Search PubMed⌕ Search

Biomedical subjects

C A Stewart

Publications and source records attributed to C A Stewart.

At least 55 records · Page 3Linked to original sources
PubMed1996

Evidence for endogenous C1q modulates TNF-alpha receptor synthesis and autocrine binding of TNF-alpha associated with lipid A activation of murine macrophages for nitric oxide production.

The role of endogenously synthesized complement subcomponent C1q on autocrine binding of tumor necrosis factors (TNF-alpha) and on TNF-alpha receptor (TNF-R) mRNA synthesis by mouse macrophages was investigated. Activation of C3H mouse peritoneal macrophages (C3H-PM phi) by Lipid A induced TNF-alpha and nitric oxide (NO) to kill tumor targets. Such activation also increased macrophage-endogenous C1q synthesis and secretion in a dose-dependent fashion. Antibody for C1q markedly inhibited C3H-PM phi NO production in response to Lipid A, but had no effect on TNF-alpha production. C3H-PM phi treated with C1q or Lipid A displayed increased TNF-R mRNA synthesis and in combination with Lipid A and anti-C1q antibody inhibited TNF-R and nitric oxide synthase (NOS) mRNA synthesis compared with Lipid A only, but had no effect on TNF mRNA synthesis. In vitro treatment of C3H-PM phi with C1q also increased TNF-alpha binding to their surfaces. Taken together, the data indicate that endogenously synthesized C1q is operative in promoting TNF-R mRNA synthesis and resultant autocrine binding of TNF-alpha for induction of NOS in the process of NO-mediated tumor cytotoxicity by Lipid A-activated macrophages.

Adjuvants, Immunologic↗
PubMed1996

Transfection of L929 cells with complement subcomponent C1q B-chain antisense cDNA inhibits tumor necrosis factor-alpha binding to mediate cytotoxicity and nitric oxide generation.

The role of complement subcomponent C1q in the modulation of TNF-alpha binding to L929 cells to mediate cytotoxicity and nitric oxide (NO) generation was investigated. Transfection of L929 with murine C1q B-chain antisense plasmid cDNA rendered them markedly less susceptible to TNF-mediated cytotoxicity coincident with a decreased capacity for TNF-alpha binding and expression of cell surface C1q protein. The inhibitory effects of L929 transfection with C1q B-chain antisense were transiently expressed at 24 hr post-transfection with full recovery of cellular functions by 72 hr. Transfected L929 cells were fully reconstituted in their TNF-alpha binding and in their cytotoxic response following exposure to soluble C1q which was bound to their cell surface. Transfection with C1q B-chain antisense also significantly inhibited NO generation by L929 cells in response to stimulation by TNF-alpha, IFN-alpha/beta, and LPS. Taken together, these results indicate that endogenously synthesized C1q is prerequisite for binding of TNF-alpha to L929 cells to mediate cytotoxicity and NO generation.

Animals↗
PubMed1996

Repeated ECS induces GluR1 mRNA but not NMDAR1A-G mRNA in the rat hippocampus.

The neural basis underlying the cognitive side effects of ECT is unknown. Recent studies suggest that the memory dysfunction may be caused by alterations in hippocampal synaptic efficacy [20]. In situ hybridisation was used to examine the possible receptor mechanisms responsible for this effect. Repeated ECS markedly increased mRNA expression for the GluR1 subunit of the AMPA receptor, but not the NMDAR1A-G subtypes of the NMDA receptor, relative to control treatments. This effect was present 24 h after the last seizure and may be responsible for the expression of the ECS-induced increase in synaptic efficacy.

Animals↗
PubMed1996

Chronic mild stress and sucrose consumption: validity as a model of depression.

Sucrose consumption and preference were examined in rats subjected to a 6-week regimen of unpredictable mild stressors, after Willner et al. (11). These subjects were compared with groups exposed to: 1. only the food deprivation element of the stress protocol; or 2. the stress protocol without the food deprivation element. A control group was not exposed to stressors. Body weight and sucrose consumption were significantly reduced in stressed and food-deprived animals compared to the other 2 groups. These variables therefore appeared dependent on food deprivation and independent of other elements of the stress protocol. Neither sucrose consumption per gram body weight nor sucrose preference differed significantly among the 4 groups. These results indicate that food deprivation is not only necessary, but sufficient, to produce sucrose consumption deficits in rats. It is, therefore, likely that reduced sucrose consumption in stressed rats results solely from diminished body weight rather than exposure to the series of stressors. We conclude that sucrose consumption is not a valid index of reward responsiveness. Other measures (such as place-preference conditioning or intracranial self-stimulation threshold) should be evaluated also with respect to body weight change when considering the validity of stressor-based models of depressive disorder.

Animals↗
PubMed1996

Complement subcomponent C1q modulation of TNF-alpha binding to L929 cells for enhanced TNF-mediated cytotoxicity.

Complement subcomponent C1q has been recently implicated in the modulation of autocrine binding of TNF-alpha to murine macrophages for induction of nitric oxide synthase. In the present study, the putative role of C1q in increasing TNF-alpha binding to L929 cells to mediate cytotoxicity was explored. TNF-sensitive L929 cells (L929-S) had higher total endogenous cellular and surface C1q levels and bound correspondingly more phycoerythrin-labelled rTNF-alpha (PE-TNF) than did a TNF-resistant L929 variant (L929-R). Pretreatment of L929-S with soluble C1q increased their sensitivity to TNF-mediated cytotoxicity coincident with increased binding of PE-TNF, but similar treatment of L929-R had no effect. Pretreatment of L929-S with an inhibitor of C1q secretion, 3,4 dehydro-D,L-proline (DHP), resulted in a decrease in their TNF-mediated cytotoxicity, as well as reduced binding of PE-TNF. Subsequent exposure of DHP-treated L929-S with exogenous soluble C1q restored their TNF-mediated cytotoxicity and binding of PE-TNF. These results provide evidence for the modulation of TNF-alpha binding to TNF sensitive tumour targets L929 by either endogenously synthesized or exogenously added C1q to promote TNF-mediated cytotoxicity by mechanisms which remain to be elucidated.

Animals↗
PubMed1996

A prospective study of the effectiveness of low dose omeprazole as initial therapy in Zollinger-Ellison syndrome.

BACKGROUND: The proton pump inhibitors (omeprazole and lansoprazole) are the drugs of choice for the medical management of gastric acid hypersecretion in Zollinger-Ellison syndrome (ZES). These drugs are safe for long-term therapy but are acid-labile and high doses are expensive. The recommended starting dose of omeprazole is 60 mg/day. However, it has been shown in recent studies that the maintenance dose of omeprazole could be safely reduced to 20 mg once or twice a day in more than two-thirds of patients with ZES. The purpose of this study is to determine if an initial starting dose of omeprazole 20 mg/day is safe and effective in patients with ZES. METHODS: Forty-nine consecutive patients with ZES being treated with ranitidine for at least 2 weeks were admitted to the NIH. Omeprazole 20 mg was started on day 1 of the admission and ranitidine discontinued 4 h after the first dose. Gastric acid output was measured for 1 h prior to the next omeprazole dose on day 2, then on day 3 if the value was > 10 mmol/h on the previous day. If acid-peptic symptoms developed or the gastric acid output remained > 10 mmol/h on day 3, the patient was considered to have failed omeprazole 20 mg/day initial therapy and the dose titrated daily to achieve adequate control of acid-peptic symptoms and gastric secretion. RESULTS: In 33 of the 49 patients (68%) omeprazole 20 mg/day was successful as initial therapy. Sixteen patients (32%) failed this initial omeprazole dose (eight patients owing to persistent peptic symptoms and eight patients owing to inadequate acid control). The final daily omeprazole dose required in these patients was 40 mg in eight patients (16%), 60 mg in one patient (2%) and 80 mg in seven patients (14%). Basal acid output (BAO) was the only clinical or laboratory feature that was significantly different between the two groups in which low dose initial omeprazole therapy was or was not successful; all patients with basal acid output < 20 mmol/h had a successful outcome. CONCLUSIONS: Because of the need to rapidly control gastric acid hypersecretion owing to the high risk of complications from peptic ulcer disease, patients with ZES should continue to be started on omeprazole 60 mg/day and the dose adjusted by acute titration methods as is currently recommended. After a maintenance dose is established, attempts should be undertaken to reduce the dose to 20 mg/ day once or twice a day. Only the minority of patients with ZES in whom basal acid output is known to be < 20 mmol/h (20% of patients) should be started on a low initial omeprazole dose.

Adult↗
PubMed1996

Normal appearance of arachnoid granulations on contrast-enhanced CT and MR of the brain: differentiation from dural sinus disease.

PURPOSE: To determine the imaging appearance and frequency with which arachnoid granulations are seen on contrast-enhanced CT and MR studies of the brain. METHODS: We retrospectively reviewed 573 contrast-enhanced CT scans and 100 contrast-enhanced MR studies of the brain for the presence of discrete filling defects within the venous sinuses. An anatomic study of the dural sinuses of 29 cadavers was performed, and the location, appearance, and histologic findings of focal protrusions into the dural sinus lumen (arachnoid granulations) were assessed and compared with the imaging findings. RESULTS: Discrete filling defects within the dural sinuses were found on 138 (24%) of the contrast-enhanced CT examinations. A total of 168 defects were found, the majority (92%) within the transverse sinuses. One third were isodense and two thirds were hypodense relative to brain parenchyma. Patients with filling defects were older than patients without filling defects (mean age, 46 years versus 40 years). Discrete intrasinus signal foci were noted on 13 (13%) of the contrast-enhanced MR studies. The foci followed the same distribution as the filling defects seen on CT scans and were isointense to hypointense on T1-weighted images, variable in signal on balanced images, and hyperintense on T2-weighted images. Transverse sinus arachnoid granulations were noted adjacent to venous entrance sites in 62% and 85% of the CT and MR examinations, respectively. Arachnoid granulations were found in 19 (66%) of the cadaveric specimens, in a similar distribution as that seen on the imaging studies. CONCLUSION: Discrete filling defects, consistent with arachnoid granulations, may be seen in the dural sinuses on 24% of contrast-enhanced CT scans and on 13% of MR studies. They are focal, well-defined, and typically located within the lateral transverse sinuses adjacent to venous entrance sites. They should not be mistaken for sinus thrombosis or intrasinus tumor, but recognized as normal structures.

Adult↗
PubMed1995

Tumor-derived factor synergizes with IFN-gamma and LPS, IL-2 or TNF-alpha to promote macrophage synthesis of TNF-alpha and TNF receptors for autocrine induction of nitric oxide synthase and enhanced nitric oxide-mediated tumor cytotoxicity.

Evidence has previously been presented for an immunomodulatory role of a soluble activity, designated as tumor-derived recognition factor (TDRF), which was produced constitutively by P815 mastocytoma, L 1210 leukemia and other murine tumor targets. TDRF synergized with IFN-gamma and IL-2 to promote TNF-alpha and mRNA synthesis and release by murine macrophages for increased autocrine induction of nitric oxide (NO)-mediated tumor cytotoxicity. We have now further assessed the modulatory role of TDRF on TNF-alpha, TNF receptors (TNF-R) and NOS mRNA synthesis. Macrophages activated by INF-gamma priming and triggering by rTNF-alpha bacterial lipopolysaccharide (LPS) of IL-2 evoked greater NO generation in the presence than in the absence of L1210 targets. TDRF-containing culture fluid from L1210 targets was subsequently confirmed to synergize with IFN-gamma and rTNF-alpha, LPS or IL-2 triggering agents to promote increased TNF-alpha mRNA for autocrine induction of NOS mRNA synthesis with resultant augmentation of NO generation. IFN-gamma selectively upregulated TNF-R1 mRNA expression, whereas either IL-2 or LPS upregulated only TNF-R2 mRNA expression. TDRF combined with IFN-gamma to further upregulate TNF-R1 mRNA and with either IL-2 or LPS to further upregulate TNF-R2, mRNA expression. These findings indicate that TDRF activity synergizes with either IL-2 or LPS triggering agents for enhanced activation of IFN-gamma-primed macrophages by promotion of TNF-alpha and TNF-R mRNA synthesis for autocrine induction of NOS with resultant increased NO-mediated tumor cytotoxicity.

Amino Acid Oxidoreductases↗
PubMed1995

Exogenous interferon-gamma induces endogenous synthesis of interferon-alpha and -beta by murine macrophages for induction of nitric oxide synthase.

Murine macrophages (M phi) are activated either by interferon-gamma (IFN-gamma) or interferon-alpha/beta (IFN-alpha/beta) in combination with bacterial lipopolysaccharide (LPS) to induce synthesis of tumor necrosis factor alpha (TNF-alpha) and nitric oxide synthase (iNOS) mRNA synthesis for generation of tumor cytotoxic nitric oxide (NO). In the present study, the effect of exogenous IFN-gamma on the induction of endogenous mRNA synthesis and secretion of IFN-alpha/beta by murine M phi was investigated. Neutralizing antibodies to IFN-alpha/beta reversed TNF-alpha and NOS mRNA synthesis, as well as nitric oxide (NO)-mediated tumor cytotoxicity. Quantitative reverse transcription polymerase chain reaction (RT-PCR) revealed that treatment of M phi with IFN-gamma induced increases in both IFN-alpha and IFN-beta mRNA synthesis by approximately 2-fold and 10-fold, respectively, which corresponded to a 2-fold increase in secretion of IFN-alpha/beta by ELISA. These data indicate that exogenous IFN-gamma induces endogenous synthesis and secretion of IFN-alpha/beta by M phi, which appears to act in concert with endogenously synthesized TNF-alpha for the autocrine induction of NOS mRNA synthesis.

Animals↗
PubMed1994

Ketamine prevents ECS-induced synaptic enhancement in rat hippocampus.

Electrical induction of seizure activity profoundly impairs hippocampal long-term potentiation (LTP) in rats. A similar effect may account for the memory dysfunction observed after electroconvulsive stimulation in humans and other species. The co-administration of ketamine with the induction of electroconvulsive seizures (ECS) was evaluated as a possible method for reducing the impact of ECS on hippocampal synaptic plasticity in rats. Electrophysiological studies in vivo showed that both the enhancement of the EPSP slope and the subsequent reduction of experimentally induced LTP in the dentate gyrus by repeated, spaced ECS were significantly attenuated by ketamine anaesthesia. The findings suggest that ketamine may protect against ECS-induced memory impairment and thus prove useful in reducing the transient cognitive impairment following electroconvulsive therapy (ECT).

Animals↗
PubMed1994

Prohibitin expression during cellular senescence of human diploid fibroblasts.

Prohibitin is an evolutionarily conserved gene postulated to possess tumor suppressor activity and to contribute to the limited lifespan of human diploid fibroblast-like cells. Prohibitin mRNA and protein expression and its ability to become post-translationally modified were determined in human diploid fibroblast-like cells of different in vitro ages. The expression of prohibitin mRNA and protein changes little with increasing in vitro age; however, its protein product is post-synthetically modified in younger but not older cells. These results suggest that prohibitin is similar to the retinoblastoma gene product whose anti-proliferative activity remains active in older cells because it is not post-synthetically modified.

Cell Cycle↗
PubMed1994

Retrograde amnesia and memory reactivation in rats with ibotenate lesions to the hippocampus or subiculum.

The retrograde effects of hippocampal lesions on spatial memory were studied. Rats were given a series of 48 place-navigation trials in an open-field water-maze followed, either 3 days or 14 weeks later, by ibotenic acid lesions of the hippocampus (HPC) or subiculum (SUB), or by sham-surgery (SHAM). Two weeks after surgery they were given a retention test without a hidden escape platform. There was a significant decline in performance with time in the SHAM group, but with the 14-week SHAM group performing significantly better than chance levels, whereas both lesioned groups performed at chance at both retention intervals. All rats were then retrained for 24 trials. SHAM rats escaped rapidly within 2 trials, suggesting a reactivation of memory rather than relearning. The HPC groups were severely impaired during retraining, with a developing trend towards better performance in the 3-day group. After 24 trials of training with the escape platform placed in the opposite quadrant of the pool, this new location was learned successfully by SHAM and SUB rats, but not by HPC rats. These results indicate that selective hippocampal formation lesions can cause deficits in retrieval but do not reveal a time-dependent gradient of memory consolidation.

Amnesia, Retrograde↗
PubMed1993

Mechanistic differences between migration inhibitory factor (MIF) and IFN-gamma for macrophage activation. MIF and IFN-gamma synergize with lipid A to mediate migration inhibition but only IFN-gamma induces production of TNF-alpha and nitric oxide.

Previously we found that murine macrophage migration inhibition (MMI) was mediated by IFN-gamma-priming and lipid A triggering. With the recent availability of human recombinant migration inhibitory factor (MIF), which is distinctly different from IFN-gamma and other cytokines, we have now attempted to explore possible mechanistic differences between IFN-gamma and MIF to mediate MMI. Neither MIF not IFN-gamma were active alone, but effectively primed murine inflammatory macrophages for subsequent triggering by lipid A to mediate MMI. A specific neutralizing antibody for rMIF abrogated MMI mediated only by MIF and not by IFN-gamma-primed macrophages. Distinct differences were also found between the mechanisms by which MIF and IFN-gamma synergized with lipid A for activation in that IFN-gamma-primed and lipid A triggered macrophages produced TNF and nitric oxide (NO), whereas MIF-primed cells did not. Macrophages primed with IFN-gamma and triggered by rTNF were inhibited in their migration, whereas MIF failed to synergize with rTNF for MMI. An inhibitor of NO production NG-monomethyl-L-arginine inhibited MMI mediated by higher activating concentrations of lipid A and by IFN-gamma-primed and lipid A triggered macrophages, but had no effect on MIF-primed cells in concert with lipid A for increased expression of both TNF-alpha mRNA and NO synthase mRNA. Taken together, our results indicate that both MIF and IFN-gamma prime macrophages to synergize with lipid A to mediate MMI but by different mechanisms. The activation process by IFN-gamma to mediate migration inhibition appears to resemble requirements for rendering macrophages tumor cytotoxic in the production of TNF for autocrine-mediated NO generation by primed macrophages. In contrast, MIF-mediated MMI was independent of requirements for either TNF or NO production.

Amino Acid Oxidoreductases↗
PubMed1993

Diurnal variation in thermal and metabolic parameters of the golden hamster (Mesocricetus auratus).

The purpose of this study is to examine diurnal variation in several thermal and metabolic parameters of the golden hamster, Mesocricetus auratus. Metabolic rate, core temperature, and evaporative water loss were measured during night and day at several ambient temperatures. Wet minimal thermal conductance, dry minimal thermal conductance, basal metabolic rate, minimal net heat production and the lower critical temperature difference were estimated from these measurements. Wet and dry minimal thermal conductance, evaporative water loss, core temperature, basal metabolic rate, and lower critical temperature difference were greater during the active phase than during the resting phase. The diurnal variation in wet minimal thermal conductance was much smaller than that predicted from published allometric equations. The diurnal variation in wet minimal thermal conductance was 9% of the 24-h mean. The diurnal variation in dry minimal thermal conductance was 26% of the 24-h mean. The higher active-phase core temperature and basal metabolic rate may function to enhance peak metabolic performance during the active phase. The lower resting phase metabolism and core temperature may reduce energetic costs. The greater active-phase lower critical temperature difference may be a result of the greater active-phase basal metabolic rate. Diurnal variation in minimal thermal conductance may be caused by changes in peripheral circulation.

Animals↗
PubMed1993

Inhibitor of C1q secretion suppresses the macrophage response to lipid A for nitric oxide but not for TNF production: evidence for a role of C1q in autocrine binding of TNF.

Studies were designed to further define the modulatory role of complement subcomponent C1q in macrophage activation by Lipid A to mediate production of TNF and cytotoxic nitric oxide (NO). Pretreatment of macrophages for 24 h with 2.5 mM 3,4,dehydro-D,L-proline (DHP), an inhibitor of C1q secretion, suppressed their response to Lipid A activation for cytotoxicity of P815 tumor targets which correlated with a corresponding decrease in NO production. In contrast, DHP-pretreated macrophages displayed an increase in the release of TNF in response to Lipid A as compared to untreated controls. Time kinetic studies indicated that DHP-pretreated macrophages produced higher sustained levels of TNF activity during 1 to 24 h culture with Lipid A than did untreated control macrophages. This was confirmed by increased TNF mRNA expression in response to Lipid A by DHP-treated cells. DHP-pretreated macrophages had reduced levels of cell surface C1q as determined by cytofluorometric analysis of the binding of FITC-labeled anti-C1q, F(ab')2. Macrophages were also found to have reduced binding capacity for phycoerythrin-labeled rTNF (PE-TNF) by cytofluorometric analysis following DHP treatment. Exposure of DHP-pretreated macrophage to soluble C1q at 4 degrees C restored their reduced binding of PE-TNF. C1q was confirmed to bind to macrophages at 4 degrees C as detected by FITC anti-C1q, F(ab')2 and such C1q binding promoted a corresponding increased binding of PE-TNF. Macrophages which were plated over immobilized C1q were also markedly enhanced in their binding of PE-TNF probe. Our results indicate that the inhibition of macrophage secretion of C1q by DHP pretreatment, was accompanied by an increased TNF mRNA expression and release with a decrease in NO generation following Lipid A activation. Since TNF binding to DHP-treated macrophages was reconstituted by the binding of exogenous C1q to the cells, it appears that C1q may be involved in the modulation of autocrine binding of TNF for subsequent generation of cytotoxic NO.

Animals↗