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Biomedical subjects

J Chin

Publications and source records attributed to J Chin.

At least 19 recordsLinked to original sources
PubMed1992

Iron regulates the activity of the iron-responsive element binding protein without changing its rate of synthesis or degradation.

The iron-responsive element binding protein (IRE-BP) interacts with specific sequence/structure motifs (iron-responsive elements) within the mRNAs encoding ferritin and the transferrin receptor and thereby post-transcriptionally regulates the expression of these two proteins involved in cellular iron homeostasis. The activity of the IRE-BP is itself regulated by iron such that when cells are treated with an iron source, the RNA binding activity is decreased. The expression of recombinant human IRE-BP in murine cells has been examined as have the expressions of the endogenous IRE-BP of both human and rabbit cells. In all cases, iron down-modulated the RNA binding activity of the IRE-BP, but in no instance was this decrease in activity accompanied by a decrease in the level of the protein as judged by quantitative Western blots. Moreover, the rate of synthesis of the IRE-BP and its rate of degradation have been found to be unaltered by iron manipulation of cells in culture. Consistent with IRE-BP regulation occurring post-translationally, the iron regulation of its activity was found to be unaffected by cycloheximide. These data are discussed in terms of a model of IRE-BP regulation involving the modification of the protein's iron-sulfur center.

Animals↗
PubMed1992

Reciprocal control of RNA-binding and aconitase activity in the regulation of the iron-responsive element binding protein: role of the iron-sulfur cluster.

Several mechanisms of posttranscriptional gene regulation are involved in regulation of the expression of essential proteins of iron metabolism. Coordinate regulation of ferritin and transferrin receptor expression is produced by binding of a cytosolic protein, the iron-responsive element binding protein (IRE-BP) to specific stem-loop structures present in target RNAs. The affinity of this protein for its cognate RNA is regulated by the cell in response to changes in iron availability. The IRE-BP demonstrates a striking level of amino acid sequence identity to the iron-sulfur (Fe-S) protein mitochondrial aconitase. Moreover, the recombinant IRE-BP has aconitase function. The lability of the Fe-S cluster in mitochondrial aconitase has led us to propose that the mechanism by which iron levels are sensed by the IRE-BP involves changes in an Fe-S cluster in the IRE-BP. In this study, we demonstrate that procedures aimed at altering the IRE-BP Fe-S cluster in vitro reciprocally alter the RNA binding and aconitase activity of the IRE-BP. The changes in the RNA binding of the protein produced in vitro appear to match the previously described alterations of the protein in response to iron availability in the cell. Furthermore, iron manipulation of cells correlates with the activation or inactivation of the IRE-BP aconitase activity. The results are consistent with a model for the posttranslational regulation of the IRE-BP in which the Fe-S cluster is altered in response to the availability of intracellular iron and this, in turn, regulates the RNA-binding activity.

Aconitate Hydratase↗
PubMed1992

Sequence and molecular characterization of human monocyte/neutrophil elastase inhibitor.

cDNA encoding human monocyte/neutrophil elastase inhibitor (EI), a M(r) approximately 42,000 protein with serpin-like functional properties, has been sequenced. The 1316-base-pair sequence was obtained from overlapping clones and amplified DNA from libraries of monocyte-like and neutrophil-like cells. Hybridization with EI cDNA identified three EI mRNA species of 1.5, 1.9, and 2.6 kilobases in U937 monocyte-like cells and no hybridizing mRNA in lymphoblastoid cells lacking detectable EI. The cDNA open reading frame encodes a 379-amino acid protein, of which 167 residues were confirmed by tryptic peptides. Although EI may function extracellularly as well as intracellularly, its deduced sequence lacks a typical cleavable N-terminal signal sequence. Sequence analysis established that EI is a member of the serpin superfamily. EI has greatest homology (50.1% identity of amino acids) with plasminogen activator inhibitor 2, also a monocyte protein, and ovalbumin and gene Y, which were previously grouped as an ancient branch of the serpin superfamily. The extent of EI identity with the functionally related serpin alpha 1 antitrypsin is only 30.1%. Sequence alignment indicates that the reactive center P1 residue is Cys-344, consistent with abrogation of elastase inhibitory activity by iodoacetamide and making EI a naturally occurring Cys-serpin. The cleavable bond, Cys-Met, suggests an oxidation-sensitive molecule capable of inhibiting more than one serine protease. Oxidation sensitivity would limit the place of action of EI to the immediate vicinity of carrier cells. The molecular structure will help clarify the likely role of EI in regulating protease action and preventing tissue damage by phagocytic cells.

Amino Acid Sequence↗
PubMed1992

An iron-sulfur cluster plays a novel regulatory role in the iron-responsive element binding protein.

Post-transcriptional regulation of genes important in iron metabolism, ferritin and the transferrin receptor (TfR), is achieved through regulated binding of a cytosolic protein, the iron-responsive element binding protein (IRE-BP), to RNA stem-loop motifs known as iron-responsive elements (IREs). Binding of the IRE-BP represses ferritin translation and represses degradation of the TfR mRNA. The IRE-BP senses iron levels and accordingly modifies binding to IREs through a novel sensing mechanism. An iron-sulfur cluster of the IRE-BP reversibly binds iron; when cytosolic iron levels are depleted, the cluster becomes depleted of iron and the IRE-BP acquires the capacity to bind IREs. When cytosolic iron levels are replete, the IRE-BP loses RNA binding capacity, but acquires enzymatic activity as a functional aconitase. RNA binding and aconitase activity are mutually exclusive activities of the IRE-BP, and the state of the iron-sulfur cluster determines how the IRE-BP will function.

Aconitate Hydratase↗
PubMed1992

Increases in plasma beta-endorphin concentrations during exercise do not contribute to increases in heart rate following autonomic blockade in man.

1. Intrinsic heart rate (IHR: heart rate following autonomic blockade with atropine and propranolol) increases with exercise. The opioid antagonist naloxone has been shown to decrease IHR at rest, raising the possibility that increases in IHR with exercise are beta-endorphin related, since beta-endorphin concentrations have also been shown to rise during exercise. 2. We examined the effects of naloxone (10 mg) on IHR and plasma beta-endorphin levels during aerobic exercise in eight healthy, male subjects in a single blind, crossover study. 3. IHR increased with 25 min bicycling from 97.1 +/- 1.4 to 129.7 +/- 1.2 beats min-1 (mean +/- s.e. mean). This rise was not affected by administration of naloxone. 4. Plasma beta-endorphin concentration rose from 31.1 +/- 3.8 to 94.9 +/- 23.9 pg ml-1 after 25 min exercise. This exercise-induced rise in beta-endorphin concentration was further increased (P less than 0.05) in the presence of naloxone. 5. Our results confirm a rise in IHR and beta-endorphin concentrations with acute exercise but indicate that the changes in IHR are not endorphin-related.

Adolescent↗
PubMed1992

Sympathetic nervous function in human heart as assessed by cardiac spillovers of dihydroxyphenylglycol and norepinephrine.

BACKGROUND: Measurement of cardiac norepinephrine spillover may indicate the amount of transmitter at neuroeffector sites but does not distinguish neuronal release or reuptake in determining this amount or provide information about other aspects of sympathetic function. This report examines how cardiac spillover of the norepinephrine metabolite dihydroxyphenylglycol (DHPG) provides additional distinct information about cardiac sympathetic function. METHODS AND RESULTS: Arterial and coronary venous blood samples were taken during cardiac catheterization and intravenous infusion of [3H]norepinephrine in 57 subjects. Subjects were given intravenous yohimbine or underwent mental stress, handgrip exercise, and cycling exercise to activate sympathetic nerves or were given intravenous desipramine to block norepinephrine reuptake. Cardiac DHPG spillover (601 +/- 41 pmol/min) was eightfold greater than norepinephrine spillover (78 +/- 10 pmol/min) at rest and increased during sympathetic activation by 65% of the increase of norepinephrine. This and the desipramine-sensitive cardiac production of [3H]-labeled DHPG from [3H]norepinephrine indicated that 10.5 times more endogenous norepinephrine is recaptured than escapes into plasma; that more than 90% of recaptured norepinephrine is sequestered into storage vesicles; and that under resting conditions, most cardiac spillover of DHPG and turnover of norepinephrine are from metabolism of transmitter leaking from vesicles; the latter process is independent of exocytotic transmitter release with a rate at rest over 100-fold that of norepinephrine spillover and over 10-fold that of norepinephrine reuptake. CONCLUSIONS: Cardiac spillover of DHPG provides information about processes close to or within sympathetic nerve endings that cannot be provided by measurements of norepinephrine spillover alone. This includes quantitative information about the role of neuronal uptake in terminating the actions of norepinephrine at neuroeffector sites and the importance of vesicular-axoplasmic exchange of norepinephrine as a dynamic process contributing to norepinephrine turnover.

Cardiac Output, Low↗
PubMed1992

Octreotide inhibits the meal-induced increases in the portal venous pressure of cirrhotic patients with portal hypertension: a double-blind, placebo-controlled study.

The aim of this study was to determine the effects of the long-acting somatostatin analog, octreotide, on portal venous pressure and collateral blood flow in cirrhotic patients with portal hypertension during fasting and postprandial states. In a double-blind, placebo-controlled study, we investigated the effects of octreotide on the hepatic venous pressures and azygos blood flow of 21 patients before and after a standard liquid meal containing 40 gm of protein in 250 ml. Octreotide significantly reduced azygos blood flow from a mean of 499 +/- 65 ml/min to a mean of 355 +/- 47 ml/min (p < 0.01), but it had no effect on the hepatic venous pressure gradient. The hepatic venous pressure gradient of patients in the placebo group increased significantly, from a fasting mean of 16.4 +/- 1.6 mm Hg to a mean of 20.0 +/- 1.7 mm Hg 30 min after the meal (p < 0.01). In a second protocol hepatic venous pressures were measured in 20 patients at 30-min intervals for 2 hr after ingestion of the mixed meal. Again the placebo group showed a significant increase in the hepatic venous pressure gradient 30 min after the meal (20.4 +/- 1.5 mm Hg vs. 18.2 +/- 1.2 mm Hg; p < 0.05), but the group receiving octreotide showed no significant changes during the 2 hr of observation. We conclude that octreotide significantly reduces azygos blood flow, with little effect on portal venous pressure, and that it appears to inhibit postprandial increases in portal pressure in cirrhotic patients with portal hypertension.

Blood Flow Velocity↗
PubMed1992

The global epidemiology of the HIV/AIDS pandemic and its projected demographic impact in Africa.

The global epidemiology of HIV/AIDS has evolved to the point that the pandemic now predominantly affects heterosexuals, especially in developing countries. This article summarizes the status of the HIV/AIDS pandemic as of the early 1990s; provides estimates and short-term projections of AIDS mortality in a hypothetical country of sub-Saharan Africa; projects the potential demographic impact of AIDS in a hypothetical sub-Saharan country; and describes the major problems associated with modelling the long-term demographic impact of this pandemic. Estimated AIDS cases and deaths up to 1992 were extrapolated from public health surveillance data and through use of the WHO model. Estimates of HIV seroprevalence were based on available HIV serological data. For developed countries, HIV estimates developed by national experts and/or national AIDS programmes were used, and for developing countries estimates by regional experts were used or were prepared by WHO. For the first half of the 1990s, projections of AIDS cases and deaths were derived from the WHO model; beyond the mid-1990s, the potential effects of AIDS on selected demographic indicators were derived from a demographic projection model developed by the World Bank. Although estimates and long-term projections cannot be made with great precision, the general dimensions of the HIV/AIDS pandemic have been more clearly delineated now at the start of its second decade. Epidemiological data indicate that in industrialized countries, where extensive spread of HIV began in the late 1970s or early 1980s, the majority of HIV infections occurred during the first half of the 1980s.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1991

Role of degranulation in activation of the respiratory burst in human neutrophils.

The neutrophil response to infection and inflammation includes membrane fusion or degranulation and activation of the membranous respiratory burst oxidase. The role of degranulation in the activation of the burst was explored in resting and activated cells. Exposed membrane proteins of intact cells were labeled with impermeant reagents. Phorbol ester-activated neutrophils and enucleated cells which are granule depleted both exhibit increased labeling with [125I]lactoperoxidase over that of resting cells. The binding of antibodies to granule membranes by cells activated with phorbol ester or treated with cytochalasin B and lithium chloride were similarly increased. These data indicate that insertion of granule membrane into the cell membrane occurs during activation and enucleation of neutrophils. Hyperosmolarity, known to inhibit degranulation, also exhibited an inhibitory effect on the respiratory burst oxidase in the presence of phorbol ester or latex. Pre-treatment of cells with phorbol ester followed by an increase in osmolarity, however, still resulted in activation. Temperatures below 17 degrees C abruptly and simultaneously abolish degranulation and activation of the respiratory burst oxidase. Pre-treatment of neutrophils with phorbol ester at 37 degrees C, followed by measurement of oxidase activity at decreased temperatures, on the other hand, revealed a linear Arrhenius plot above and below 17 degrees C. These results suggest that membrane fusion or degranulation is a step in activation of the respiratory burst.

Chlorides↗
PubMed1991

Is adrenaline released by sympathetic nerves in man?

Radiotracer methods were used to measure the rates of regional release of adrenaline and noradrenaline into plasma in man. This was done as a partial test of a theory of essential hypertension pathogenesis which envisages an important cotransmitter function for neuronally released adrenaline. In healthy resting men no release of adrenaline could be detected from the heart, lungs or liver. Adrenaline was released into the right renal vein but an adrenal medullary source is suspected. With the relatively limited activation of the cardiac sympathetic outflow which accompanied mental challenge and isometric exercise, cardiac adrenaline release remained undetectable. During supine bicycle exercise, which increased cardiac noradrenaline release 10-30 fold, to a mean value of 197 ng/min, cardiac adrenaline release averaged 2.36 ng/min. In two clinical conditions associated with persistently elevated plasma adrenaline concentrations, cardiac failure and adrenaline-secreting phaeochromocytoma, regional release of adrenaline was clearly evident. Thus, in normal man during exercise, and in patients with cardiac failure at rest, adrenaline is released from non-adrenal sources, and probably from sympathetic nerves. Whether neuronal adrenaline release of the degree found would be sufficient to facilitate noradrenaline release, augment sympathetically-mediated cardiovascular responses and contribute to the development of arterial hypertension remains to be tested.

Adrenal Gland Neoplasms↗
PubMed1991

Magnetic resonance imaging for detecting and treatment monitoring of orthotopic murine bladder tumor implants.

We assessed the feasibility of magnetic resonance imaging (MRI) for detection and treatment monitoring of early stage orthotopic murine bladder (MBT-2) tumor implants. Thirty mice were scheduled for imaging at six, 14, 18 and 21 days after tumor implantation. Using a volume imaging coil, MRI demonstrated very early orthotopic tumors, the detection of which would otherwise have been impossible by clinical signs only. Sequential accurate assessment of tumor size was achieved by inflation of the bladders with a fixed volume of Gadolinium-DTPA contrast. The presence of established MBT-2 intravesical tumors was confirmed by gross pathology and light microscopy of the corresponding whole mount bladder sections. Histological examination of the corresponding tumor specimens revealed the presence of transitional cell bladder carcinoma which correlated very well with the topography and depth of tumor involvement as indicated on MRI. The The mice tolerated repeated MR imaging well. Early tumors at day 14 were detectable on MRI (with serial tumor growth to day 21), with no clinical signs of disease. In a subsequent study, response to intravesical tumor necrosis factor alpha (TNF-alpha) immunotherapy was monitored with serial MRI. The serial MR images from six tumor-bearing mice (three controls and three TNF-alpha treated) have been selected to illustrate the consistent findings of this study. Sequential MRI scans of TNF-alpha treated mice revealed retardation of tumor growth that correlated well with the corresponding histologic examination. The orthotopic tumor and MRI model described is ideal for preclinical evaluation of new potential intravesical chemotherapy and immunotherapy agents.

Administration, Intravesical↗
PubMed1991

Evaluation of a standardized survey design proposed for use in epidemiological research on AIDS.

A Monte Carlo model simulating actual populations was employed to evaluate the precision in estimation of a standardized sampling method proposed by the Global Programme on AIDS of the World Health Organization, for general use in collecting population-based data on HIV seroprevalence. It appears that in real populations, where there is likely to be 'pocketing' of infection, the proposed methodology will generally fail to provide estimates accurate to within 1% of the true population value. However, if the primary objective of a particular survey is to construct confidence intervals that include the true population HIV seroprevalence rate, then this survey method appears to be a reasonable choice. This study also suggests that selection of only one adult per household improves the precision of resulting estimates. However, since selection of only one adult per household would require that more households be visited, any gain in precision would need to be weighed against the likely increase in cost of household visits.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Adrenaline release by the human heart.

1. Radiotracer methods were used to measure the rates of regional release of adrenaline and noradrenaline to plasma in humans. 2. No release of adrenaline could be detected from the heart, lungs, liver and kidneys at rest. 3. With the relatively mild activation of the cardiac sympathetic outflow associated with mental challenge and isometric exercise, cardiac adrenaline release remained undetectable. 4. During supine bicycle exercise, which increased cardiac noradrenaline release 10-20 fold, to a mean value of 128 ng/min, cardiac adrenaline release averaged 1.63 ng/min. 5. Whether neuronal adrenaline release of this degree in the heart is sufficient to facilitate noradrenaline release and to augment sympathetically mediated cardiac responses remains to be tested.

Epinephrine↗
PubMed1991

Estimation and projection of adult AIDS cases: a simple epidemiological model.

Many HIV/AIDS (acquired immunodeficiency syndrome) models have been developed to help our understanding of the dynamics and interrelationships of the determinants of HIV (human immunodeficiency virus) spread and/or to develop reliable estimates of the eventual extent of such spread. These models range from very simple to very complex. WHO has developed a simple model for short-term projections of AIDS, details of which are presented here along with results obtained using the model to estimate and project AIDS cases for the USA, sub-Saharan Africa, and south/south-east Asia. WHO has also developed, based on the model described in this paper, a computer program (Epi Model), which will enable the user to easily change the values of any of the variables required by the WHO model.

Acquired Immunodeficiency Syndrome↗
PubMed1990

IL-1 binds to high affinity receptors on human osteosarcoma cells and potentiates prostaglandin E2 stimulation of cAMP production.

IL-1 is a potent bone resorbing agent. Its mechanism of action is unknown, but the presence of osteoblasts was shown to be necessary for IL-1 stimulation of bone resorption by isolated osteoclasts. This study examines the presence of IL-1R and IL-1 effects in osteoblastic cells from a clonal human osteosarcoma cell line, Saos-2/B-10. We found that the binding affinity and the number of binding sites increases substantially during the postconfluent stage. Scatchard and curve-fitting analysis revealed one class of high affinity binding sites, with Kd/Ki's of 40 +/- 17 pM (mean +/- SD) for IL-1 alpha (n = 5) and 9 +/- 7 pM for IL-1 beta (n = 5) and 2916 +/- 2438 (n = 6) receptors/cell. Incubation of the cells with 125I-IL-1 alpha (100 pM) at 4 degrees C, followed by incubation at 37 degrees C up to 4 h, revealed internalization of receptor-bound IL-1 alpha. Chemical cross-linking studies showed that the IL-1R in Saos-2/B-10 cells had a molecular mass of approximately 80 kDa. To assess the biologic effect of IL-1 in Saos-2/B-10 cells, we determined PGE2 content and adenylate cyclase activity. Although IL-1 had no effect on PGE2 synthesis, both IL-1 alpha and IL-1 beta enhanced PGE2 stimulation of adenylate cyclase two- to four-fold in a dose-dependent manner. The half-maximal effect for IL-1 alpha was seen at 8 to 10 pM and for IL-1 beta at 0.6 to 1.8 pM. IL-1 did not enhance basal adenylate cyclase or stimulation by parathyroid hormone, isoproterenol, or forskolin. IL-1 enhancement of PGE2-stimulated adenylate cyclase was detected between 1 to 2 h, was maximal at 4 to 5 h, was not prevented by cycloheximide treatment, and was seen in membranes from IL-1 pretreated cells. These data show effects of IL-1 on a human osteoblast-like cell line that are mediated by high affinity receptors. These IL-1 effects could contribute to the biologic action of IL-1 on bone.

Adenylyl Cyclases↗
PubMed1990

Current and future dimensions of the HIV/AIDS pandemic in women and children.

The WHO estimates that during the first decade of the HIV/AIDS pandemic there were about 500,000 cases of AIDS in women and children, most of which have been unrecognised. During the 1990s, WHO estimates that the pandemic will kill an additional 3 million or more women and children world wide. HIV infection among heterosexual populations has been increasing throughout the world during the 1980s. AIDS has become the leading cause of death for women aged 20-40 in major cities in the Americas, Western Europe, and sub-Saharan Africa. In these cities, infant and child mortality could be as much as 30% greater than what would otherwise have been expected. During the 1990s, not only can hundreds of thousands of paediatric AIDS cases be expected, but also more than a million uninfected children will be orphaned because their HIV-infected mothers and fathers will have died from AIDS.

Acquired Immunodeficiency Syndrome↗