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Biomedical subjects

L Carter

Publications and source records attributed to L Carter.

At least 19 recordsLinked to original sources
PubMed1995

Lysine residues at positions 234 and 236 in yeast porin are involved in its assembly into the mitochondrial outer membrane.

Various point mutations of lysyl residues in yeast mitochondrial porin (283 residues) were tested for their ability to assemble in vitro into the outer membranes of intact yeast mitochondria. Assembly was evaluated by protection from proteinases. The extent of assembly of two of the mutants, K234E and K236E porins, was much less than for wild-type in either post-translational or co-translational assembly assays. Lysine to glutamate mutants at other positions and K234R porin assembled as well as wild-type, but K234Q porin was poorly inserted. When both Lys-234 and Lys-236 were mutated, K234R/K236R porin was inserted better than K234Q/K236Q porin, which was inserted better than K234E/K236E; however, none of these mutants assembled as well as wild-type porin. It was concluded that optimal assembly of yeast porin depended on the presence of positively charged residues at both positions 234 and 236 and a lysine at one of these positions. After undergoing the assembly reaction, mutants that were vulnerable to proteinase K (i.e. K234E, K234Q, and K236E porins) seemed to be incompletely digested and were, to varying degrees, resistant to extraction by Na2CO3 (pH 11.5). These experiments suggested that these mutants were incompletely inserted into the outer membrane. Both Lys-234 and Lys-236 are included in an internal pentapeptide, VKAKV, that is conserved in porins from protists, plants, and animals, and it is possible that, at least, the lysines in this tract are one of the signals for the membrane assembly of these proteins.

Amino Acid Sequence↗
PubMed1995

Alterations in rat peripheral blood neutrophil function as a consequence of colitis.

Altered peripheral neutrophil function is a feature of IBD that may contribute to the chronicity and extragastrointestinal manifestations of this disease, but clinical evidence for such alterations is confounded by variations in patient characteristics, disease onset, and use of therapeutics that can influence neutrophil function. The use of a rat model of colitis has permitted us to characterize, in a controlled manner, the causal relationship between colitis and altered peripheral neutrophil function. At various times after induction of colitis with trinitrobenzene sulfonic acid (TNBS), peripheral neutrophils were isolated and assays of phagocytosis, chemotaxis, leukotriene B4 (LTB4) synthesis, and superoxide production were performed using a variety of stimuli. Circulating neutrophil numbers increased about fourfold within 12 hr of TNBS administration and returned to normal levels over the following two weeks. LTB4 synthesis in response to calcium ionophore decreased at 12 hr after induction of colitis, then returned to control levels. The chemotactic responses of peripheral neutrophils to LTB4 and FMLP in vitro and to LTB4 and IL-8 in vivo were profoundly suppressed through the two-week study period. Phagocytosis of nitroblue tetrazolium was significantly enhanced (ca. threefold) at 12 hr after induction of colitis and remained elevated throughout the study period. Superoxide production was also significantly elevated in the early phase of colitis (by ca. fourfold), but was not different from control levels at seven and 14 days. These results demonstrate that colonic inflammation profoundly influences peripheral blood neutrophil function, although the direction and magnitude of the alteration varied among the various functions assessed. The prolonged depression of chemotactic activity may represent a physiological reaction to limit the inflammatory response.

Animals↗
PubMed1995

Defective interleukin-1-induced ACTH release in cholestatic rats: impaired hypothalamic PGE2 release.

A complete regulatory loop exists between the immune and neuroendocrine systems. Proinflammatory mediators such as endotoxin (lipopolysaccharide) and interleukin-1 (IL-1) are capable of activating the hypothalamic-pituitary-adrenal (HPA) axis at the hypothalamic level, presumably by inducing the synthesis of prostaglandins. We have recently identified abnormalities in the stress-induced activation of the HPA axis in cholestatic rats. Therefore, in rats with cholestasis due to bile duct resection and sham-resected controls, we studied alterations in proinflammatory mediator-induced activation of the HPA axis and documented the role of alterations in hypothalamic prostaglandin synthesis in these abnormalities. Systemic administration of endotoxin and IL-1 resulted in a significant attenuation of adrenocorticotropic hormone (ACTH) release into plasma in bile duct-resected compared with sham-resected animals. This suppression of endotoxin- or IL-1-induced ACTH release in bile duct-resected rats was associated with a complete absence of IL-1-induced hypothalamic release of prostaglandin E2 (PGE2) in vitro in these animals. In contrast, sham-resected rats exhibited a 70% increase in hypothalamic PGE2 secretion in vitro in response to IL-1. However, bile duct-resected rats exhibited HPA axis activation similar to that of sham-resected animals in response to intracerebroventricularly infused PGE2. Therefore, cholestasis in the rat is associated with an attenuation of central activation of the HPA axis by proinflammatory mediators that appears to be mediated, at least in part, by defective IL-1-induced hypothalamic prostaglandin production.

Adrenocorticotropic Hormone↗
PubMed1994

ML 3000 reduces gastric prostaglandin synthesis without causing mucosal injury.

In this study we characterized the effects of a novel anti-inflammatory drug, ML 3000 ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine- 5-yl]-acetic acid), on the gastric mucosa and attempted to determine the mechanism responsible for its apparent stomach-sparing properties. Acute gastric damaging properties of ML 3000 versus indomethacin were examined in the rat, while chronic-type gastric ulcer was examined in the rabbit. At doses of up to 100 mg/kg p.o., ML 3000 did not produce significant acute gastric injury, while indomethacin at 5-20 mg/kg p.o. caused mucosal necrosis and bleeding. ML 3000 significantly inhibited gastric and blood prostaglandin E2 synthesis, with the higher doses tested (30 and 100 mg/kg) producing comparable effects to that seen with indomethacin at 10 or 20 mg/kg. Gastric and blood leukotriene B4 synthesis were not significantly affected by either drug. While indomethacin caused a significant increase in leukocyte adherence to mesenteric venules, ML 3000 did not. When administered repeatedly to rabbits, diclofenac caused penetrating ulcer formation in the gastric antrum of the majority of the animals. ML 3000 did not produce any detectable damage at doses of 10 or 30 mg/kg, but an ulcer was observed in one of five rabbits given the 100 mg/kg dose. Prior administration of ML 3000 (10-100 mg/kg) did not significantly affect the extent of gastric damage induced by subsequent oral administration of ethanol. These studies demonstrate that ML 3000 spares the gastric mucosa despite significantly suppressing gastric prostaglandin synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1994

Generation of polarized antigen-specific CD8 effector populations: reciprocal action of interleukin (IL)-4 and IL-12 in promoting type 2 versus type 1 cytokine profiles.

We have generated primary effector populations from naive CD8 T cells in response to antigen and determined their patterns of cytokine secretion upon restimulation. The effect of exogenous factors on the effector generation was examined and compared with responses of antigen-specific CD4 effectors generated under comparable conditions. CD8 cells from bm1 mice were stimulated with C57BL/6 (B6) antigen presenting cells (APCs) bearing allogeneic class I and CD8 cells from female severe combined immunodeficiency (SCID) B6 mice, transgenic for a T cell receptor alpha/beta (TCR-alpha/beta) that recognizes H-Y on Db, were stimulated with APCs from male mice. In parallel, CD4 cells from bm12 mice were stimulated with alloantigen and CD4 cells from V beta 3/V alpha 11 TCR transgenics were stimulated with a peptide of pigeon cytochrome c on IEk. T cells from both transgenic mice were of naive phenotype whereas normal mice contained 10-20% memory cells. Effector CD8 populations generated were L-selectin low, CD45RB high, and CD44 high. Naive CD8 cells from SCID anti-H-Y mice made little or no cytokine immediately upon stimulation in contrast to naive CD4 which produced large amounts of interleukin 2 (IL-2). Both populations, however, generated primary effectors over 4-5 d that made substantial quantities of many cytokines upon restimulation. Both CD8 and CD4 effectors produced similar patterns of cytokines with alloantigen or specific antigen. Cytokines present during naive CD8 stimulation influenced the cytokine secretion profile of the effectors, as previously shown for CD4 cells, although secretion by CD8 effectors was generally lower than that of CD4 effectors. CD8 cells cultured with IL-2 alone made predominantly interferon gamma (IFN-gamma) and no IL-4 or IL-5, similar to CD4 cells. Priming with IFN-gamma increased IFN-gamma secretion from CD4 effectors, but had little if any effect on CD8 cells. In contrast, priming with IL-12 generated CD8 effectors, as well as CD4 effectors, producing elevated quantities of IFN-gamma, with similar levels from both the CD4 and CD8 populations. The presence of IL-4 during effector cell generation promoted synthesis of IL-4 and IL-5 from both CD8 and CD4 cells while downregulating IFN-gamma secretion. CD8 cells made only small amounts of IL-4, more than 100-fold less than CD4 cells, whereas significant levels of IL-5 were induced, only 3-10-fold lower than from CD4.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Interleukin 1 beta and corticotropin-releasing factor inhibit pain by releasing opioids from immune cells in inflamed tissue.

Local analgesic effects of exogenous opioid agonists are particularly prominent in painful inflammatory conditions and are mediated by opioid receptors on peripheral sensory nerves. The endogenous ligands of these receptors, opioid peptides, have been demonstrated in resident immune cells within inflamed tissue of animals and humans. Here we examine in vivo and in vitro whether interleukin 1 beta (IL-1) or corticotropin-releasing factor (CRF) is capable of releasing these endogenous opioids and inhibiting pain. When injected into inflamed rat paws (but not intravenously), IL-1 and CRF produce antinociception, which is reversible by IL-1 receptor antagonist and alpha-helical CRF, respectively, and by the immunosuppressant cyclosporine A. In vivo administration of antibodies against opioid peptides indicates that the effects of IL-1 and CRF are mediated by beta-endorphin and, in addition, by dynorphin A and [Met]enkephalin, respectively. Correspondingly, IL-1 effects are inhibited by mu-, delta-, and kappa-opioid antagonists, whereas CRF effects are attenuated by all except a kappa-antagonist. Finally, IL-1 and CRF produce acute release of immunoreactive beta-endorphin in cell suspensions freshly prepared from inflamed lymph nodes. This effect is reversible by IL-1 receptor antagonist and alpha-helical CRF, respectively. These findings suggest that IL-1 and CRF activate their receptors on immune cells to release opioids that subsequently occupy multiple opioid receptors on sensory nerves and result in antinociception. beta-Endorphin, mu- and delta-opioid receptors play a major role, but IL-1 and CRF appear to differentially release additional opioid peptides.

Analysis of Variance↗
PubMed1994

Temporal analysis of the anti-inflammatory effects of decentralization of the rat superior cervical ganglia.

Bilateral decentralization of the superior cervical ganglia (SCG) reduced the pulmonary inflammation that develops 4-8 h after induction of anaphylaxis in Nippostrongylus brasiliensis-sensitized rats. Histamine levels in peritoneal lavage fluid and rat mast cell protease type II in serum were increased to comparable levels in sham-operated and decentralized rats. In vitro stimulation of alveolar macrophages (ALM) with lipopolysaccharide (LPS) provoked tumor necrosis factor-alpha (TNF-alpha) release that was two to three times greater with unchallenged decentralized rats than with sham-operated rats. However, after allergen challenge LPS-stimulated TNF-alpha release from ALM of sham-operated rats increased threefold and lasted at least 24 h, whereas with decentralized rats release of this cytokine actually decreased at 4 and 8 h. The increase in the phagocytosis and respiratory burst of circulating neutrophils seen at 4 and 8 h after allergen challenge in sham-operated rats was reduced significantly by decentralization. These results suggest that the attenuation of anaphylaxis-induced pulmonary inflammation that occurs with decentralization of the SCG is primarily associated with downregulation of neutrophil and macrophage functions.

Anaphylaxis↗
PubMed1993

Decentralization of the superior cervical ganglia inhibits mast cell mediated TNF alpha-dependent cytotoxicity. 1. Potential role of salivary glands.

Decentralization or ganglionectomy of the superior cervical ganglia (SCG) reduces pulmonary inflammation, as well as chemotaxis and activation of circulating neutrophils. However, the protective effect of decentralization was abolished when combined with removal of the submandibular glands (sialadenectomy) in the same animals. Thus, it has been postulated that the submandibular glands (SMG) release an anti-inflammatory factor(s) that is controlled by cervical sympathetic nerves. Decentralization of SCG did not modify in vitro histamine release or in vivo levels of rat mast cell protease II, but it reduced mast cell (MC)-mediated tumor necrosis factor alpha (TNF alpha)-dependent cytotoxicity. Combined decentralization/sialadenectomy abrogated the inhibition of MC cytotoxic activity, as we have shown previously for pulmonary inflammation and neutrophil functions. However, sialadenectomy alone inhibited MC-mediated TNF alpha-dependent cytotoxicity, an observation which suggests that SMG produce a factor(s) that can potentiate MC cytotoxic activity. Studies of the effects of SMG-derived factors, such as epidermal growth factor, nerve growth factor, and transforming growth factor beta (TGF beta), showed that only pretreatment of MCs with TGF beta 10(-8) g/ml inhibited MC-mediated TNF alpha-dependent cytotoxicity. Thus, the modulation of MC-mediated TNF alpha-dependent cytotoxicity by cervical sympathetic innervation and SMG is complex and distinct from the modulation of pulmonary inflammation and neutrophil functions identified previously.

Animals↗
PubMed1992

Inhibition of neutrophil chemotaxis and activation following decentralization of the superior cervical ganglia.

Recent studies have shown that bilateral decentralization (sympathectomy) of the superior cervical ganglia (SCG) of rats sensitized to the parasite Nippostrongylus brasiliensis attenuated the development of pulmonary inflammation following allergen challenge. Sympathectomy inhibited total leukocyte infiltration into lung lavage fluids, particularly neutrophil infiltration. To define the effects of decentralization of the SCG on neutrophil responses, peripheral blood neutrophils of rats were isolated and tested in in vitro chemotaxis and phagocytosis assays. Neutrophils from rats that were sympathectomized 7 days previously displayed a marked reduction in chemotaxis to N-formyl-methionyl-leucyl-phenylalanine and leukotriene B4 compared to neutrophils from sham-operated or unoperated groups. Although the degree of chemotaxis was greater in blood neutrophils from parasite-infected rats than from uninfected rats, sympathectomy markedly reduced the chemotactic responses of both groups. In addition, neutrophils of sympathectomized rats were unresponsive to lipopolysaccharide-induced metabolic activation as assessed by in vitro phagocytosis and oxidative reduction of nitroblue tetrazolium. Thus, decentralization of the SCG of rats affects the chemotactic responses and functions of neutrophils. Understanding the role of the sympathetic nervous system in modulating the behavior of neutrophils will shed light on the interactions between the nervous and immune systems.

Animals↗
PubMed1992

Hemoprotein-dependent production of a neutrophil-activating factor from arachidonic acid.

Hemoproteins have been suggested to contribute to various forms of tissue injury by catalyzing the peroxidation of lipids. In this study, the ability of hemoglobin to catalyze the production of a neutrophil-activating factor from arachidonic acid was examined. Incubation of arachidonic acid, hydrogen peroxide, and hemoglobin at 37 degrees C for 30 min resulted in the production of a lipid-extractable substance that was chemotactic for neutrophils in vitro and could stimulate leukocyte adherence in vivo. These actions could be inhibited by two leukotriene B4 (LTB4) receptor antagonists. The peroxidation product cross-reacted significantly with an antibody directed against LTB4, but not with an antibody directed against LTC4. The production of this factor was hemoprotein dependent. Immunoreactive LTB4 and biological activity were produced only when hemoglobin, or another hemoprotein, cytochrome c, was present in the reaction mixture. The amount of the factor produced could be increased in a concentration-dependent manner by increasing the amounts of arachidonic acid or hydrogen peroxide in the reaction mixture. The production of this factor could be inhibited by 5-aminosalicylic acid, catalase, or deferoxamine. Separation of the lipid-extractable products of the peroxidation of arachidonic acid on high-performance liquid chromatography revealed that the immunoreactive (with anti-LTB4) and chemotactic substance had a retention time distinct from that of LTB4 and the hydroxyeicosatetraenoic acids. A lipid-extractable substance with significant cross-reactivity to anti-LTB4 could also be produced if plasma was substituted for arachidonic acid in the reaction mixture.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminosalicylic Acids↗
PubMed1990

Marked antiinflammatory effects of decentralization of the superior cervical ganglia.

Intravenous challenge with parasite antigens in Nippostrongylus brasiliensis-sensitized rats resulted in anaphylactic shock and, in some animals, death. Surviving animals showed significant drop in mean arterial blood pressure, cardiac output, and blood flow to the trachea, bronchioles, and mesentery. After anaphylaxis, changes in the cellular and protein composition in bronchoalveolar lavage fluids (BALF) were assessed. 8 h after antigen challenge, there was significant influx of inflammatory cells and an increase in the levels of histamine and serum-derived immunoglobulins (IgG and IgM) in BALF. Chemotactic activity for neutrophils was also present in BALF. Once we established this anaphylaxis-induced model of pulmonary inflammation, we sought to determine whether or not the superior cervical ganglia (SCG) modulate this inflammation. We performed bilateral superior cervical ganglionectomy or decentralization of the SCG. Our results show that decentralization significantly reduced mortality (by 68%) after anaphylaxis. Furthermore, the increases in levels of serum-derived proteins, histamine, and influx of cells (especially neutrophils) observed in BALF after anaphylaxis were attenuated by both decentralization and ganglionectomy. By contrast, hemodynamic parameters in the respiratory tract and the presence of neutrophil chemotactic activity in BALF were not influenced by decentralization. Thus, the severity of pulmonary inflammation initiated by systemic anaphylaxis is depressed by bilateral ganglionectomy or decentralization of SCG.

Animals↗
PubMed1990

The sodium-22 influx in erythrocytes from black males and females.

In order to establish a standard for sodium influx in erythrocytes for the black population, 22Na+ uptake was measured in 29 normotensive black volunteers. Nineteen males and 10 females during the follicular phase of the menstrual cycle were studied utilizing the procedure of Gambhir et al. (1). In the males, cell concentrations ranging from 0.64 to 2.0 X 10(9)/ml showed an influx of 0.42 to 1.34% of the total 22Na+ added, and in the females, using the same erythrocyte concentrations, the 22Na+ influx ranged from 0.37 to 1.1%; these differences were not significant. Intraassay variation of the 22Na+ data was 4.8%. Interassay variations have been explained elsewhere (1). These data provided a range of observed values for 22Na+ uptake in erythrocytes from a subpopulation of normotensive black males and females for comparison with hypertensive patients.

Adult↗
PubMed1990

Anti-sperm antibodies in homosexual men: prevalence and correlation with sexual behaviour.

The sera of 60 homosexual males were examined for the presence of antibodies to sperm using an indirect immunobead test (IBT). Six of 60 (10%) had antibodies of IgG isotype; in addition two of the six had antibodies of IgA isotype. The presence of antibodies was associated with the practice of unprotected receptive anal intercourse in the previous six months. Antibodies were not found in homosexual men who were celibate, or who practised only oral intercourse during the same period. There was no correlation between the presence of anti-sperm antibodies and antibodies to human immunodeficiency virus (HIV), or numbers of T lymphocytes. These preliminary results lend support to the hypothesis that antigen presentation in the lower gut may be a source of sensitisation against sperm. The possibility that anti-sperm antibodies may be a marker of receptive anal intercourse merits further investigation.

Adult↗
PubMed1989

Antibody responses in the liver and bile of rats injected with horse erythrocytes.

The intravenous injection of 1 ml of a 0.1% (or higher %) suspension of horse red blood cells (HRBC) into rats results in the appearance of high levels of agglutinating activity in bile as well as serum. Lower doses of HRBC induce reduced responses in both fluids, demonstrating that the biliary response is as dose-dependent as the serum response. The presence of IgM anti-HRBC antibody forming cells (AFC) in the liver in numbers equivalent to those detected in the spleen at day 6 of the study suggests them to be the most likely source of the biliary antibody. Also, the injection of HRBC into other parenteral sites (intramuscular [i.m.], intraperitoneal [i.p.] and intrathoracic cavity [i.t.]) results in a biliary response which is considered to originate from the IgM-, IgG- and IgA-anti-HRBC AFC detected in the liver, again in numbers approximating those detected in the spleen. Splenectomy of rats immunized i.p., i.m. and i.t. had only a minimal effect on the liver and biliary responses, indicating that AFC arising in peripheral lymphoid tissues can also relocate in liver. It is concluded that the liver is a major site of antibody synthesis following parenteral immunization leading to substantial levels of antibody being secreted into the gastrointestinal tract.

Animals↗
PubMed1989

The 20 questions task with families of schizophrenics: divergent findings.

The study attempted to replicate and extend the results of an earlier study by Wild and Shapiro (16), establishing the utility of Mosher and Hornsby's (8) 20 Questions Task as a means of differentiating families with schizophrenic patients from those of psychiatrically hospitalized but nonschizophrenic individuals. In the current study, Wild and Shapiro's original design was expanded and revised by (a) diagnosing patients using Research Diagnostic Criteria rather than hospital diagnoses and (b) including families with schizophrenic daughters and/or one-parent families, in addition to intact families with schizophrenic sons. Families were comparable on age, intelligence, and socioeconomic variables. The results failed to replicate those reported by Wild and Shapiro, and indicated that the 20 Questions Task was sensitive to differences in family constellation and offspring gender as well as offspring diagnosis. The findings suggest that forms of familial communication deviance detected with the 20 Questions Task may not be unique to families of schizophrenics, thus highlighting the need to expand research on family communication deviance in families with schizophrenic offspring to families with varied family constellations and characteristics.

Attention↗