Attributions for youth crime among British and Nigerian primary school children.
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Attitude↗
Biomedical subjects
K Pfeffer
Publications and source records attributed to K Pfeffer.
Essential role of gamma interferon in survival of colon ascendens stent peritonitis, a novel murine model of abdominal sepsis.
Despite considerable progress, peritonitis and sepsis remain life-threatening conditions. To improve the understanding of the pathophysiology encountered in sepsis, a new standardized and highly reproducible murine model of abdominal sepsis termed colon ascendens stent peritonitis (CASP) was developed. In CASP, a stent is inserted into the ascending colon, which generates a septic focus. CASP employing a stent of 14-gauge diameter (14G stent) results in a mortality of 100% within 18 to 48 h after surgery. By inserting stents of small diameters, mortality can be exactly controlled. Thus, CASP surgery with insertion of a 22G or 18G stent (22G or 18G CASP surgery) results in 38 or 68% mortality, respectively. 14G CASP surgery leads to a rapid invasion of bacteria into the peritoneum and the blood. As a consequence, endotoxemia occurs, inflammatory cells are recruited, and a systemic inflammatory response syndrome develops. Interestingly, the most pronounced upregulation of inflammatory cytokines (gamma interferon [IFN-gamma], tumor necrosis factor alpha [TNF-alpha] and interleukin-12) is observed in spleen and lungs. CASP surgery followed by stent removal at specific time intervals revealed that all animals survived if intervention was performed after 3 h, whereas removal of the septic focus after 9 h did not prevent death, suggesting induction of autonomous mechanisms of a lethal inflammatory response syndrome. 18G CASP surgery in IFN-gamma receptor-deficient (IFNgammaR-/-) mice revealed an essential role of IFN-gamma in survival of sepsis, whereas TNF receptor p55-deficient (TNFRp55-/-) mice did not show altered survival rates. In summary, this study describes a novel animal model that closely mimics human sepsis and appears to be highly suitable for the study of the pathophysiology of abdominal sepsis. Importantly, this model demonstrates a protective role of IFN-gamma in survival of bacterial sepsis.
Abdomen↗
Identification and functional importance of IL-1 receptors on rat parietal cells.
We studied the expression of interleukin-1 (IL-1) receptors and the effect of IL-1beta on the function of highly enriched (>97%) rat parietal cells. RT-PCR of parietal cell poly(A)+ RNA with primers specific for the rat IL-1 receptor revealed a single 547-kb PCR product highly homologous to the published sequence of the IL-1 receptor. Northern blot analysis of poly(A)+ RNA of rat parietal cells and brain revealed a single RNA species of 5.7 kb. Cytochemistry of parietal cell IL-1 receptor was performed with biotinylated recombinant human IL-1beta, visualized by avidin-coupled fluorescein. Corresponding to the high degree of parietal cell enrichment, 95% of the cells stained positive. Basal H+ production ([14C]aminopyrine accumulation) was not changed by IL-1beta (0.25-100 pg/ml) nor was the response to histamine or carbachol when added simultaneously with the cytokine. However, when parietal cells were preincubated with IL-1beta (0.5-5 pg/ml) for 10 min before the addition of histamine or carbachol, the response to these secretagogues was reduced by 35 and 67%, respectively. Inhibition by IL-1beta was fully reversed by the human recombinant IL-1 receptor antagonist. Preincubation of parietal cells with IL-1beta failed to alter histamine-stimulated cAMP production but markedly inhibited carbachol-induced formation of D-myo-inositol 1,4, 5-trisphosphate. In fura 2-loaded, purified parietal cells, 10 min preincubation with IL-1beta dramatically reduced the initial transient peak elevation of intracellular Ca2+ concentration in response to carbachol. We conclude that rat parietal cells express IL-1 receptors mediating inhibition of H+ production. The antisecretory effect of IL-1beta may contribute to hypoacidity secondary to acute Helicobacter pylori infection or during chronic colonization by H. pylori preferring the fundic mucosa.
1-Methyl-3-isobutylxanthine↗
Lung injury and oxidoreductases.
Acute lung injury represents a wide spectrum of pathologic processes, the most severe end of the spectrum being the acute respiratory distress syndrome. Reactive oxygen intermediates have been implicated as important in the pathobiochemistry of acute lung injury. The endogenous sources that contribute to the generation of reactive oxygen intermediates in acute lung injury are poorly defined but probably include the molybdenum hydroxylases, NAD(P)H oxidoreductases, the mitochondrial electron transport chain, and arachidonic acid-metabolizing enzymes. Our laboratory has focused, in particular, on the regulation of two of these enzyme systems, xanthine oxidoreductase (XDH/XO) and NAD(P)H oxidase. We observe that gene expression of XDH/XO is regulatory in a cell-specific manner and is markedly affected by inflammatory cytokines, steroids, and physiologic events such as hypoxia. Posttranslational processing is also important in regulating XDH/XO activity. More recently, the laboratory has characterized an NAD(P)H oxidase in vascular cells. The cytochrome components of the oxidase, gp91 and p22, appear similar to the components present in phagocytic cells that contribute to their respiratory burst. In human vascular endothelial and smooth muscle cells, oncostatin M potently induces gp91 expression. We believe that regulation of gp91 is a central controlling factor in expression of the vascular NAD(P)H oxidase. In summary, the studies support the concept that the oxidoreductases of vascular cells are expressed in a highly regulated and self-specific fashion.
Animals↗
Abnormal development of secondary lymphoid tissues in lymphotoxin beta-deficient mice.
The tumor necrosis factor (TNF) family cytokines lymphotoxin (LT) alpha and LTbeta form heterotrimers that are expressed on the surface of activated lymphocytes and natural killer cells; LTalpha homotrimers can be secreted as well. Mice with a disrupted LTalpha gene lack lymph nodes (LN), Peyer's patches (PP), and follicular dendritic cell (FDC) networks and reveal profound defects of the splenic architecture. However, it is unclear which of these abnormalities is the result of the absence in LTalpha homotrimers or LTalphabeta heterotrimers. To distinguish between these two possibilities, a mouse strain deficient in LTbeta was created employing Cre/loxP-mediated gene targeting. Mice deficient in LTbeta reveal severe defects in organogenesis of the lymphoid system similar to those of LTalpha-/- mice, except that mesenteric and cervical LN are present in most LTbeta-deficient mice. Both LTbeta- and LTalpha-deficient mice show significant lymphocytosis in the circulation and peritoneal cavity and lymphocytic infiltrations in lungs and liver. After immunization, PNA-positive B cell clusters were detected in the splenic white pulp of LTbeta-deficient mice, but FDC networks were severely underdeveloped. Collectively, these results indicate that LTalpha can signal independently from LTbeta in the formation of PNA-positive foci in the spleen, and especially in the development of mesenteric and cervical LN.
Animals↗
TNF receptor p55 controls early acute graft-versus-host disease.
Allogeneic bone marrow transplantation is frequently associated with graft-vs-host disease (GVHD). To understand the effector mechanisms of GVHD, we investigated the role of the TNF receptor p55 (TNFRp55), which is known to be important in inflammation and cytotoxicity. After the transplantation of allogeneic bone marrow and spleen cells to lethally irradiated mice, all wild-type recipients developed early lethal GVHD within 1 wk, whereas TNFRp55-deficient recipients had much reduced GVHD and survived for at least 3 wk. No defect in alloantigen presentation was found, since T cell proliferation and cytotoxicity were similar to allogeneic wild-type and TNFRp55-deficient stimulator and target cells. Also, TNF alpha release did not differ significantly between the two types of recipients. Therefore, early acute GVHD in wild-type mice was primarily due to TNFRp55-mediated tissue damage. Interestingly, lethal GVHD was not entirely dependent upon the TNFRp55. In experimental conditions using sublethal irradiation and high donor spleen cell numbers, TNFRp55-deficient recipient mice developed lethal GVHD with similar kinetics and frequency as the control mice. These data suggest that the effector mechanisms leading to organ damage in murine acute GVHD can be dissected in a cytokine pathway through the TNFRp55, as demonstrated here, and in a cellular pathway through direct interaction of cytotoxic lymphocytes with target tissues involving perforin and Fas/Fas ligand, as reported previously.
Animals↗
A rapid method for semiquantitative analysis of the human V beta-repertoire using TaqManR PCR.
Analysis of the V beta-repertoire of antigen-reactive T cell populations can be approached using either flow-cytometry or PCR-based techniques. While the former method requires a complete set of V beta-specific monoclonal antibodies (mAbs) and large cell numbers for analysis, the latter is both time-consuming and labour-intensive. To circumvent the drawbacks of both these methods we have employed the recently developed technique of TaqManR PCR to analyse the V beta-usage of human T cell populations. TaqManR PCR is based on the 5'-->3' nuclease activity of Taq polymerase. During PCR amplification an internal oligonucleotide probe, that is labelled with a fluorescent reporter and a quencher dye, is cleaved by Taq polymerase. After cleavage, quenching of the reporter dye is lost and reporter fluorescence can be detected with a fluorescence plate reader. Using one C beta-specific fluorogenic probe and a panel of V beta-specific primers, we show that fluorescence-detected amplification of TCR beta cDNA is V beta-specific and linear within a 2-3-log range of template concentration. The sensitivity of TaqManR PCR is comparable to conventional detection of PCR-products by agarose gel staining, while processing time is reduced. Furthermore, superantigen-induced skewing of the V beta-repertoire of human T cells is readily detected with this method. Thus TaqManR PCR is a reliable and fast method for semiquantitative analysis of the V beta-repertoire of human T cell populations.
Cells, Cultured↗
Low-molecular-weight tumor necrosis factor receptor p55 controls induction of autoimmune heart disease.
BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is involved in the pathogenesis of myocarditis and can bind to either tumor necrosis factor receptor (TNF-R) p55 or TNF-Rp75. However, it is not known which TNF-R mediates the specific functions of TNF in disease. To determine the role of the TNF/TNF-R system in chronic heart disease, we used a murine model of cardiac myosin-induced myocarditis that closely resembles the chronic stages of virus-induced myocarditis in humans. METHODS AND RESULTS: Mice lacking TNF-Rp55 expression after targeted disruption of the TNF-Rp55 gene were backcrossed into a genetic background susceptible to the induction of myocarditis with cardiac myosin. Here, we demonstrate that TNF-Rp55 gene-deficient mice did not develop any inflammatory infiltration into the heart after autoantigen injection, whereas control littermates showed autoimmune myocarditis at high prevalence and severity. Despite the absence of autoimmune heart disease, TNF-Rp55-/- mice produced cardiac myosin-specific IgG autoantibodies, indicating that activation of autoaggressive T and B lymphocytes had occurred. However, heart interstitial cells failed to express major histocompatibility complex (MHC) class II molecules in TNF-Rp55-/- animals, and adoptive transfer of autoreactive T cells resulted in heart disease only in TNF-Rp55-/- but not in TNF-Rp55-/- littermates. CONCLUSIONS: Cardiac myosin-induced myocarditis is dependent on autoaggressive T cells and on autoantigen presentation in association with MHC class II molecules within the heart. Thus, lack of TNF-Rp55 expression could interfere with either lymphocyte activation or target organ susceptibility. The data presented here show that the TNF-Rp55 is a key regulator for the induction of autoimmune heart disease by its controlling target organ susceptibility.
Animals↗
Listeriosis in p47(phox-/-) and TRp55-/- mice: protection despite absence of ROI and susceptibility despite presence of RNI.
The significance of host defense mechanisms in primary listeriosis in vivo is incompletely understood. Here, we show that tumor necrosis factor receptor p55-/- (TRp55-/-) mice are susceptible to Listeria monocytogenes infection in the presence of leukocyte recruitment, inflammatory cytokine production (including IFNgamma), nitric oxide synthesis, and oxidative burst formation. Mice deficient for oxidative burst (p47[phox-/-] mice) are relatively resistant to listeriosis. Despite activation of these antibacterial effector systems, TRp55-/- phagocytes in vivo are incapable of confining and eradicating L. monocytogenes inside phagolysosomes. Bone marrow chimeras reveal that for eradication of L. monocytogenes, TRp55 is crucially required only on cells from hematopoietic origin. Unexpectedly, prior to death, exocrine pancreatic cells undergo apoptosis in TRp55-/- mice. Collectively, these data demonstrate that in vivo, TRp55 initiates a protective, listericidal mechanism in phagocytes that differs from nitric oxide production and oxidative burst formation and that uncontrolled listeriosis results in necrotizing pancreatitis in TRp55-/- mice.
Animals↗
Transcriptional regulation of human xanthine dehydrogenase/xanthine oxidase.
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Cell Line↗
Mice lacking the TNF receptor p55 fail to resolve lesions caused by infection with Leishmania major, but control parasite replication.
TNF is involved in host resistance to several pathogens. Recently it was found that mice lacking the p55 receptor for TNF (TNFRp55 -/-) do not control growth of the intracellular bacteria, Listeria monocytogenes and Mycobacterium tuberculosis. Here we report that the course of infection in TNFRp55 -/- mice with another intracellular pathogen, the protozoan parasite Leishmania major, is also quite different from normal mice. TNFRp55 -/- mice developed larger lesions than control mice and failed to resolve these lesions. However, they were able to eliminate parasites within the lesions. Histologic analysis indicated that at late stages lesions from TNFRp55 -/- mice appeared similar to lesions associated with cutaneous graft-vs-host disease. Both TNFRp55 -/- and control mice developed a normal Th1-type response during infection. We also found that IFN-gamma-activated macrophages from TNFRp55 -/- mice produced nitric oxide and killed L. major in vitro, which correlated with the ability of TNFRp55 -/- mice to eliminate the parasites in vivo. The production of nitric oxide by macrophages from TNFRp55 -/- mice required the presence of the parasites, however, since in their absence TNF could only synergize with IFN-gamma for nitric oxide production when added to normal, but not TNFRp55 -/-, macrophages. These results indicate that neither macrophage microbicidal activity nor nitric oxide production is absolutely dependent on the p55 receptor for TNF. Furthermore, they uncover a previously undefined role for TNFRp55 in resolution of parasite-induced inflammatory lesions.
Animals↗
Defective Peyer's patch organogenesis in mice lacking the 55-kD receptor for tumor necrosis factor.
Lymphotoxin alpha (LT-alpha) may form secreted homotrimers binding to p55 and p75 tumor necrosis factor (TNF) receptors or cell surface-bound heterotrimers with LT-beta that interact with the LT-beta receptor. Genetic ablation of LT-alpha revealed that mutant mice have no detectable lymph nodes or Peyer's patches and that the organization of the splenic white pulp in T and B cell areas is disturbed. In this report we describe a novel function for the p55 TNF receptor during ontogeny and demonstrate that mice deficient for p55 completely lack organized Peyer's patches. In contrast, lymph nodes and spleen are present in p55-deficient mice and lymphocytes segregate normally into B and T cell areas in these organs. Lamina propria and intraepithelial lymphocytes of the small intestine were detected in normal number and distribution in p55 mutant mice. Lymphocytes and endothelial cells from p55-deficient mice express normal levels of adhesion molecules considered important for lymphocyte migration to mucosal organs; this indicates that the lack of Peyer's patches does not result from a defect in lymphocyte homing. In summary, the p55 receptor for TNF selectively mediates organogenesis of Peyer's patches throughout ontogeny, suggesting that the effects of LT-alpha on the development of lymphoid organs may be mediated by distinct receptors, each functioning in an organ-specific context.
Animals↗
Crucial role of 55-kilodalton TNF receptor in TNF-induced adhesion molecule expression and leukocyte organ infiltration.
Stimulation of leukocyte adhesion to the endothelium by TNF is mediated by the up-regulation of adhesion molecules on the endothelial cell surface. C57BL/6 mice and syngenic 55-kDa TNF receptor-deficient mice (TNFRp55-/- mice) were challenged with TNF, and the kinetics of intracellular adhesion molecule-1, ICAM-1, mucosal addressin cell adhesion molecule-1, vascular adhesion molecule-1 (VCAM-1), and E-selectin expression were examined in various organs. TNF induced sustained VCAM-1 expression within 4 h in lung, liver, and kidney. In the lungs, but not in other organs, transient E-selectin expression was induced by TNF within 0.5 h and peaked at 4 h. The TNF-induced expression of VCAM-1 and E-selectin was found to be exclusively controlled by the 55-kDa TNF-receptor (TNFRp55) as demonstrated by analysis of TNFRp55-/- mice. Furthermore, TNF triggered mononuclear cell and neutrophil infiltration of lung, liver, and kidney in C57BL/6 mice but not TNFRp55-/- mice. Interestingly, MAdCAM-1 expression in the marginal sinus of the spleen was detected in wild-type mice but was absent in TNFRp55-/- mice. Together, the data suggest that in vivo the 55-kDa TNF receptor mediates the induction of VCAM-1 and E-selectin expression and is critically involved in the control of leukocyte organ infiltration.
Animals↗
Tumor necrosis factor receptor p55 mediates deletion of peripheral cytotoxic T lymphocytes in vivo.
Cellular death of activated lymphocytes down-regulates immune responses and is involved in maintaining self tolerance. Signals associated with ligation of the membrane molecule Fas lead to lymphocyte apoptosis, but additional, Fas-independent mechanisms have been postulated. Here, we show a marked expansion and prolonged persistence of functional activated cytotoxic T cells in mice lacking the tumor necrosis factor (TNF) receptor p55. In the absence of this receptor, peripheral lymphocyte apoptosis was significantly reduced in vivo. The prolonged thymocyte survival was associated with functional anergy, since the T cells no longer proliferated in vitro when stimulated with peptide antigen. However, specific cytotoxic effector function was easily detected in vitro. We conclude that the TNF receptor p55 is involved in peripheral T cell deletion in vivo.
Animals↗
Children's auditory perception of movement of traffic sounds.
This study examined children's auditory perception of traffic sounds, focusing on identification of vehicle movement. Children in three age groups (5 years, 8 years and 11 years) were presented with recorded sounds of a car approaching, passing and going away from the listener. The auditory perception of movement was identified as a problem area for children, particularly younger children. The number of correctly identified vehicle sounds was found to significantly increase with age. Age differences in some aspects of auditory perception of vehicle movement were more noted than others. Identification of an approaching vehicle was the most difficult task for the 5-year-olds. The role of the attention-demanding characteristics of some traffic sounds and their correct identification was discussed, approaching vehicles catching the attention much later in the stimulus array than passing or receding vehicles. The implications of the results for road safety training were discussed.
Accident Prevention↗
CD28 signals through acidic sphingomyelinase.
T cell receptor recognition of antigen can lead either to T lymphocyte differentiation and proliferation or to a state of unresponsiveness, which is dependent on whether appropriate costimulatory signals are provided to the mature T cell. We have investigated a novel intracellular signaling pathway provided by the costimulatory molecule CD28. CD28 engagement triggers the activation of an acidic sphingomyelinase (A-SMase), which results in the generation of ceramide, an important lipid messenger intermediate. A-SMase activation by CD28 occurred in resting as well as in activated primary T cells or leukemic Jurkat cells. In contrast, ligation of either CD3 or CD2 did not result in A-SMase activation. Overexpression of recombinant A-SMase in Jurkat T cells substituted for CD28 with regard to nuclear factor-kB activation. These data suggest that CD28 provides an important costimulatory signal by activation of an acidic sphingomyelinase pathway.
Animals↗
Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice.
Understanding the immunological mechanisms of protection and pathogenesis in tuberculosis remains problematic. We have examined the extent to which tumor necrosis factor-alpha (TNF alpha) contributes to this disease using murine models in which the action of TNF alpha is inhibited. TNF alpha was neutralized in vivo by monoclonal antibody; in addition, a mouse strain with a disruption in the gene for the 55 kDa TNF receptor was used. The data from both models established that TNF alpha and the 55 kDa TNF receptor are essential for protection against tuberculosis in mice, and for reactive nitrogen production by macrophages early in infection. Granulomas were formed in equal numbers in control and experimental mice, but necrosis was observed only in mice deficient in TNF alpha or TNF receptor. TNF alpha and the 55 kDa TNF receptor are necessary conditions for protection against murine M. tuberculosis infection, but are not solely responsible for the tissue damage observed.
Amino Acid Oxidoreductases↗
T-lymphocyte development and function in gene-targeted mutant mice.
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Animals↗