This suggests that the effect of GM-CSF on glucose utilization by these cells is not mediated by prostanoids and is at least partially independent of the mass action of elevated glucose concentration. These findings indicate that GM-CSF may be an important member of the cytokine cascade that mediates the acute in vivo metabolic response of immune-competent cells in sepsis or endotoxemia.

Animals↗
PubMed1992

Contrasting effects of misoprostol on systemic and intrapulmonary lipopolysaccharide-induced tumor necrosis factor-alpha.

Tumor necrosis factor-alpha (TNF), a cytokine produced by mononuclear phagocytes in response to lipopolysaccharide stimulation, is a potent mediator of the inflammatory cascade. However, the immunomodulatory signals regulating TNF expression in the host are poorly defined. Recently, metabolites of the prostaglandin E series have been shown to inhibit TNF production in vitro. In order to determine if PGE1 alters TNF activity in vivo, rats were given misoprostol, a synthetic PGE1 analogue, or saline by gavage and subsequently challenged with either intravenous or intratracheal Escherichia coli lipopolysaccharide. These in vivo data show that PGE1 is a potent inhibitor of TNF production by systemic mononuclear phagocytes. In contrast, alveolar macrophages appear to be refractory to misoprostol's suppressive effects on LPS-induced TNF. This study supports in vitro observations that mononuclear phagocytes within different compartments exhibit differential responsiveness to immunomodulators.

Animals↗
PubMed1992

A new scale for assessing behavioral agitation in dementia.

The primary purpose of the present study was to develop a reliable and valid rating instrument for assessing treatment efficacy for behavioral problems in the cognitively impaired elderly. The Behavioral and Emotional Activities Manifested in Dementia (BEAM-D) Scale was developed for the operational assessment of troublesome and disruptive behaviors in dementia. Each behavioral category of the BEAM-D was clinically considered to be a significant deviation from normative behavior for the geriatric dementia patient. The reliability and validity of the BEAM-D was assessed in a group of 45 patients diagnosed with primary degenerative dementia. The mean interrater reliability of BEAM-D items was 0.90. Concurrent validity was established by comparison with currently used rating scales, the Brief Psychiatric Rating Scale (BPRS) and the Sandoz Clinical Assessment-Geriatric (SCAG). Stepwise regression analysis revealed that the items of the BEAM-D had a strong relationship with conceptually similar behavioral dimensions on the BPRS and SCAG.

Aged↗
PubMed1992

Epitope mapping of monoclonal antibodies to Torpedo acetylcholine receptor gamma subunits, which specifically recognize the epsilon subunit of mammalian muscle acetylcholine receptor.

Epitopes for four monoclonal antibodies (mAbs) to the gamma subunit of Torpedo nicotinic acetylcholine receptor (AChR), and one mAb crossreactive with the gamma and delta subunits of Torpedo AChR were mapped using overlapping synthetic peptides corresponding to the complete amino acid sequence of Torpedo gamma subunit. The epitopes for all mAbs were within a 50 residue sequence region, on the cytoplasmic surface of the AChR. Three mAbs crossreacted with mammalian muscle AChRs. Two of them specifically recognized the epsilon subunit of AChRs at adult neuromuscular junction. The epsilon-specific mAbs were used, in conjunction with mAbs specific for the alpha and beta subunits and anti-peptide antisera specific for the epsilon, gamma and delta subunits, to identify in Western blots the subunit complement of embryonic and adult bovine muscle AChRs.

Amino Acid Sequence↗
PubMed1992

Effect of granulocyte colony-stimulating factor on sepsis-induced changes in neutrophil accumulation and organ glucose uptake.

Neutropenia was seen in rats made septic by subcutaneous (sc) injection of Escherichia coli. The sepsis-induced increase in glucose uptake by tissues distant from the site of infection was not associated with increased myeloperoxidase (MPO) activity. Only the skin and muscle at the site of infection demonstrated an increase in both glucose uptake and MPO activity. Granulocyte colony-stimulating factor (G-CSF) attenuated the sepsis-induced decrease in circulating neutrophils. Both glucose uptake and MPO activity of skin and muscle adjacent to the infection site showed a smaller increase in G-CSF treated rats. In contrast, septic rats injected with G-CSF exhibited a greater number of leukocytes and a larger reduction in the number of bacteria in the sc lavage fluid. These results demonstrate that G-CSF is a potent immunomodulator that stimulates neutrophil function and also increases their recruitment to the site of infection, resulting in improved bacterial killing and host defense.

Animals↗
PubMed1992

Effect of pyocyanine, a pigment of Pseudomonas aeruginosa, on production of reactive nitrogen intermediates by murine alveolar macrophages.

In this study we investigated the effect of pyocyanine, a pigment produced by Pseudomonas aeruginosa, on production of reactive nitrogen intermediates by macrophages. We found that addition of pyocyanine to cultures of murine alveolar macrophages inhibited the capacity of these cells to produce reactive nitrogen intermediates (measured as nitrite) in a dose-dependent manner without altering cell viability, cytokine-induced Ia expression, or production of tumor necrosis factor.

Animals↗
PubMed1992

Antibodies to tumor necrosis factor-alpha inhibit liver regeneration after partial hepatectomy.

Certain cytokines that are produced in liver may act as growth factors to facilitate wound healing and, hence, may influence liver regeneration. However, this hypothesis has not been directly tested. To determine whether the cytokine response evoked by partial hepatectomy (PH) modulates the process of liver regeneration, adult male rats were injected intraperitoneally with either goat polyclonal antibodies to rat tumor necrosis factor (TNF; 15 micrograms/g body wt) or an equal amount of goat anti-rat immunoglobulin G 1 h before PH. Animals were killed at 12, 24, 48, or 72 h post-PH, 1 h after injection with [3H]thymidine. Serum TNF levels were measured with the L929 cytotoxicity assay, titers of antibody to TNF were determined by enzyme-linked immunoabsorbent assay, and interleukin-6 (IL-6) concentrations were measured by B9 cell bioassay. Liver regeneration was assessed by [3H]thymidine incorporation into hepatic DNA and by immunohistochemical evidence of proliferating cell nuclear antigen (PCNA) expression. Antibodies to TNF were detected in treated rats but not in controls. Titers were highest at 12 h and progressively fell. Although TNF was never detected in serum, treatment with anti-TNF pre-PH significantly inhibited increases in serum IL-6 concentration post-PH. Anti-TNF pretreatment also inhibited [3H]thymidine incorporation into DNA, as well as expression of PCNA by both hepatocytes and liver nonparenchymal cells. These data indicate that TNF positively modulates liver regeneration after PH.

Animals↗
PubMed1992

Modulation of glucose metabolic response to endotoxin by granulocyte colony-stimulating factor.

The present study examines whether in vivo administration of granulocyte colony-stimulating factor (G-CSF) and the resultant neutrophilia alters basal glucose metabolism or modulates the glucose metabolic response to a subsequent endotoxin [lipopolysaccharide (LPS)] challenge. Rats were injected with human recombinant G-CSF (50 micrograms/kg sc) twice daily for 2 days preceding an injection of LPS. Animals treated with G-CSF showed an eightfold increase in blood polymorphonuclear leukocytes (PMNs) but no detectable changes in hemodynamics or glucose metabolism. In control animals, LPS transiently decreased circulating PMN number, but by 4 h neutrophils had returned to control levels. LPS produced a greater reduction in circulating neutrophils in G-CSF-treated animals, which did not return to pretreatment levels by 4 h. G-CSF also produced marked changes in the glucose metabolic response to LPS. Rates of whole body glucose production and utilization in both control and G-CSF-treated rats were rapidly increased by LPS; however, the increment in glucose flux was 55-100% greater in the latter group. The enhanced rate of hepatic glucose production in this group occurred despite lower plasma levels of lactate and glucagon. The elevated rate of whole body glucose utilization was attributable to the G-CSF-enhanced LPS-induced increase in glucose uptake by the ileum, spleen, liver, and lung. Furthermore, LPS increased glucose uptake by skeletal muscle in G-CSF-treated rats but not in control animals. The enhanced glucose disposal in G-CSF-treated rats was not mediated by increases in plasma glucose or insulin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Effect of dichloroacetate on mechanical performance and metabolism of compromised diaphragm muscle.

We investigated the effect of dichloroacetate (DCA) on tension generation and carbohydrate metabolism of the rat diaphragm in vitro. Isolated diaphragms were placed in individual organ chambers and were hooked to force-displacement transducers. Net lactate production and glucose and lactate oxidation were measured in vitro. Diaphragmatic fatigue was precipitated by in vivo endotoxemic shock, by in vitro hypoxia, or by in vitro repetitive tetanic stimulation. In diaphragms isolated from endotoxemic rats, DCA increased tension generation by 30 and 20% at stimulation frequencies of 20 and 100 Hz, respectively. Associated with changes in mechanical performance, DCA reduced net lactate production by 53% after 60 min of incubation and increased glucose oxidation 54% but had no effect on lactate oxidation. During in vitro hypoxia, DCA reduced net diaphragmatic lactate production by 30% and increased glucose oxidation by 45% but did not attenuate hypoxic fatigue. DCA had no effect on tension generation during repetitive tetanic stimulation. We conclude that DCA improves in vitro diaphragmatic fatigue due to endotoxicosis but not due to hypoxia or repetitive stimulation.

Animals↗
PubMed1992

Reversal of hyperdynamic response to continuous endotoxin administration by inhibition of NO synthesis.

Septic shock is characterized by an increase in cardiac output and a fall in systemic vascular resistance index and mean arterial pressure. Endotoxin alters the smooth muscle function of blood vessels, probably by means of an increased production of the potent vasodilator nitric oxide (NO). The present study was accomplished to determine how the inhibition of NO synthesis influences cardiovascular performance in an ovine model of hyperdynamic endotoxemia. Endotoxemia was induced in five range ewes (41 +/- 2 kg) by continuous infusion of Escherichia coli endotoxin (LPS, 10 ng.kg-1.min-1) over the entire study period. After 24 h of LPS infusion, cardiac output increased from 5.2 +/- 0.3 to 7.9 +/- 0.6 (SE) 1/min (P less than 0.05) and mean arterial pressure and systemic vascular resistance index fell from 92 +/- 5 to 79 +/- 6 mmHg (P = 0.08) and from 1,473 +/- 173 to 824 +/- 108 dyn.s.cm-5.m2 (P less than 0.05), respectively. The pulmonary shunt fraction increased from 0.23 +/- 0.03 to 0.32 +/- 0.03 (P less than 0.05). The intravenous administration of the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (25 mg/kg) 24 h after the start of the LPS infusion changed these values to approximately baseline levels over the subsequent 4 h. Although N omega-nitro-L-arginine methyl ester increased pulmonary arterial pressure and pulmonary vascular resistance (P less than 0.05), right and left ventricular stroke volume index showed no significant changes. It is concluded that NO has a major function in cardiovascular performance in endotoxemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Epidermal growth factor, a phorbol ester, and 3',5'-cyclic adenosine monophosphate decrease the transcription of the luteinizing hormone/chorionic gonadotropin receptor gene in MA-10 Leydig tumor cells.

In a recent series of experiments we have shown that the previously recognized ability of mouse epidermal growth factor (mEGF), cAMP, or phorbol 12-myristate 13-acetate (PMA) to reduce the density of LH/CG receptors in MA-10 cells is secondary to a reduction in receptor messenger RNA (mRNA). As a follow-up to these studies we now present experiments designed to determine if the reduction in LH/CG receptor mRNA is due to a decrease in transcription of the receptor gene and/or an increase in the rate of degradation of the mRNA. The potential effects of mEGF, cAMP, or PMA on the degradation of the LH/CG receptor mRNA were measured in MA-10 cells treated with Actinomycin D or in kidney cells permanently transfected with the LH/CG receptor complementary DNA driven by a heterologous promoter. Both experimental strategies revealed that none of these compounds increase the rate of degradation of the receptor mRNA. If anything, a stabilizing effect was noted. The potential effects of mEGF, cAMP, or PMA on the transcription of the LH/CG receptor gene in MA-10 cells were measured using nuclear run-off assays. All three compounds induced a rapid decrease in the transcription of the LH/CG receptor gene. The time course of these effects is similar, and by 2 h all of the stimuli had decreased transcription to 15-30% of control. Our studies show that the mEGF-, cAMP- and PMA-induced down-regulation of the LH/CG receptor in MA-10 cells is primarily (if not entirely) due to a decrease in the transcription of the receptor gene.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1992

The 5'-flanking region of the rat luteinizing hormone/chorionic gonadotropin receptor gene confers Leydig cell expression and negative regulation of gene transcription by 3',5'-cyclic adenosine monophosphate.

The LH/CG receptor is a G protein-coupled receptor present on gonadal cells whose levels are modulated by a number of hormones, growth factors, and second messenger analogs. With the recently cloned cDNA for the LH/CG receptor, it has been shown that changes in the levels of the cognate mRNA are involved, at least in part, in the observed changes in receptor density. In order to study the transcriptional regulation of the LH/CG receptor we have isolated a 2-kilobase region of the 5'-flanking region of the rat LH/CG receptor gene and subcloned nucleotide -1 (relative to the translational initiation codon) to -1370 into a luciferase reporter plasmid. We show here that this region of the LH/CG receptor gene is able to enhance luciferase activity in MA-10 cells, a line of Leydig tumor cells that normally express LH/CG receptors, as opposed to human kidney 293 cells, which do not. Furthermore, the addition of 8-bromo-cAMP to MA-10 cells, under conditions known to decrease LH/CG receptor numbers and receptor mRNA levels, decreases the relative luciferase activity to about 26% of control. This decrease in reporter gene activity is severely blunted in a subclone of MA-10 cells with a cAMP-resistant phenotype. Our studies show, for the first time, that sequence(s) present with 1370 base pairs of the translational start site of the rat LH/CG receptor gene are sufficient for conferring expression of this gene in Leydig cells and for the negative modulation of LH/CG receptor gene transcription by high concentrations of cAMP.

Animals↗
PubMed1992

Normal host defenses and impairments associated with the delayed resolution of pneumonia.

The lung is constantly exposed to infectious challenges and depends on a complex system of defense mechanisms to facilitate the clearance of pathogens and prevent the development of infection. Both the upper airway and lower respiratory tract have mechanical, humoral, and cellular mechanisms in place to protect the airways from diverse microorganisms. Impairment in any arm of this system can result in the predisposition of the host to respiratory infections, which may be of a recurrent nature. Defects may be congenital or acquired, and may be iatrogenic in the hospitalized patient. An understanding of these defects may lead to more effective therapies and preventive modalities for decreasing the number and severity of respiratory infections.

Aging↗
PubMed1991

The effects of ethanol, tumor necrosis factor, and granulocyte colony-stimulating factor on lung antibacterial defenses.

In summary, evidence is emerging indicating that alcohol-abusing hosts are seriously undermined by profound disturbances in cytokine production and activity. These alterations likely play a critical role in the development and clinical sequelae of their immunosuppressed status. Recombinant technology currently provides the clinician with the potential to immunologically reconstitute and restore host defenses in these hosts. While the ultimate role of these agents in patients will require extensive clinical investigations into their multiple biologic effects and interactions, cytokines, when properly employed, will likely have a major impact on the prevention and treatment of many life-threatening diseases. For the first time, we possess the potential to regulate essential functions of the host defense system which may prevent the development and mitigate the severity of infections in these and other immunocompromised hosts.

Alcoholic Intoxication↗
PubMed1991

Granulocyte colony-stimulating factor enhances pulmonary host defenses in normal and ethanol-treated rats.

Ethanol suppresses functions of the polymorphonuclear leukocyte (PMNL), seriously compromising normal host defenses against pneumonia. Because granulocyte colony-stimulating factor (G-CSF) augments the number and function of PMNL, the effect of G-CSF on the antibacterial defenses of the lung in normal and acutely intoxicated rats was studied. Animals received G-CSF or vehicle twice a day for 2 days, then ethanol or saline, followed by challenge with Klebsiella pneumoniae. K. pneumoniae elicited an intrapulmonary influx of PMNL in control rats that was markedly suppressed by prior ethanol administration. G-CSF augmented the recruitment of PMNL into the lungs of control rats and significantly attenuated the adverse effects of ethanol on PMNL entry into the lung. G-CSF enhanced intrapulmonary bactericidal activity against this pathogen in normal and ethanol-treated rats. All intoxicated rats pretreated with the vehicle died, while greater than 90% of rats pretreated with G-CSF survived. These findings suggest a potential role for G-CSF in mitigating the adverse effects of ethanol on PMNL delivery and pulmonary host defenses.

Alcoholic Intoxication↗
PubMed1991

Endotoxin-induced alterations in contractility of isolated blood vessels from sheep.

The present study examined reactivity to norepinephrine (NE) and KCl in isolated, suffused blood vessels from the systemic and pulmonary circulations of endotoxin-treated and control sheep. A possible mechanism underlying an endotoxin-induced alteration in vascular reactivity was also investigated. Chronically instrumented sheep were given Escherichia coli endotoxin (1.5 micrograms/kg). Eight to 12 h later these endotoxin-treated animals exhibited a significantly increased cardiac output and decreased systemic vascular pressure and resistance. The pulmonary vascular pressure and resistance were not changed. The isolated superficial femoral artery from the endotoxin sheep exhibited depressed contractions in response to KCl (75 mM) and to NE (10(-7)-10(-5) M), whereas the pulmonary artery (tertiary branch) did not exhibit altered reactivity. The decreased sensitivity to NE in the femoral artery from endotoxin sheep did not appear to involve an alteration of alpha- or beta-adrenoceptors, or an increased release of vasodilator prostanoids, or endothelium-derived relaxing factor.

Animals↗