Search PubMed⌕ Search

Biomedical subjects

L Shapiro

Publications and source records attributed to L Shapiro.

At least 145 records · Page 8Linked to original sources
PubMed1994

Monokine antagonism is reduced in patients with IDDM.

Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) have been implicated as immune effector molecules in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). Recently, an increased frequency of the A1/A1 genotype of an IL-1 receptor antagonist (IL-1Ra) gene polymorphism was observed in patients with IDDM. Therefore, we investigated plasma IL-1Ra and soluble TNF p55 receptor (TNFsRp55) levels in 18 men with recent-onset IDDM, 10 men with long-standing IDDM, and 35 age-matched healthy men. No differences in plasma IL-1Ra were found among the three groups. However, when the plasma IL-1Ra levels in the subjects with IDDM and the control subjects were analyzed according to IL-1Ra genotypes, we found a 30% lower level of plasma IL-1Ra in subjects with IDDM carrying the A1/A1 genotype compared with the levels in those carrying the A1/A2 genotype (372 +/- 40 vs. 530 +/- 54 ng/l, respectively, P = 0.025). In contrast, no significant association was seen between plasma IL-1Ra and IL-1Ra genotype in the control subjects. The TNFsRp55 level in heparinized plasma was 17% lower in patients with IDDM than in control subjects (3.93 +/- 0.22 vs. 4.72 +/- 0.24 micrograms/l, respectively, P = 0.038). These findings could not be explained by metabolic derangement in the IDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Cytokines in acute myocardial infarction: selective increase in circulating tumor necrosis factor, its soluble receptor, and interleukin-1 receptor antagonist.

Cytokines play a pathogenetic role in a variety of infective and inflammatory diseases. In the present study, we had two objectives: (a) to define the kinetics of tumor necrosis factor (TNF) in plasma after acute myocardial infarction (AMI) in patients treated with early thrombolysis, and (b) to measure other cytokines, interleukin-1 (IL-1) and TNF receptor antagonists, in plasma. TNF-alpha, but not IL-1 beta or IL-8, was present in plasma of 6 of 7 patients with severe AMI (Killip class 3 or 4). No TNF (< 50 pg/ml) was detected in a group of 11 patients with uncomplicated myocardial infarction (Killip class 1) or in control patients without AMI. Soluble TNF receptor type I and IL-1 receptor antagonist (IL-1Ra) were also significantly increased in the group with severe AMI compared with those with uncomplicated AMI. Circulating TNF is increased only in AMI complicated by heart failure at hospital admission. This finding may have diagnostic and therapeutic relevance.

Aged↗
PubMed1993

Ciliary neurotrophic factor is an endogenous pyrogen.

Fever is initiated by the action of polypeptide cytokines called endogenous pyrogens, which are produced by the host during inflammation, trauma, or infection and which elevate the thermoregulatory set point in the hypothalamus. Ciliary neurotrophic factor (CNTF) supports the differentiation and survival of central and peripheral neurons. We describe the activity of CNTF as intrinsically pyrogenic in the rabbit. CNTF induced a monophasic fever which rose rapidly (within the first 12 min) following intravenous injection; CNTF fever was blocked by pretreatment with indomethacin. The fever induced by CNTF was not due to contaminating endotoxins. Increasing doses of CNTF resulted in prolongation of the fever, suggesting the subsequent induction of additional endogenous pyrogenic activity. After passive transfer of plasma obtained during CNTF-induced fever, endogenous pyrogen activity was not present in the circulation; CNTF also did not induce the endogenous pyrogens interleukin 1, tumor necrosis factor, or interleukin 6 in vitro. Nevertheless, a second endogenous pyrogen may originate within the central nervous system following the systemic injection of CNTF. Of the four endogenous pyrogens described to date (interleukin 1, tumor necrosis factor, interferon, and interleukin 6), CNTF, like interleukin 6, utilizes the cell-surface gp 130 signal-transduction apparatus.

Adult↗
PubMed1993

Induction of circulating and erythrocyte-bound IL-8 by IL-2 immunotherapy and suppression of its in vitro production by IL-1 receptor antagonist and soluble tumor necrosis factor receptor (p75) chimera.

The objective of this study was 1) to investigate the in vivo production of IL-8 in patients undergoing IL-2 immunotherapy and 2) to study the influence of IL-1Ra, soluble TNF receptor p75 (TNFsRp75), and a TNFsRp75-Fc fusion protein on IL-2-induced IL-8 production in vitro. Circulating IL-8 was assessed both in plasma and erythrocyte lysates prepared from patients undergoing IL-2 immunotherapy. IL-8 was detectable in the plasma within 2-4 h after the first IL-2 infusion, reached a peak level after 4 h, and declined rapidly to undetectable within 8 h. Erythrocyte-bound IL-8 was also detected within 4 h of the first IL-2 dose, but levels were higher than those measured in plasma and remained elevated long after the plasma levels had become undetectable. On day 4 of therapy, the increases in both plasma and the erythrocyte-lysate IL-8 levels induced by an IL-2 injection were less pronounced than on day 1. Although IL-1Ra and TNFsRp75-Fc individually had only a modest suppressive effect on IL-2-induced IL-8 production by PBMC in vitro, the combination of IL-1Ra and TNFsRp75-Fc markedly down-regulated IL-2-induced IL-8 synthesis and steady-state mRNA levels. TNFsRp75 had no effect on IL-2-induced IL-8 synthesis. Our studies suggest that the transient detection of IL-8 in plasma early in the course of IL-2 treatment is due to erythrocyte sequestration and that suppressed synthesis, due in part to high levels of circulating IL-1 and TNF antagonists, may play a role later in the course of treatment.

Calcium↗
PubMed1993

A method for the detection of erythrocyte-bound interleukin-8 in humans during interleukin-1 immunotherapy.

Interleukin-8 (IL-8) has been recently shown to bind to human erythrocytes with high affinity and is therefore potentially difficult to detect in serum or plasma. IL-8 is transiently elevated in the serum of baboons after the administration of interleukin-1 alpha (IL-1 alpha). The objective of this study was to investigate whether IL-8 can be detected in the plasma or in detergent-lysed erythrocytes from cancer patients undergoing treatment with IL-1 alpha. Using a specific radioimmunoassay (RIA), plasma IL-8 was detected within 1-2 h after the first IL-1 alpha infusion. Thereafter, the levels declined rapidly and after 4-8 h were undetectable. Erythrocyte-bound IL-8 was detectable 1-2 h after the increase in plasma levels. The erythrocyte-bound IL-8 levels were higher than those measured in plasma and remained elevated long after the plasma levels had become undetectable. Erythrocyte membranes accounted for all of the erythrocyte-associated IL-8, as IL-8 was undetectable in the cytosol after erythrocyte lysis. The assay used in these studies detects IL-8 in erythrocyte lysates when it cannot be measured in plasma and may therefore be useful in monitoring IL-8 production in vivo.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Polar location of the chemoreceptor complex in the Escherichia coli cell.

The eukaryotic cell exhibits compartmentalization of functions to various membrane-bound organelles and to specific domains within each membrane. The spatial distribution of the membrane chemoreceptors and associated cytoplasmic chemotaxis proteins in Escherichia coli were examined as a prototypic functional aggregate in bacterial cells. Bacterial chemotaxis involves a phospho-relay system brought about by ligand association with a membrane receptor, culminating in a switch in the direction of flagellar rotation. The transduction of the chemotaxis signal is initiated by a chemoreceptor-CheW-CheA ternary complex at the inner membrane. These ternary complexes aggregate predominantly at the cell poles. Polar localization of the cytoplasmic CheA and CheW proteins is dependent on membrane-bound chemoreceptor. Chemoreceptors are not confined to the cell poles in strains lacking both CheA and CheW. The chemoreceptor-CheW binary complex is polarly localized in the absence of CheA, whereas the chemoreceptor-CheA binary complex is not confined to the cell poles in strains lacking CheW. The subcellular localization of the chemotaxis proteins may reflect a general mechanism by which the bacterial cell sequesters different regions of the cell for specialized functions.

ATP-Binding Cassette Transporters↗
PubMed1993

Requirement of the carboxyl terminus of a bacterial chemoreceptor for its targeted proteolysis.

The bacterium Caulobacter crescentus yields two different progeny at each cell division; a chemotactically competent swarmer cell and a sessile stalked cell. The chemotaxis proteins are synthesized in the predivisional cell and then partition only to the swarmer cell upon division. The chemoreceptors that were newly synthesized were located at the nascent swarmer pole of the predivisional cell, an indication that asymmetry was established prior to cell division. When the swarmer cell differentiated into a stalked cell, the chemoreceptor was specifically degraded by virtue of an amino acid sequence located at its carboxyl terminus. Thus, a temporally and spatially restricted proteolytic event was a component of this differentiation process.

Amino Acid Sequence↗
PubMed1993

Bacterial chromosome origins of replication.

Bacteria regulate chromosomal replication from one specific origin. We compare the regulatory requirements, DNA structures, and biochemical properties of the prototypic Escherichia coli origin with those of evolutionarily distant Bacillus subtilis and Caulobacter crescentus origins. The ubiquitous DnaA protein is a major regulator of all three bacterial origins. Unique features of these origins, however, may reflect specific regulatory requirements placed on them.

Bacteria↗
PubMed1993

Detection of tumor necrosis factor soluble receptor p55 in blood samples from healthy and endotoxemic humans.

The tumor necrosis factor (TNF) soluble receptor derived from the cell surface p55 TNF receptor (TNFsRp55) is a naturally occurring substance generated during infection and inflammation. TNFsRp55 inhibits biologic effects of TNF. An RIA was developed to quantitate TNFsRp55 in human blood. Recovery of TNFsRp55 from blood anticoagulated with EDTA was optimal compared with recovery from serum or heparinized plasma. TNF did not interfere with the assay. With the RIA based on radiolabeled nonglycosylated Escherichia coli-derived recombinant TNFsRp55, a mean concentration of 198 +/- 15 pg/mL was found in 14 volunteers. When glycosylated CHO cell-derived TNFsRp55 was used, the mean level was 1656 +/- 95 pg/mL. Infusion of endotoxin into volunteers induced TNFsRp55, which peaked at 517 +/- 99 pg/mL for the E. coli-based RIA and 7300 +/- 1810 pg/mL for the CHO cell-based RIA. These findings demonstrate that blood collected in EDTA is optimal for measuring circulating TNFsRp55 and that this soluble receptor is present in health but elevated during endotoxemia.

Adolescent↗
PubMed1993

An unusual promoter controls cell-cycle regulation and dependence on DNA replication of the Caulobacter fliLM early flagellar operon.

Transcription of flagellar genes in Caulobacter crecentus is programmed to occur during the predivisional stage of the cell cycle. The mechanism of activation of Class II flagellar genes, the highest identified genes in the Caulobacter flagellar hierarchy, is unknown. As a step toward understanding this process, we have defined cis-acting sequences necessary for expression of a Class II flagellar operon, fliLM. Deletion analysis indicated that a 55 bp DNA fragment was sufficient for normal, temporally regulated promoter activity. Transcription from this promoter-containing fragment was severely reduced when chromosomal DNA replication was inhibited. Extensive mutational analysis of the promoter region from -42 to -5 identified functionally important nucleotides at -36 and -35, between -29 and -22, and at -12, which correlates well with sequences conserved between fliLM and the analogous regions of two other Class II flagellar operons. The promoter sequence does not resemble that recognized by any known bacterial sigma factor. Models for regulation of Caulobacter early flagellar promoters are discussed in which RNA polymerase containing a novel sigma subunit interacts with an activation factor bound to the central region of the promoter.

Base Sequence↗
PubMed1993

Asymmetric expression of the gyrase B gene from the replication-competent chromosome in the Caulobacter crescentus predivisional cell.

The bacterium Caulobacter crescentus undergoes an asymmetric cell division resulting in the formation of two different daughter cells, a motile swarmer cell and a nonmotile stalked cell. These two cell types differ in their program of gene expression, their ability to replicate DNA, and the physical properties of their nucleoids. We show here that two genes, gyrB (encoding the gyrase B subunit) and orf-1, are specifically transcribed from the chromosome in the portion of the predivisional cell destined for the progeny stalked cell. This is in contrast to a subset of flagellar genes which are transcribed from the chromosome in the incipient swarmer portion of the predivisional cell. gyrB and orf-1 are within a newly identified cluster of genes involved in DNA replication and recombination, including dnaN and recF. The transcription of gyrB and orf1 occurs from the replication-competent chromosome in stalked and predivisional cells and is silenced in swarmer cells. We hypothesize that selective silencing of groups of genes in the chromosomes at the swarmer and stalked poles of the predivisional cell results in the different developmental programs and the difference in replicative ability of the two progeny cells.

Amino Acid Sequence↗
PubMed1993

Polarized cells, polar actions.

The recognition of polar bacterial organization is just emerging. The examples of polar localization given here are from a variety of bacterial species and concern a disparate array of cellular functions. A number of well-characterized instances of polar localization of bacterial proteins, including the chemoreceptor complex in both C. crescentus and E. coli, the maltose-binding protein in E. coli, the B. japonicum surface attachment proteins, and the actin tail of L. monocytogenes within a mammalian cell, involve proteins or protein complexes that facilitate bacterial interaction with the environment, either the extracellular milieux or that within a plant or mammalian host. The significance of this observation remains unclear. Polarity in bacteria poses many problems, including the necessity for a mechanism for asymmetrically distributing proteins as well as a mechanism by which polar localization is maintained. Large structures, such as a flagellum, are anchored at the pole by means of the basal body that traverses the peptidoglycan wall. But for proteins and small complexes, whether in the periplasm or the membrane, one must invoke a mechanism that prevents the diffusion of these proteins away from the cell pole. Perhaps the periplasmic proteins are retained at the pole by the presence of the periseptal annulus (35). The constraining features for membrane components are not known. For large aggregates, such as the clusters of MCP, CheA, and CheW complexes, perhaps the size of the aggregate alone prevents displacement. In most cases of cellular asymmetry, bacteria are able to discriminate between the new pole and the old pole and to utilize this information for localization specificity. The maturation of new pole to old pole appears to be a common theme as well. Given numerous examples reported thus far, we propose that bacterial polarity displays specific rules and is a more general phenomenon than has been previously recognized.

Bacteria↗
PubMed1993

Cytokines and sepsis: pathophysiology and therapy.

Current therapies for sepsis are unsatisfactory, with a 50% mortality rate in patients with septic shock, regardless of etiology. Persuasive evidence shows that the majority of damage induced during sepsis is pursuant to induction and overproduction of endogenous cytokine immune mediators. Interleukin-1 and tumor necrosis factor act synergistically as strategic triggers of the cascade of cytokine-induced pathophysiology. Anticytokine therapeutic strategies, directed primarily at interleukin-1 and tumor necrosis factor modulation, have produced preliminary but exciting results in treating sepsis and other inflammatory diseases.

Animals↗
PubMed1993

Oxytocin and complex social behavior: species comparisons.

The neurohypophyseal peptide hormone oxytocin functions as a neuropeptide in several brain areas in addition to its role as a posterior pituitary hormone. Several studies have determined significant differences in patterns of oxytocin receptor binding in the brains of two closely related species of vole. One of the defining features of these two species is remarkably different reproductive behavior strategies. The prairie vole forms long-term monogamous relationships; the montane vole is polygamous. One potential measure of the formation of a pair bond in prairie voles is the development of intense aggressive behavior directed at male conspecifics following a mating bout. Oxytocin had little effect on aggressive behavior when administered before mating but had profound effects on the aggression of male prairie voles when administered after mating. Oxytocin had relatively modest effects on the behavior of montane voles, and neither the behavior nor the peptide effects were affected by mating experience. The data indicate that differences in peptide binding in these two species of vole may be functionally related to difference in social behavior.

Animals↗