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Biomedical subjects

C A Stewart

Publications and source records attributed to C A Stewart.

At least 37 records · Page 2Linked to original sources
PubMed1999

p38 kinase is activated in the Alzheimer's disease brain.

The p38 mitogen-activated protein kinase is a stress-activated enzyme responsible for transducing inflammatory signals and initiating apoptosis. In the Alzheimer's disease (AD) brain, increased levels of phosphorylated (active) p38 were detected relative to age-matched normal brain. Intense phospho-p38 immunoreactivity was associated with neuritic plaques, neuropil threads, and neurofibrillary tangle-bearing neurons. The antibody against phosphorylated p38 recognized many of the same structures as an antibody against aberrantly phosphorylated, paired helical filament (PHF) tau, although PHF-positive tau did not cross-react with the phospho-p38 antibody. These findings suggest a neuroinflammatory mechanism in the AD brain, in which aberrant protein phosphorylation affects signal transduction elements, including the p38 kinase cascade, as well as cytoskeletal components.

Aged↗
PubMed1999

The effect of pulsed electromagnetic fields on osteoporosis at the knee in individuals with spinal cord injury.

The purpose of this study was to determine the effects of pulsed electromagnetic fields on osteoporotic bone at the knee in individuals with chronic spinal injury. The study consisted of 6 males with complete spinal cord injury at a minimum of 2 years duration. Bone mineral density (BMD) was obtained at both knees at initiation, 3 months, 6 months, and 12 months using dual energy X-ray absorptiometry. In each case, 1 knee was stimulated using The Bone Growth Stimulator Model 3005 from American Medical Electronics, Incorporated and the opposite knee served as the control. Stimulation ceased at 6 months. At 3 months BMD increased in the stimulated knees 5.1% and declined in the control knees 6.6% (p < .05 and p < .02, respectively). By 6 months the BMD returned to near baseline values and at 12 months both knees had lost bone at a similar rate to 2.4% below baseline for the stimulated knee and 3.6% below baseline for the control. There were larger effects closer to the site of stimulation. While the stimulation appeared useful in retarding osteoporosis, the unexpected exaggerated decline in the control knees and reversal at 6 months suggests underlying mechanisms are more complex than originally anticipated. The authors believe a local as well as a systemic response was created.

Absorptiometry, Photon↗
PubMed1999

Liver transplantation at the University of Pennsylvania and the Children's Hospital of Philadelphia.

The liver transplant program at the University of Pennsylvania and the Children's Hospital of Philadelphia experienced healthy growth in its clinical activity in the past 5 years. Patterns of referral and patient evaluation were established, care of patients while waiting on the list or being followed after transplantation was streamlined. We are now achieving excellent outcomes while transplanting relatively sicker patients. Innovative surgical procedures are implemented resulting in more efficient utilization of cadaveric and living-donor liver grafts. The protocols that are used for patient care are more standard, yet flexible and accommodate recent advancement in transplantation immunobiology. This progress of the clinical program was enhanced by careful preservation of the academic mission of the institution, which encourages the liver transplant faculty to be involved in NIH-supported clinical and basic science research.

Adult↗
PubMed1998

Inhibition by phenyl N-tert-butyl nitrone of early phase carcinogenesis in the livers of rats fed a choline-deficient, L-amino acid-defined diet.

Male Wistar rats were fed a choline-deficient, L-amino acid-defined (CDAA) diet alone or in combination with a nitrone-based free radical trapping agent, phenyl N-tert-butyl nitrone (PBN) in the drinking water at the concentrations of 0.013, 0.065, and 0.130% for 12 weeks. PBN inhibited the changes that are normally induced in the livers of rats by the CDAA diet feeding, i.e., development of putative preneoplastic lesions, proliferation of connective tissue, reduction of glutathione S-transferase activity, formation of 8-hydroxyguanine in DNA, and an increase in inducible cyclo-oxygenase (COX2) activity. PBN, however, did not prevent the increases in the COX2 mRNA or protein levels brought on by the CDAA diet These results indicate that the loss of glutathione S-transferase activity and COX2 induction may play significant roles in rat liver carcinogenesis by the CDAA diet and that PBN prevents neoplasia not only by its radical scavenging activity but also by inhibiting COX2 activity at the catalytic level.

Amino Acids↗
PubMed1998

Transfer of human serum IgG to nonobese diabetic Igmu null mice reveals a role for autoantibodies in the loss of secretory function of exocrine tissues in Sjögren's syndrome.

The NOD (nonobese diabetic) mouse has been studied as an animal model for autoimmune insulin-dependent diabetes and Sjögren's syndrome. NOD.Igmu null mice, which lack functional B lymphocytes, develop progressive histopathologic lesions of the submandibular and lachrymal glands similar to NOD mice, but in the absence of autoimmune insulitis and diabetes. Despite the focal appearance of T cells in salivary and lachrymal tissues, NOD.Igmu null mice fail to lose secretory function as determined by stimulation of the muscarinic/cholinergic receptor by the agonist pilocarpine, suggesting a role for B cell autoantibodies in mediating exocrine dryness. Infusion of purified serum IgG or F(ab')2 fragments from parental NOD mice or human primary Sjögren's syndrome patients, but not serum IgG from healthy controls, alters stimulated saliva production, an observation consistent with antibody binding to neural receptors. Furthermore, human patient IgG fractions competitively inhibited the binding of the muscarinic receptor agonist, [3H]quinuclidinyl benzilate, to salivary gland membranes. This autoantibody activity is lost after preadsorption with intact salivary cells. These findings indicate that autoantibodies play an important part in the functional impairment of secretory processes seen in connection with the autoimmune exocrinopathy of Sjögren's syndrome.

Animals↗
PubMed1998

Iron absorption in patients with Zollinger-Ellison syndrome treated with long-term gastric acid antisecretory therapy.

BACKGROUND: Gastric acid secretion is important for absorption of dietary non-haem iron, and iron deficiency is common in gastric hyposecretory states such as after gastric resection. It is not known if prolonged, continuous treatment with potent acid suppressants such as omeprazole will lead to iron deficiency or lower body iron stores. AIM: To assess iron stores and the occurrence of iron deficiency anaemia in patients with Zollinger-Ellison syndrome (ZES) treated long-term with gastric antisecretory drugs. METHODS: One hundred and nine patients with ZES but without previous gastric resections were studied. All patients underwent assessment of acid control on antisecretory agents, determination of tumour extent, evaluation of haematological parameters (Hct, haemoglobin, WBC, MCV, MCHC), and determination of serum iron parameters (iron, ferritin, transferrin, iron/ transferrin ratio). Acid control values for the last 4 years were reviewed, the presence or absence of acid hyposecretion determined using three different criteria and this result correlated with haematological and iron parameters. RESULTS: Eighty-nine patients were taking omeprazole, nine patients were taking histamine H2-antagonists and 11 patients were taking no drugs following curative resection. The mean duration of omeprazole treatment was 5.7 years (range 0.7-12.5 years) and total duration of any treatment was 10.1 years (range 0.7-21 years). Acid hyposecretion was present by at least one criterion in 45% of patients. There were no significant differences between patients with or without acid hyposecretion, taking or not taking omeprazole, having different durations of omeprazole treatment or different durations of total time receiving any antisecretory treatment, for any serum iron parameter, haematological parameter, or for the frequency of iron deficiency. Males and females did not differ in percentage with low ferritin levels or percentage with iron deficiency. CONCLUSIONS: Continuous treatment with omeprazole for 6 years or continuous treatment with any gastric antisecretory drug for 10 years does not cause decreased body iron stores or iron deficiency. These results suggest that, in contrast to recent results which show yearly monitoring of vitamin B12 in such patients is needed, such monitoring for iron parameters is not necessary.

Adolescent↗
PubMed1998

Interaction of alpha-phenyl-N-tert-butyl nitrone and alternative electron acceptors with complex I indicates a substrate reduction site upstream from the rotenone binding site.

Mitochondrial complexes I, II, and III were studied in isolated brain mitochondrial preparations with the goal of determining their relative abilities to reduce O2 to hydrogen peroxide (H2O2) or to reduce the alternative electron acceptors nitroblue tetrazolium (NBT) and diphenyliodonium (DPI). Complex I and II stimulation caused H2O2 formation and reduced NBT and DPI as indicated by dichlorodihydrofluorescein oxidation, nitroformazan precipitation, and DPI-mediated enzyme inactivation. The O2 consumption rate was more rapid under complex II (succinate) stimulation than under complex I (NADH) stimulation. In contrast, H2O2 generation and NBT and DPI reduction kinetics were favored by NADH addition but were virtually unobservable during succinate-linked respiration. NADH oxidation was strongly suppressed by rotenone, but NADH-coupled H2O2 flux was accelerated by rotenone. Alpha-phenyl-N-tert-butyl nitrone (PBN), a compound documented to inhibit oxidative stress in models of stroke, sepsis, and parkinsonism, partially inhibited complex I-stimulated H2O2 flux and NBT reduction and also protected complex I from DPI-mediated inactivation while trapping the phenyl radical product of DPI reduction. The results suggest that complex I may be the principal source of brain mitochondrial H2O2 synthesis, possessing an "electron leak" site upstream from the rotenone binding site (i.e., on the NADH side of the enzyme). The inhibition of H2O2 production by PBN suggests a novel explanation for the broad-spectrum antioxidant and antiinflammatory activity of this nitrone spin trap.

Animals↗
PubMed1997

Quantitation of protein-bound 3-nitrotyrosine and 3,4-dihydroxyphenylalanine by high-performance liquid chromatography with electrochemical array detection.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) have been implicated in myriad disease etiologies and may represent an obligate pathologic sequelus of inflammation. Unfortunately, few sensitive and specific analytical techniques exist for the routine assay of biomarkers indicative of ROS and RNS elaboration. In this study, high-performance liquid chromatography is used in conjunction with coulometric electrochemical array (HPLC-EC) detection to allow ultrasensitive determination of protein-bound 3-nitrotyrosine and 3, 4-dihydroxyphenylalanine (3-hydroxytyrosine) as specific in situ biomarkers of protein exposure to reactive nitrating and oxidizing species. Tyrosine and derivatives can be analyzed simultaneously with practical detection limits for tyrosine, 3-NT, and 3,4-Dopa being 10, 50, and 2 pmol, respectively, in as little as 20 microL of sample. HPLC-EC array detection allows two-dimensional resolution of chromatograms, greatly facilitating peak detection and confidence assignment. A method of sample preparation wherein tyrosine analogs are enzymatically hydrolyzed from protein without the need for sample extraction, concentration, or derivatization is reported.

Animals↗
PubMed1997

Management of the Zollinger-Ellison syndrome in pregnancy.

OBJECTIVE: There is almost no information on the management of patients with functional pancreatic endocrine tumors such as Zollinger-Ellison syndrome during pregnancy. The purpose of this study was to develop an approach for the management of such cases during pregnancy on the basis of experience with five recent cases. STUDY DESIGN: Five women with Zollinger-Ellison syndrome who had seven pregnancies were the subject of this study. Each patient had an initial evaluation to confirm the diagnosis and to establish gastrinoma location and for the presence or absence of multiple endocrine neoplasia type I. In patients with Zollinger-Ellison syndrome diagnosed before conception, various medical or surgical treatments were established before conception and were used to control acid secretion throughout the pregnancy. The presence of upper gastrointestinal symptoms during pregnancy, maternal and fetal complications, gender, and weight of the infant were determined in all cases. Acid control was determined in four of the five patients during six pregnancies. RESULTS: The interval between the onset of Zollinger-Ellison syndrome and the subsequent pregnancy varied from 0.6 to 9.9 years (mean 6.9 +/- 1.7 years). Zollinger-Ellison syndrome was unrecognized before pregnancy in two patients (40%); it was diagnosed between 0.2 and 2.4 years after the pregnancy. In three patients the time of diagnosis varied from 2.6 to 9 years before pregnancy. All patients had symptoms from gastric hypersecretion and elevated fasting serum gastrin levels that varied from 20% above normal to 37-fold above normal with mean of 2536 pg/ml (range 124 to 6970 pg/ml). Four of the five patients (80%) had positive secretin and calcium provocative tests. Two patients had multiple endocrine neoplasia type I. The five patients had seven pregnancies. Acid secretion was treated during pregnancy with antacids only (one patient), ranitidine alone (one patient), prior curative gastrinoma resection (one patient, two pregnancies), prior parietal cell vagotomy with incomplete tumor resection (one patient, two pregnancies), and prior parathyroidectomy and use of ranitidine in a patient with multiple endocrine neoplasia type I. In five pregnancies in three of the cases, no gastric antisecretory medications were needed during pregnancy. The mean acid secretion during pregnancy was 11.9 mEq/hr (range 0 to 42 mEq/hr). In the two cases with poor acid control and unrecognized Zollinger-Ellison syndrome mild fetal complications occurred. CONCLUSIONS: It is possible for patients with Zollinger-Ellison syndrome to have pregnancies that are not complicated by gastric acid hypersecretion. If the Zollinger-Ellison syndrome is diagnosed before pregnancy, curative resection with parietal cell vagotomy may obviate the need for gastric antisecretory drugs. If metastases are present or the diagnosis of Zollinger-Ellison syndrome is made after conception, ranitidine in the lowest possible dose should be used to control acid secretion. If acid secretion in uncontrolled, the dose may be increased or omeprazole may be used.

Adult↗
PubMed1997

Nitrone-based free radical traps as neuroprotective agents in cerebral ischaemia and other pathologies.

Nitrone-based spin trapping compounds have been shown to protect experimental animals from pathology associated with ischaemia/reperfusion injury, endotoxaemia, natural and accelerated aging, certain xenobiotics, and physical trauma. Moreover, these compounds have an intriguing nootropic action. Nitrones affect pathophysiological correlates in both the central nervous system and peripheral organ systems. These compounds have been shown to affect cellular oxidation state and oxidatively sensitive enzyme systems, but the precise mode of nitrone action has not been elucidated. Recent discoveries regarding the ability of nitrones to suppress gene transcriptional events associated with pathophysiological states, particularly the elaboration of NF kappa B-regulated cytokines and inducible nitric oxide synthase, argue that nitrones may act at a proximal level to oxidatively sensitive signal amplification systems.

Animals↗
PubMed1997

Seizures, memory and synaptic plasticity.

Electrophysiological studies of the rodent hippocampus show that repeated seizure activity has a profound, deleterious effect on an important form of synaptic plasticity (long-term potentiation, LTP) which has been suggested to underlie memory formation. It appears that seizure activity incrementally causes an indiscriminate and widespread induction of long-term potentiation, consuming and thereby reducing overall hippocampal plasticity available for information processing. Consistent with this finding, severe deficits in a form of learning known to be mediated by hippocampal function are observed in rat subjected to repeated electroconvulsive seizures (ECS). The effect on synaptic function gradually resolves over a period of around 40 days, paralleling the time course of the transitory cognitive impairment seen following electrical seizure induction (ECT) in humans being treated for severe affective disorder. The effect is likely to be mediated by NMDA receptor activation during seizure activity, as the phenomenon can be prevented by the administration of a non-competitive NMDA receptor associated channel blocker (ketamine) immediately before seizure induction. The mechanisms described may account for the inter-ictal cognitive disturbance observed in patients suffering from poorly controlled epilepsy.

Animals↗
PubMed1997

Value of somatostatin receptor scintigraphy: a prospective study in gastrinoma of its effect on clinical management.

BACKGROUND & AIMS: Recently [111In-DTPA-D-Phe1]-octreotide was approved for somatostatin receptor scintigraphy (SRS) of gastroenteropancreatic tumors. SRS and other tumor localization methods can be time consuming, expensive, and involve patient inconvenience. The role of SRS in comparison to other tumor localization modalities remains undefined because the relative effects of these methods on management have not been studied. The aim of this study was to determine whether SRS alters clinical management in Zollinger-Ellison syndrome. METHODS: One hundred twenty-two consecutive patients were studied prospectively. Each patient was assigned to one of five different clinical categories. Conventional imaging studies (ultrasonography, computerized tomography, magnetic resonance image, angiography, and bone scan) were performed, and the management was proposed. SRS was then performed. Clinical management was reassessed, and whether SRS altered management was determined based on six criteria. RESULTS: SRS was superior to any single imaging study. SRS altered management in 47% overall and in 22%-60% of patients in the five different clinical categories. Primary tumor localization and clarification of equivocal localization results from conventional studies were the principal reasons for altering management. SRS was equally useful in patients with or without metastatic liver disease. CONCLUSIONS: Because of the ability of SRS to alter clinical management combined with its superior sensitivity, high specificity, simplicity, and cost-effectiveness, SRS should be the initial imaging modality for patients with gastrinomas.

Adult↗
PubMed1997

Using metaphors to assess anticipatory perceptions of personal death.

The Revised Death Fantasy Scale (RDFS) is an 18-item measure based on metaphors of personal death. It was constructed to assess psychological aspects of contemplating personal death, at levels of awareness less conscious than those tapped by conventional self-report measures. It contains two subscales: Positive Metaphors and Negative Metaphors. In several studies the RDFS has shown evidence of reliability and validity. The scale may be potentially useful in health-related research and in the training and support of individuals whose work is related to death and dying.

Attitude to Death↗
PubMed1997

Distinguishing small hepatic hemangiomas from vascular liver metastases in gastrinoma: use of a somatostatin-receptor scintigraphic agent.

PURPOSE: To compare somatostatin-receptor scintigraphy and conventional imaging modalities in the differentiation of small hepatic hemangiomas from small liver metastases in Zollinger-Ellison syndrome. MATERIALS AND METHODS: Twenty-nine patients had hypervascular liver lesions smaller than 2 cm that could have been either metastases or hemangiomas. Fourteen patients had metastases, 14 had hemangiomas, and one had both. Scintigraphy was compared with computed tomography (CT), magnetic resonance (MR) imaging, and angiography for the correct identification of the lesions. RESULTS: The hemangiomas and liver metastases both had a mean size of 1.3 cm. In the patients with hepatic hemangiomas, scintigraphy showed no lesions. CT, angiography, or MR imaging showed a lesion in 40%-93%. With metastases present, any liver lesion was detected in 93% with scintigraphy versus 20%-60% with another modality. Scintigraphy depicted liver metastases in 93% of patients, which was higher than the sensitivities of other modalities. The accuracy (96%) and positive (100%) and negative (93%) predictive values of scintigraphy for detecting liver metastases were superior to those of other modalities. There were 45 liver metastases and 31 hemangiomas; a per lesion analysis gave results similar to the per patient analysis results. CONCLUSION: In Zollinger-Ellison syndrome, somatostatin-receptor scintigraphy provides an excellent diagnostic tool to differentiate small hepatic hemangiomas from small liver metastases.

Adult↗
PubMed1996

Repeated electroconvulsive stimulation impairs synaptic plasticity in the dentate gyrus in vivo but has no effect in CA1 in vitro.

Repeated electroconvulsive stimulation (ECS) spaced at 48 h intervals significantly increased the synaptic response in the dentate gyrus in vivo, as measured by input/output curves, and reduced the degree of long-term potentiation (LTP) obtained following high frequency stimulation. An identical course of ECS had no effect on synaptic responses recorded in the stratum radiatum of CA1 in vitro and did not impair high frequency-induced LTP. These results suggest that either ECS has a selective effect on the sub-fields of the hippocampus or that in vitro recording techniques are unsuitable for detecting the increase in synaptic efficacy produced by the treatments.

Animals↗
PubMed1996

Somatostatin receptor scintigraphy: its sensitivity compared with that of other imaging methods in detecting primary and metastatic gastrinomas. A prospective study.

OBJECTIVE: To compare the sensitivity of somatostatin receptor scintigraphy done using [111In-DTPA-DPhe1]octreotide with that of other imaging methods in the localization of gastrinomas in patients with the Zollinger-Ellison syndrome. DESIGN: Prospective study. SETTING: Referral-based clinical research center. PATIENTS: 80 consecutive patients with the Zollinger-Ellison syndrome. INTERVENTIONS: Conventional tumor localization studies (ultrasonography, computed tomography [CT], magnetic resonance imaging [MRI], selective angiography, and bone scanning) and somatostatin receptor scintigraphy done using [111In-DTPA-DPhe1]octreotide with single-photon emission CT imaging at 4 and 24 hours. Patients with possible liver metastases had biopsies done for confirmation, and 15 patients had exploratory laparotomies done to assess primary tumor localization. RESULTS: Extrahepatic gastrinomas or liver metastases were identified by ultrasonography in 19% of patients, by CT in 38% of patients, by MRI in 45% of patients, by angiography in 40% of patients, and by somatostatin receptor scintigraphy in 70% of patients. Somatostatin receptor scintigraphy was as sensitive as the other tests combined (59%), and when the results of all other tests were added to the somatostatin receptor scintigraphy results, tumors were localized in 75% of patients. Among patients with a possible primary tumor, the results of ultrasonography were positive in 9%, the results of CT were positive in 31%, the results of MRI were positive in 30%, the results of angiography were positive in 28%, and the results of somatostatin receptor scintigraphy were positive in 58%. Somatostatin receptor scintigraphy was as sensitive as all of the other imaging studies combined; when the results of scintigraphy were added to the results of the other studies, possible primary tumors were identified in 68% of patients. In 24 patients who had histologically proven metastatic liver disease, sensitivities for the detection of any metastatic liver lesions were 46% for ultrasonography, 42% for CT, 71% for MRI, 62% for angiography, and 92% for somatostatin receptor scintigraphy. Somatostatin receptor scintigraphy was significantly better than all of the conventional imaging methods in the identification of gastrinomas later found at surgery (P = 0.004), but it still missed 20% of gastrinomas. CONCLUSIONS: Somatostatin receptor scintigraphy is the single most sensitive method for imaging either primary or metastatic liver lesions in patients with the Zollinger-Ellison syndrome. Because of its sensitivity, simplicity, and cost-effectiveness, it should be the first imaging method used in these patients. For patients with negative results on somatostatin receptor scintigraphy, guidelines about the use of other imaging studies are proposed.

Adolescent↗
PubMed1996

IFN-alpha beta reconstitutes the deficiency in lipid A-activated AKR macrophages for nitric oxide synthase.

AKR mouse peritoneal macrophages (PM) were previously found to have a defect in their response to lipid A for nitric oxide (NO)-mediated tumor cytotoxicity, which was related to a lower level of C1q synthesis and reconstituted by exogenous IFN-gamma or C1q. We used AKR-PM as a model to further define the role of IFN-alpha beta in modulation of induction of macrophage nitric oxide synthase (NOS) in response to lipid A. Studies have revealed that AKR-PM produced a significantly lower level of IFN-alpha beta than responsive C3H-PM in response to lipid A. AKR-PM failed to increase NOS mRNA synthesis and NO generation when exposed to lipid A, although they had normal levels of TNF-alpha bioactivity and mRNA expression. This partial deficiency of AKR-PM to lipid A stimulation was reconstituted completely by exogenous IFN-alpha beta for both synthesis of NOS mRNA and release of NO. The failure of AKR-PM to produce NOS to lipid A stimulation appears to be related to reduced secretion of IFN-alpha beta and the resultant failure to express TNF-alpha type II receptor (TNF-RII) mRNA, which in turn decreases TNF-alpha binding to its receptor for autocrine induction of NOS. Insufficient synthesis and secretion of endogenous IFN-alpha beta may be the primary reason for AKR-PM refractoriness to induction of NOS in response to lipid A. furthermore, the close correlation between lack of IFN-alpha beta secretion and decreased TNF-RII mRNA synthesis may implicate a critical role for IFN-alpha beta in the upregulation of macrophage TNF-RII receptor expression for autocrine induction of NOS during lipid A stimulation.

Animals↗