[Bronchial asthma: options for prophylaxis and nonmedical therapy].
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Allergens↗
Biomedical subjects
Y Katz
Publications and source records attributed to Y Katz.
IL-13 results in differential regulation of the complement proteins C3 and factor B in tumour necrosis factor (TNF)-stimulated fibroblasts.
IL-13, like IL-4, a product of activated T cells, has multiple biological actions, primarily on B cells and monocytes. The purpose of the present study was to compare the effects of IL-13 with those of IL-4 on the synthesis of complement proteins in fibroblasts. Dermal fibroblasts were developed from skin biopsies. Confluent monolayers were stimulated with the relevant cytokine or combinations of cytokines and biosynthetically labelled with 35S-methionine. The specific proteins were analysed using immunoprecipitation and SDS-PAGE. Addition of IL-13 to fibroblast cultures treated with TNF-alpha resulted in a dose-dependent increase in C3 protein biosynthesis and a concomitant down-regulation of factor B protein biosynthesis. In TNF-stimulated fibroblasts, the addition of IL-13, 100 ng/ml, induced a 2.45-fold increase in the synthesis of C3, while in the same cells under identical conditions the synthesis of factor B was only 42% of the level without IL-13. Similar effects of IL-13 were noted on IL-1-treated fibroblasts. These effects were specific for C3 and factor B, and no alteration of the constitutive or TNF-induced synthesis of C1s or C1 inhibitor proteins was observed. IL-13 altered the synthesis of C3 and factor B proteins also in fibroblasts stimulated with interferon-gamma (IFN-gamma) in addition to TNF, in the same direction as it did in cells stimulated with TNF alone. IL-13 has similar effects to those of IL-4 on the synthesis of C and factor B in TNF- and IL-1-stimulated fibroblasts. The observed effects of IL-13 are IL-4-independent, as anti-IL-4 antibody abrogates IL-4-induced effects, but has no effect on IL-13-induced responses. This interaction between different cytokines on the synthesis of proinflammatory and immunoregulatory proteins may have significance, particularly at local sites of inflammation, and may affect the synthesis of complement proteins in inflamed joint as in rheumatoid arthritis.
Adolescent↗
Synthesis of complement proteins in amnion.
The amnion is a metabolically active tissue that has been identified as a site of synthesis of numerous products. We report that amnion tissue explants and amnion-derived epithelial cells synthesize and secrete six proteins of the complement system, C1r, C1s, C1 inhibitor, factor B, C3, and factor H. Synthesis of C2 was minimal and variable, and C5 was not detected. The six synthesized proteins had size and subunit composition characteristic of proteins synthesized in HEp2, a long term cell line derived from malignant epithelial cells. Constitutive and regulated synthesis of five of the six proteins was similar in amnion tissue and cells. However, synthesis of factor B was different in tissue and cells; constitutive synthesis was 12-fold higher in tissue than in cells, and interleukin-1 did not alter synthesis in tissue, but increased synthesis by 11.7-fold in cells. These results indicate that amnion may be a source of complement proteins present in the amnion fluid and may contribute to local host defense along with endometrial glandular epithelial cells, which synthesize C3. Furthermore, our results suggest that amnion tissue is stimulated in vivo to synthesize factor B and cannot respond to interleukin-1 with a further increase in the synthesis rate.
Adult↗
A controlled trial of tranexamic acid therapy for the reduction of bleeding during treatment of acute myeloid leukemia.
In order to determine the efficacy of the antifibrinolytic agent tranexamic acid (TA) in reducing bleeding and platelet transfusions during the treatment of acute myeloid leukemia (AML), we conducted a randomized placebo-controlled double-blind study. Patients with AML undergoing induction or postremission consolidation chemotherapy were randomized into TA or placebo groups. Patients were not given platelet transfusions prophylactically but only when bleeding occurred. The severity of any bleeding event was scored. Thirty eight patients were randomized during induction. There were no significant differences between the two groups in the number of bleeding events and their severity or in the number of platelet transfusions given. Eighteen patients were studied during consolidation. In contrast, to the induction period, during consolidation there was a significantly less severe bleeding tendency in the TA group resulting in a lower platelet transfusion requirement [3.7 +/- 4.1 vs. 9.3 +/- 3.3 platelet units (p < .05)]. TA was well tolerated and no side effects were seen and no specific thromboembolic events were noticed. We conclude that giving TA during the thrombocytopenic period of AML patients undergoing consolidation chemotherapy is beneficial and safely reduces platelet transfusions.
Acute Disease↗
Compound heterozygous complement C3 deficiency.
Complete deficiency of the third component of the complement system is a result of defects in the two alleles of the C3 gene. In this study a family with C3 deficiency is reported; the parents expressed a distinct abnormality of the C3 gene and their two children had compound heterozygous C3 deficiency. These are the first reported cases of compound heterozygous complement deficiency. Our results indicate that the maternal abnormality leads to synthesis of an abnormal proC3 protein which is not secreted from the cells. The paternal abnormality results in ablation of synthesis of the proC3 protein.
Autoradiography↗
[Role of breast milk feeding in avoidance of asthma and other allergic disorders].
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Asthma↗
Inherited human complement C3 deficiency. An amino acid substitution in the beta-chain (ASP549 to ASN) impairs C3 secretion.
We recently described a case of hereditary complement C3 deficiency (C3D) in a New Zealand male who has a small amount of serum C3 (7 micrograms/ml), a normal size 5.2-kilobase C3 mRNA that is present in normal quantities, and a normal size M(r) 180,000 proC3 molecule that is synthesized in normal amounts. Secretion of C3 from this patient's cells was greatly diminished, however, and an aberrant C3 trypsin cleavage profile indicated an abnormality in the proC3 structure. To determine the primary structure of the C3D proC3 molecule, the corresponding cDNA was cloned and sequenced in the present study, revealing a normal signal peptide, tetraarginine linker, and thiolester domain. One nucleotide substitution in exon 13 (G1705 AC to AAC) was found, however, that resulted in an amino acid change in a highly conserved region of the C3 beta-chain (Asp549 to Asn). This substitution has not been described in any individual with either C3 Fast or C3 Slow phenotypes. Immunoprecipitation of C3 from L-cells transfected with full-length normal and C3D cDNAs demonstrated that C3 was secreted by the cells transfected with the normal C3 cDNA; however, only a C3 precursor was detected in the intracellular compartment of the cells transfected with the C3D cDNA and none detected extracellularly. Immunofluorescence studies revealed a perinuclear localization of C3 in the C3D transfectants, arrested early in the secretory pathway. Allele-specific polymerase chain reaction analysis demonstrated that this New Zealand family is a compound heterozygous C3D kindred, with the Asn549 point mutation being inherited from the mother and a yet undescribed C3 defect being inherited from the father. Taken together, these data indicate that 1) C3 deficiency is caused in a New Zealand kindred by two distinct molecular genetic mutations, one being an amino acid substitution in a highly conserved region of the beta-chain that results in impaired C3 secretion, and 2) the molecular basis of this deficiency has not been described in any other C3-deficient individual, providing additional evidence that multiple defects cause inherited C3 deficiency in humans.
Alleles↗
Interactions between laudanosine, GABA, and opioid subtype receptors: implication for laudanosine seizure activity.
We examined the interactions of D,L-laudanosine, a potentially epileptogenic metabolite of the neuromuscular relaxant atracurium besylate, with gamma-aminobutyric acid (GABA) and opioid binding sites, all of which have been implicated in seizure activity. Laudanosine was almost ineffective at [3H]muscimol binding to high-affinity GABA receptors (IC50 = 100 microM). However, laudanosine displayed an inhibitory effect at the low-affinity GABA receptors labeled by [3H]bicuculline methochloride, with an IC50 value of 10 microM. At the opioid receptor subtype, laudanosine lowered radiolabeled opioid binding at the mu 1, mu 2, delta, kappa 1, and kappa 3 receptors with Ki values of 2.7, 13, 5.5, 21, and 24 microM, respectively, concentrations seen clinically in blood and approaching those measured in cerebrospinal fluid. Saturation studies of mu 1, mu 2, delta, and kappa 3 sites in the presence of laudanosine revealed competitive interactions, with increases in the apparent Kd values but without significant changes in the maximal numbers of binding sites. In addition, we investigated whether the in vitro laudanosine-opioid receptor interaction would also be expressed by analgesic physiologic effects. We found that laudanosine elicited a dose-dependent analgesia in mouse tail-flick assay that was attenuated by coadministration of beta-funaltrexamine (mu 1- and mu 2-selective antagonist) and of naloxonazine (mu 1 antagonist), but not by nor-binaltorphimine (kappa 1-selective antagonist) or naltrindole (delta-selective antagonist), indicating a mu 1 mechanism for analgesia-mediated property of laudanosine. There is evidence suggesting mu 2 activity as well, but this is due to the ability of laudanosine to elicit analgesia when given intrathecally. We also observed cross-tolerance between laudanosine and morphine, as well as a partial effect of laudanosine on gastrointestinal transit. These results suggest an interaction between laudanosine and the low-affinity GABA receptor, as well as opioid mu 1 and mu 2 receptors.
Animals↗
[Inhaled corticosteroids--a safe treatment for asthma?].
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Administration, Inhalation↗
Anesthesia and the Meyer-Overton rule. I. Potencies and perturbations.
The Meyer-Overton rule is used extensively in the analysis of general anesthesia, but there is no satisfactory explanation of its origins. In this article we explore its physical content and show that it is not possible to explain this rule by using anesthetic potencies alone: we must consider also the perturbations at anesthetic sites. We then show that, under certain conditions, the Meyer-Overton rule can be used as a "perturbation gauge." The findings contradict the common belief that the rule provides little information about interactions of anesthetic molecules with the membrane constituents of the anesthetic site.
Anesthesia, General↗
Anesthesia and the Meyer-Overton rule. II. A solution theory view of anesthesia and perturbations.
Solution theory arguments play a significant role in the analysis of general anesthesia. However, the results are of limited value, due to the complexity of the systems to which these arguments are applied. This article suggests that we can advance our understanding of anesthesia by the analysis of a solution of hard spheres as an "ideal anesthetic medium." We obtain a precise definition of perturbation, which links together its structural and thermodynamical aspects in an accurate theory. It follows that this link applies to virtually all material systems, including the complex biological systems where anesthesia occurs. The derived relations: (i) explain the unique role of helium in hyperbaria; (ii) suggest how to establish a hierarchy of importance among possible causes of anesthesia; (iii) indicate the role of the Meyer-Overton rule in analyzing structural models of anesthesia; and (iv) depict the physical meaning of correlations, commonly used in anesthetic work, and show why they are more accurate than the Meyer-Overton rule.
Anesthesia, General↗
Effects of chronic prenatal, neonatal and adult exposure to barbiturates on mitochondrial benzodiazepine receptors in mouse testis.
In the present study we investigated the effect of chronic exposure to phenobarbital, administered to mice during the prenatal or neonatal period, as well as to adult mice, on mitochondrial benzodiazepine receptors in the testis. Three modes of treatment were investigated: (1) offspring of pregnant mice receiving food containing 3 g/kg phenobarbital until gestational day 18 were killed at 22 or 50 days of age and assayed for receptor binding (prenatal group); (2) offspring of untreated mice were injected subcutaneously once daily with 50 mg/kg phenobarbital on days 2-21 of age and killed at 22 or 50 days of age (neonatal group); (3) adult mice were injected subcutaneously once daily for 3 weeks with 50 or 100 mg/kg phenobarbital (adult group). Prenatal or neonatal exposure to phenobarbital did not alter the testicular weight in all groups (except for the neonatally exposed group killed at 22 days of age), or the mitochondrial benzodiazepine receptor binding characteristics. However, the maximal number of these receptors in the testes of mice in the adult group receiving 100 mg/kg phenobarbital was significantly increased (42%, P < 0.05), compared to controls. The administration of 50 mg/kg phenobarbital to the adult group also induced an increase (27%, non-significant) in testicular mitochondrial benzodiazepine receptors. Phenobarbital administration did not affect the receptor affinity values or the weight of the testis. It is unclear whether these receptor alterations due to chronic phenobarbital exposure of adult mice reflect functional changes in the testis.
Animals↗
Inherited complement C3 deficiency: a defect in C3 secretion.
The molecular basis of inherited complement C3 deficiency in a 20-year-old newly diagnosed male patient was studied. Using an enzyme-linked immunosorbent assay, the patient's C3 serum level was found to be approximately 7 micrograms/ml, which is less than 1% of normal. In contrast, Northern analysis indicated that the patient's C3 mRNA was of normal size and quantity. Peripheral blood monocytes (PBM) and skin fibroblast cultures (F) from the patient and from healthy donors were labeled for 2 h with [35S] methionine. Analysis of cell lysates and supernatants by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated normal levels of C3 in lysates of patient's PBM and F. However, C3 secretion in the patient's cells was extremely reduced, with pulse-chase experiments demonstrating a long delay in the disappearance of intracellular C3. Secretion of C1r and factor B by the patient's cells was normal. Lipopolysaccharide and interleukin-1 increased C3 synthesis in the patient's PBM and F, but had no effect on the secretion. SDS-PAGE analysis of trypsin-cleaved intracellular C3 revealed an aberrant cleavage profile for the patient's C3. Collectively, these data indicate that C3 deficiency in this patient is due to a defect in the C3 secretion, probably as the result of abnormality in the proC3 structure.
Adolescent↗
Glutamine metabolism and utilization: relevance to major problems in health care.
Glutamine plays an important role in normal and pathophysiological states. In this review we describe the biochemical synthesis and degradation pathways of glutamine, as well as its utilization by the immune system and in rapidly dividing cells. Also discussed are glutamine behaviour in catabolic states and the therapeutic implications of this amino acid in total parenteral nutrition, digestive diseases and cancer.
Animals↗
Developmentally regulated effects of lipopolysaccharide on biosynthesis of the third component of complement and factor B in human fibroblasts and monocytes.
Developmental regulation of the effects of lipopolysaccharide (LPS) on complement protein biosynthesis was studied in human fibroblasts from fetuses, newborn infants and adults, and in human monocytes from newborn infants and adults, using RNA blot analysis and immunoprecipitation of metabolically radiolabelled cell lysates. The responsiveness of the third component of complement (C3) and factor B protein synthesis to LPS is limited by translational mechanisms in the newborn infant and by pretranslational mechanisms in the fetus. Translation of RNA from LPS-induced cells in a rabbit reticulocyte lysate cell-free translating system indicated no differences in specific translational activity between LPS-induced adult and neonatal RNA, suggesting that LPS-induced neonatal C3 and factor B transcripts are translationally competent, but lack either access to relevant protein synthetic pathways or co-factor(s) necessary for translation. Interferon-gamma (IFN-gamma) enhanced translational activity of LPS-induced C3 and factor B transcripts in neonatal cells, suggesting that lack of translation in these cells may be due to the absence of a necessary co-factor. Experiments with LPS and cycloheximide or LPS and interleukin-1 alpha (IL-1 alpha) suggested that a newly synthesized protein did not participate in translational regulation and that LPS induction did not alter translational activity of IL-1 alpha-induced C3 and factor B transcripts. We conclude that the responsiveness of C3 and factor B protein synthesis to LPS is regulated at developmentally unique and specific steps in gene expression.
Adolescent↗
Adrenal mitochondrial benzodiazepine receptors are sensitive to agents active at the dopamine receptor.
Male rats were treated for 21 days with drugs known to affect prolactin secretion, in order to assess the effects of these drugs on mitochondrial benzodiazepine receptors (MBRs). Sulpiride, a selective dopamine D2 receptor antagonist and hyperprolactinemic agent, decreased MBR density in the adrenal gland (49%; P < 0.005), whereas metoclopramide, another dopamine antagonist with a preference for dopamine D2 receptors, increased adrenal gland MBR density (31%; P < 0.05). Bromocriptine, a specific dopamine agonist, increased MBR density in this organ (87%; P < 0.001). None of the three agents influenced kidney or testicular MBRs. These data indicate that the mechanism of organ-specific alterations in MBRs seems to be prolactin independent.
Adrenal Glands↗
Regulation of synthesis of complement proteins in HEp2 cells.
We investigated the synthesis of complement proteins in HEp2 cells and its regulation. Using metabolic labeling with [35S]methionine, immunoprecipitation, and SDS-PAGE, we demonstrated that HEp2 cells synthesized C1r, C1s, C1 inhibitor, C3, C4, factor B, and factor H. The constitutive synthesis of C1r and C1s were the highest among these proteins, whereas the synthesis of C4 was observed only when the cells were stimulated with IFN-gamma. C1r and C1s were secreted readily, whereas the rate of the secretion of C4 and C1 inhibitor was much slower. Activated forms of C1r, C1s, and complexes of C1 inhibitor--C1s were found. IL-1 and TNF induced 6- and 7-fold increases in the synthesis of C3 and factor B. IFN-gamma induced increases in the synthesis of all seven proteins, the most pronounced effects being on the synthesis of C4 and C1 inhibitor--15- and 44-fold, respectively.
Complement System Proteins↗
Localized periorbital edema induced by aspirin.
We documented localized periorbital edema in two patients with aspirin sensitivity without underlying chronic urticaria. The reaction developed 30 min after ingestion of 62.5 and 125 mg of aspirin, respectively. No systemic symptoms were observed. Other NSAIDs did not induce symptoms. These patients were able to tolerate doses of aspirin after pretreatment with terfenadine. These observations suggest that histamine plays a central role in aspirin-induced skin reaction. Despite the fact that terfenadine blocks the drug-induced reaction, this protocol should be used with caution and only where there is no feasible alternative to aspirin.
Adolescent↗