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Biomedical subjects

T H Lee

Publications and source records attributed to T H Lee.

At least 19 recordsLinked to original sources
PubMed1992

The progressive changes of neuronal activities of the nigral dopaminergic neurons upon withdrawal from continuous infusion of cocaine.

Sensitivity of the nigral dopamine neurons to intravenous apomorphine was examined in rats pretreated with continuous cocaine or saline for two weeks. One day after withdrawal from pretreatment, a subsensitivity was observed while a supersensitivity was found on day 7, along with a significant increase in the baseline firing rates. In humans, an increased sensitivity of dopamine soma/dendritic autoreceptors may partly account for the symptomatology associated with the intermediate phase of withdrawal from cocaine binges.

Animals↗
PubMed1992

Allogeneic leukocytes but not therapeutic blood elements induce reactivation and dissemination of latent human immunodeficiency virus type 1 infection: implications for transfusion support of infected patients.

Various immunologic stimuli and heterologous viral regulatory elements have been shown to increase susceptibility to, and replication of, human immunodeficiency virus type 1 (HIV-1) in lymphocytes and monocytes in vitro. Transfusion of allogeneic blood components from heterologous donors constitutes a profound immunologic stimulus to the recipient, in addition to being a potential route of transmission of lymphotropic viral infections. To investigate the hypothesis that transfusions, and particularly those containing leukocytes, activate HIV-1 replication in infected recipient cells, we cocultured peripheral blood mononuclear cells (PBMC) from three anti-HIV-1-positive individuals with allogeneic donor PBMC, as well as partially purified populations of donor lymphocytes, monocytes, granulocytes, platelets, and red blood cells (RBC) and allogeneic cell-free plasma. Allogeneic PBMC induced a dose-related activation of HIV-1 expression in in vivo infected cells, followed by dissemination of HIV-1 to previously uninfected patient cells. Activation of HIV-1 replication was observed with donor lymphocytes, monocytes, and granulocytes, whereas no effect was seen with leukocyte-depleted RBC, platelets, or plasma (ie, therapeutic blood constituents). Allogeneic donor PBMC were also shown to upregulate HIV-1 expression in a "latently" infected cell line, and to increase susceptibility of heterologous donor PBMC to acute HIV-1 infection. Studies should be performed to evaluate whether transfusions of leukocyte-containing blood components accelerate HIV-1 dissemination and disease progression in vivo. If so, HIV-1-infected patients should be transfused as infrequently as possible and leukocyte-depleted (filtered) blood components should be used to avoid this complication.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Downregulation of interleukin 8 gene expression in human fibroblasts: unique mechanism of transcriptional inhibition by interferon.

The chemotactic cytokine interleukin 8 (IL-8) is produced upon stimulation by various agents in many cell types, including connective-tissue fibroblasts. Tumor necrosis factor (TNF) and IL-1 are potent inducers of IL-8 expression. Earlier we showed that TNF-induced stimulation of IL-8 mRNA accumulation in human FS-4 fibroblasts was inhibited by interferon beta (IFN-beta) or IFN-gamma. Here we show that this inhibition is not specific for TNF, since IFN-beta also reduced IL-8 mRNA accumulation induced by IL-1 or the double-stranded RNA poly (I-C). Treatment with IFN-beta also decreased TNF-induced IL-8 protein accumulation. Interestingly, the inhibitory effect was much less pronounced when IFN-beta was added greater than or equal to 1 hr before TNF. The inhibitory action of IFN-beta on IL-8 mRNA accumulation was undiminished in the presence of inhibitors of protein synthesis. Nuclear run-on assays demonstrated that IFN-beta caused a marked inhibition of TNF-induced IL-8 gene transcription; the transcriptional activation of several other TNF-induced genes was not inhibited by IFN-beta. The results suggest that the specific inhibition of the transcriptional activation of IL-8 by IFN is due either to a transient inactivation of a factor required for IL-8 transcription or to the activation of a selective inhibitory factor.

Cell Line↗
PubMed1992

Rapid classification of positive blood cultures. Prospective validation of a multivariate algorithm.

OBJECTIVE: To develop and validate a model predicting whether a positive blood culture represents a true positive or a contaminant in hospitalized patients, using only information available when the initial culture result becomes available. DESIGN: Prospective cohort study with derivation and validation sets. SETTING: Urban tertiary care hospital. PATIENTS: Clinical data were collected within 24 hours of the initial culture from a random sample of inpatients who had blood cultures performed, and data from the episodes in which growth was reported were included. There were 219 episodes in the derivation set and 129 episodes in the validation set. MAIN OUTCOME MEASURE: True bacteremia. Reviewers blinded to potential clinical predictors and initial laboratory results classified 115 (53%) of the episodes in the derivation set and 57 (44%) of the episodes in the validation set as true positives. RESULTS: Independent multivariate predictors of bacteremia were organism type, days until the blood culture became positive, multiple positive cultures, and clinical risk score. These factors were used to develop a model stratifying patients into four risk groups. In the derivation set's lowest-risk group, 92% (65/71) of positives represented contaminants, and in the highest-risk group, 97% (86/89) of positives represented true positives. In the validation set, the misclassification rates were 14% (8/59) in the low-risk group, and 11% (5/44) in the high-risk group. These two groups together comprised 76% of all episodes. CONCLUSION: This model can help clinicians quantify the likelihood that a given positive blood culture represents a true positive when the laboratory first calls, which may be helpful in subsequent decision making.

Adult↗
PubMed1992

Nonrandom distribution of gp120 N-linked glycosylation sites important for infectivity of human immunodeficiency virus type 1.

More than 20 consensus N-linked glycosylation sites occur in the gp120 coding sequence of most isolates of human immunodeficiency virus type 1. Based on the N-linked glycosylation pattern of a well-characterized recombinant gp120, it is likely that N-linked sugars are present at most, if not all, of the consensus glycosylation sites of the heavily glycosylated gp120. In this study, we evaluated the relative importance of each of the 24 N-linked glycosylation sites of gp120 in the molecular clone HXB2 to viral infectivity. The ability of HXB2-derived mutants, each having 1 of the 24 N-linked glycosylation sites mutated by site-directed mutagenesis, to infect CD4-positive SupT1 cells was compared with that of the wild-type virus. We found that most of the individual consensus N-linked glycosylation sites are dispensable for viral infectivity. The five consensus N-linked glycosylation sites that are likely to have important roles in infectivity are all located in the amino-terminal half of gp120, indicating that the N-linked glycosylation sites that are important for infectivity of human immunodeficiency virus type 1 are not randomly distributed in gp120. We predict that a partially glycosylated gp120 with most of the dispensable N-linked glycosylation sites removed may be a better vaccine candidate than the fully glycosylated gp120.

Amino Acid Sequence↗
PubMed1992

Long-term survival of emergency department patients with acute chest pain.

To evaluate the long-term prognosis of patients with acute chest pain, prospective clinical data and long-term follow-up data (mean 30.1 +/- 9.4 months) were collected for 1,956 patients who presented to the emergency department of an urban teaching hospital with this chief complaint. During follow-up of the 1,915 patients who were discharged alive from the emergency department or hospital, there were 113 (6%) cardiovascular deaths. No differences were detected in the post-discharge cardiovascular survival rates after 3 years of experience with patients who were discharged from the emergency department with a known prior diagnosis of angina or myocardial infarction (89%) and patients who had been admitted and found to have acute myocardial infarction (85%), angina (87%), or other cardiovascular diagnoses (87%). Patients who were discharged from either the hospital or the emergency department without cardiovascular diagnoses had an excellent prognosis. Multivariate Cox regression analysis identified 5 independent correlates of cardiovascular mortality after discharge: age, prior history of coronary disease, ischemic changes on the emergency department electrocardiogram, congestive heart failure and cardiogenic shock. These findings indicate that the postdischarge cardiovascular mortality of patients with chest pain who are discharged from the emergency department with a known history of coronary disease is similar to that of admitted patients with angina or myocardial infarction. These data suggest that the same types of prognostic evaluation strategies that have been developed for admitted patients with ischemic heart disease should also be considered when such patients present to the emergency department but are not admitted.

Adult↗
PubMed1992

Cutaneous responses to vasoactive intestinal polypeptide in chronic idiopathic urticaria.

Cutaneous wheal and flare responses to increasing concentrations of calcitonin gene-related peptide, substance P, neurokinin A, vasoactive intestinal polypeptide (VIP), compound 48/80, and phosphate-buffered saline were measured in 10 patients with chronic idiopathic urticaria and 10 healthy controls. A significant increase in VIP-induced wheal, but not flare or cutaneous blood flow, was seen in urticarial patients compared with controls (p less than 0.001). No significant differences in responses to other tested compounds were found between these groups. These data point to an increased sensitivity of microvasculature to VIP in patients with chronic idiopathic urticaria.

Adult↗
PubMed1992

Cutaneous histamine metabolism in chronic urticaria.

Impaired metabolism of histamine in the skin of patients with chronic idiopathic urticaria (CIU) might explain the observed enhanced and prolonged skin responses to intradermal histamine. Histamine metabolism was measured in homogenates from unaffected forearm skin in nine patients with CIU and in skin of age- and sex-matched control subjects with a radiochromatographic assay, and the results are expressed as nanograms of histamine metabolized per milligram of protein per hour. Endogenous histamine content was determined by RIA. There was a highly significant increase in endogenous histamine content in the skin of patients with urticaria (407.8 +/- 188.3 ng/mg of protein) compared with that in skin of control subjects (240.0 +/- 73.0 ng/mg of protein) (mean +/- 1 SD; p less than 0.02), which suggests either an increase in mast cell number or histamine concentration per cell. No significant difference was observed in the metabolism of histamine between patient and control group; therefore, an alternative mechanism may underlie differences in skin reactivity to histamine.

Chronic Disease↗
PubMed1992

Genetic analysis using DNA polymorphism of the linkage between chromosome 11q13 and atopy and bronchial hyperresponsiveness to methacholine.

Previous studies have suggested that there is a genetic predisposition for the development of asthma and atopy. A recent study has also demonstrated that there is a striking link between chromosome 11q and the IgE response underlying asthma and rhinitis. To assess the linkage between chromosome 11q (region D11S97) and atopy or bronchial hyperresponsiveness (BH), we have studied nine families of two and, in many instances, three generations with the index case having asthma and/or atopy. With variable number of tandem repeat analysis with the probe, p lambda-MS.51, we have been unable to confirm a significant link between region D11S97 of chromosome 11q and either atopy or BH to methacholine. We have demonstrated that atopy and BH produce similar log of odds scores with linkage analysis at each recombination fraction from 0.001 to 0.5 with both Hinf1 and Taq1 restriction digests and that the use of either a positive skin prick test or positive RAST as a definition of atopy does not significantly alter the log of odds score.

Adolescent↗
PubMed1992

Effect of dietary fish oil supplementation on the antigen-induced late-phase response in the skin.

We have studied the effect of dietary fish oil supplementation (3.2 gm/day of eicosapentaenoic acid and 2.2 gm/day of docosahexaenoic acid) for 10 weeks on the antigen-induced, cutaneous late-phase response (LPR) in 16 atopic individuals. All subjects developed an LPR to intradermal allergen injection. The mean +/- SEM area of induration at 6 hours was 1840 +/- 472 mm2. A biopsy was performed at the LPR site at 6 hours. Subjects were then randomized to receive fish oil or placebo olive oil in a double-blind, parallel fashion, for 10 weeks. After the diet, there were no significant differences between fish oil and placebo treatment in the size of the immediate wheal-and-flare response or the extent of induration at 4 and 6 hours, as compared with prediet values in each group. Histologically, at 6 hours, there was a significant infiltrate into the allergen site compared with that of the control diluent site of total inflammatory cells (p less than 0.002) as well as of eosinophils (p less than 0.001). However, there were no significant differences when pre- and postdiet values were compared. Hence, we conclude that dietary fish oil supplementation does not inhibit the cutaneous LPR clinically or histologically.

Adult↗
PubMed1992

Intracellular recording from dopamine neurons in the substantia nigra: double labelling for identification of projection site and morphological features.

We have adapted an intracellular recording technique that allows differentiation of dopamine neurons in vitro based on their projection sites and morphology. We pre-labelled 'nigrostriatal' dopamine neurons in vivo by stereotaxically injecting rhodamine-labelled microspheres (RFM) into the dorsal striatum. Following slice preparation, dense neuronal labelling with RFM was observed in the medial two-thirds of the substantia nigra zona compacta. The visible neurons in the superficial layers were not viable; consequently, we recorded from dopamine neurons that were located directly below the clusters of fluorescent neurons. Each recorded neuron was subsequently filled with N-(2-aminoethyl) biotinamide (1) to confirm whether it projected to the dorsal striatum (by presence of both RFM and biotinamide) and (2) to examine its morphological features. Four of 7 dopamine neurons successfully recovered were double labelled and exhibited multipolar cell bodies with dendrites projecting into the zona reticulata. No differences in the resting membrane potential, spontaneous activity, or membrane response to constant current injections were observed between the confirmed nigrostriatal dopamine neurons and the others. Our technique should allow pharmacological manipulations of selective dopamine pathways in vitro and help in elucidating various factors responsible for differential regulation of populations of dopamine neurons.

Animals↗
PubMed1992

The pathobiology of bronchial asthma.

Early studies of patients dying from status asthmaticus revealed marked inflammation of the bronchial tree. Subsequent histological studies of the airways and examination of bronchoalveolar lavage fluid of subjects with mild asthma have confirmed the presence of airway inflammation in life. There is epithelial edema and desquamation, subepithelial deposition of collagen and fibronectin, and an inflammatory cell infiltrate in the mucosa. There are increased numbers of activated eosinophils, CD25-positive T lymphocytes, and immature macrophages with the phenotypic characteristics of blood monocytes. An increased expression of HLA class II is present on epithelium, macrophages, and other infiltrating cells. The severity of clinical asthma correlates with several measurements of the severity of the inflammatory response, suggesting a crucial role for airway inflammation in the pathophysiology of the disease. There is considerable interest and research into the mechanisms underlying the pathogenesis and maintenance of the inflammatory response in asthma. The development and maintenance of the inflammatory response in asthma is likely to be a consequence of a complicated interaction between various cells and the mediators they generate. The characterization of an ever-increasing number of cytokines is of particular interest. Interleukin-3, interleukin-5, and granulocyte-macrophage colony-stimulating factor are hematopoietic growth factors that increase the survival of eosinophils in culture and enhance certain eosinophil functions, such as mediator generation and toxicity. Alveolar macrophages derived from asthmatic subjects produce twofold to threefold more GM-CSF than do those from normal control subjects. Using in situ hybridization, the presence of IL-5 mRNA has been demonstrated in bronchial biopsies from asthmatic subjects. Thus IL-3, IL-5, and GM-CSF influence eosinophil function and survival, and may be generated by T lymphocytes and/or alveolar macrophages within the airways in asthma. In addition to these three cytokines, IL-4 and interferon-gamma may be crucial to the regulation of IgE biosynthesis. TNF-alpha and IL-1 are potentially important in the up-regulation of endothelial adhesion molecules. An important step in the recruitment of leukocytes to an inflammatory focus is margination to the vascular endothelium. Our understanding of the molecular events involved in migration of leukocytes to an inflammatory focus has been advanced by the discovery and characterization of a variety of cell adhesion molecules. The potential role of ELAM-1 and ICAM-1 in allergic inflammation is suggested by their up-regulation on vascular endothelium in association with late cutaneous responses to allergen and by their role in certain primate models of asthma.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex Hormones↗
PubMed1992

A novel secretory tumor necrosis factor-inducible protein (TSG-6) is a member of the family of hyaluronate binding proteins, closely related to the adhesion receptor CD44.

TSG-6 cDNA was isolated by differential screening of a lambda cDNA library prepared from tumor necrosis factor (TNF)-treated human diploid FS-4 fibroblasts. We show that TSG-6 mRNA was not detectable in untreated cells, but became readily induced by TNF in normal human fibroblast lines and in peripheral blood mononuclear cells. In contrast, TSG-6 mRNA was undetectable in either control or TNF-treated human vascular endothelial cells and a variety of tumor-derived or virus-transformed cell lines. The sequence of full-length TSG-6 cDNA revealed one major open reading frame predicting a polypeptide of 277 amino acids, including a typical cleavable signal peptide. The NH2-terminal half of the predicted TSG-6 protein sequence shows a significant homology with a region implicated in hyaluronate binding, present in cartilage link protein, proteoglycan core proteins, and the adhesion receptor CD44. The most extensive sequence homology exists between the predicted TSG-6 protein and CD44. Western blot analysis with an antiserum raised against a TSG-6 fusion protein detected a 39-kD glycoprotein in the supernatants of TNF-treated FS-4 cells and of cells transfected with TSG-6 cDNA. Binding of the TSG-6 protein to hyaluronate was demonstrated by coprecipitation. Our data indicate that the inflammatory cytokine (TNF or IL-1)-inducible, secretory TSG-6 protein is a novel member of the family of hyaluronate binding proteins, possibly involved in cell-cell and cell-matrix interactions during inflammation and tumorigenesis.

Amino Acid Sequence↗
PubMed1992

Precipitating factors of asthma.

Asthma is characterised by bronchial hyperresponsiveness. This feature of the asthmatic diathesis predisposes patients to wheezing in response to a number of different factors. These precipitating factors include specific allergen acting via sensitised mediator cells through an IgE-dependent mechanism. There are irritants which may work through a non-specific manner, or stimuli such as exercise and hyperventilation, which probably also act through mediator release via a non-IgE-dependent manner. The mechanism whereby physical stimuli such as exercise induce bronchoconstriction is of interest, because it increases the context in which the mast cell may participate in acute asthmatic bronchoconstriction. Respiratory infections also commonly provoke asthma, especially in infants and may, indeed, precipitate the asthmatic state itself. Finally, drugs can often trigger asthma attacks and the mechanisms of asthma precipitated by non-steroidal anti-inflammatory drugs such as aspirin have been the subject of recent research.

Air Pollution↗
PubMed1992

Genetic analysis of the linkage between chromosome 11q and atopy.

Previous work has suggested that there is a genetic predisposition for the development of both asthma and atopy. A recent study has also shown that there is a striking link between chromosome 11q and the IgE response underlying asthma and rhinitis. To further assess the linkage between chromosome 11q and atopy, we have studied nine families of two and, in many instances, three generations with the index case having asthma and/or atopy. Using two restriction fragment length polymorphism probes associated with the regions 11q12-q13.2, namely PYGM and INT2, we have been unable to confirm a significant link between this region of chromosome 11q and atopy as defined by a positive skin-prick test and/or a raised specific IgE and/or a raised total IgE.

Adolescent↗