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L Osborn

Publications and source records attributed to L Osborn.

At least 19 recordsLinked to original sources
PubMed2001

Deaths and injuries from house fires.

BACKGROUND: We sought to define the factors associated with house fires and related injuries by analyzing the data from population-based surveillance. METHODS: For 1991 through 1997, we linked the following data for Dallas: records from the fire department of all house fires (excluding fires in apartments and mobile homes), records of patients transported by ambulance, hospital admissions, and reports from the medical examiner of fatal injuries. RESULTS: There were 223 injuries (91 fatal and 132 nonfatal) from 7190 house fires, for a rate of 5.2 injured persons per 100,000 population per year. Rates of injury related to house fires were highest among blacks (relative risk, 2.8; 95 percent confidence interval, 2.1 to 3.6) and in people 65 years of age or older (relative risk, 2.6; 95 percent confidence interval, 1.9 to 3.5). Census tracts with low median incomes had the highest rates of injury related to house fires (relative risk as compared with census tracts with high median incomes, 8.1; 95 percent confidence interval, 2.5 to 32.0). The rate of injuries was higher for fires that began in bedrooms or living areas (relative risk, 3.7); that were started by heating equipment, smoking, or children playing with fire (relative risk, 2.6); or that occurred in houses built before 1980 (relative risk, 6.6). Injuries occurred more often in houses without functioning smoke detectors (relative risk, 1.5; 95 percent confidence interval, 1.0 to 2.4). The prevalence of functioning smoke detectors was lowest in houses in the census tracts with the lowest median incomes (P<0.001). CONCLUSIONS: Rates of injuries related to house fires are highest in elderly, minority, and low-income populations and in houses without functioning smoke detectors. Efforts to prevent injuries and deaths from house fires should target these populations.

Adolescent↗
PubMed2000

The management of depression: the implications for managed care--roundtable discussion: Part 3.

From the standpoint of managed care, the rising cost of depression can be addressed in multiple ways. In the final portion of the roundtable discussion, the faculty discuss not only disease management programs for depression, but other initiatives health plans (including at the pharmacy level) are undertaking to address the rising costs associated with depression. They also discuss the effect of mental health coverage "parity" laws, which can be expected to drive costs even higher.

Antidepressive Agents↗
PubMed1996

Structure of a functional fragment of VCAM-1 refined at 1.9 a resolution.

The crystal structure of the functional amino-terminal two-domain fragment of human vascular cell adhesion molecule 1 (VCAM-1) has been determined at 1.9 A resolution. The crystals contain two copies of the molecule in the asymmetric unit. The structure was solved by multiple isomorphous replacement, using lead and selenium derivatives. Anomalous scattering had to be used to resolve the phase ambiguity of a lead derivative. Since the selenium derivative has very small isomorphous differences, the local scaling algorithm had to be used to obtain an interpretable difference Patterson map. The initial phases were improved by non-crystallographic averaging, solvent flattening and histogram matching. The structure has been refined to a crystallographic R factor of 20.4% (15-1.9 A, F>/= 3sigma) and consists of two Ig domains (D1 and D2). The angle between these domains differs by 12 degrees between the two copies of the molecule in the crystallographic asymmetric unit, demonstrating that some movement is possible at the interface. In the amino-terminal domain D1 there is an 'extra' disulfide bond, in addition to the conserved cross-sheet disulfide bond, at the top of the molecule. This bond, a hallmark of the integrin-binding subclass of Ig superfamily proteins, makes the top of this domain very compact. The feature that projects most prominently from D1 is the CD loop, near the base of the domain. The key residue for integrin binding, Asp40, is located in this loop and is easily accessible.

Journal Article↗
PubMed1995

An alternately spliced mRNA encoding functional domains of murine MAdCAM-1.

cDNA clones representing a small (0.8 kb) form of murine mucosal addressin cell adhesion molecule-1 (MAdCAM-1) mRNA were obtained and sequenced. The sequence was identical to the published 1.6 kb murine MAdCAM-1 cDNA sequence, except that 432 nucleotides encoding the mucin-like and IgA-homologous portions were deleted. This cDNA most likely represents an alternately spliced mRNA. Substantial amounts of both the short and long MAdCAM-1 mRNAs are present in murine mesenteric lymph node. Ig fusion proteins displaying either the short or long forms of MAdCAM-1 can bind Mn(++)-activated JY cells bearing human alpha 4 beta 7 integrin, indicating that the two N-terminal Ig-like domains of MAdCAM-1 are sufficient to bind its integrin counter-receptor.

Alternative Splicing↗
PubMed1995

Domains 1 and 4 of vascular cell adhesion molecule-1 (CD106) both support very late activation antigen-4 (CD49d/CD29)-dependent monocyte transendothelial migration.

We investigated the role of the 6 domain (6D) and 7 domain (7D) forms of human VCAM-1 as counter-receptors for the alpha 4 beta 1 integrin (VLA-4) in monocyte migration induced by C5a. Across Chinese hamster ovary (CHO) cell monolayers transfected with VCAM-6D or VCAM-7D, monocyte migration was not inhibited by treatment of monocytes with mAb to CD18. Addition of mAb to alpha 4 to the CD18 mAb inhibited monocyte migration by 90% across CHO VCAM-6D and CHO VCAM-7D. mAbs to domain 1 (4B9) or domain 4 (GH12) of VCAM-1 each inhibited migration across CHO VCAM-7D partially, when monocytes were also treated with anti-CD18 mAb. When the VCAM-1 mAbs were combined, migration of these monocytes across CHO VCAM-7D was further inhibited to the same degree as with mAbs to alpha 4 plus CD18. IL-1-treated human umbilical vein endothelium (HUVE) supported CD18-independent, VLA-4-mediated monocyte migration to C5a. A mAb to domain 1 of VCAM-1 almost completely inhibited the CD18-independent migration across HUVE activated with IL-1 for 2 h or 20 h, but was less inhibitory when HUVE was treated with IL-1 for 5 h. However, when mAbs to domain 1 and domain 4 were combined, CD18-independent migration was inhibited completely under all conditions tested. These results suggest that either domain 1 or domain 4 of VCAM-1 can mediate VLA-4-dependent monocyte transendothelial migration, that VLA-4 interaction with these two domains can account for all of the VLA-4-mediated migration, and that the expression of VCAM-1 variants on HUVE depends partly on the duration of IL-1 activation.

Animals↗
PubMed1995

Molecular mapping of functional antibody binding sites of alpha 4 integrin.

Integrin alpha 4 beta 1 is a leukocyte receptor for fibronectin and vascular cell adhesion molecule-1 (VCAM-1). It is important in inflammatory recruitment of leukocytes, lymphopoiesis, and a number of development events. Here we have mapped a panel of functional monoclonal antibodies (mAbs) recognizing the integrin alpha 4 chain, using murine/human chimeric constructs expressed in COS7 cells. We find that: 1) mAbs that induce homotypic aggregation (epitope A mAbs) map to the most N-terminal 100 amino acids of the human alpha 4 chain; 2) mAbs that block adhesion of alpha 4 beta 1 to VCAM-1 and fibronectin (epitope B mAbs) map to a 52-amino-acid region between residues 152 and 203 of human alpha 4; 3) epitope B mAbs that do or do not induce aggregation (epitope B2 and B1 mAbs, respectively) map to the same regions and are therefore indistinguishable by this analysis; 4) mAbs that neither induce homotypic aggregation nor block adhesion (epitope C mAbs) map to a distinct region of the molecule comprising amino acids 422-606. The N-terminal region of the alpha 4 chain identified by functional A and B epitope mAbs does not correspond to ligand binding sites identified in other alpha subunits, such as cation binding sites or the "I-domain," which alpha 4 lacks, and thus represents a novel site for epitope functionality among the integrins.

Animals↗
PubMed1995

The crystal structure of an N-terminal two-domain fragment of vascular cell adhesion molecule 1 (VCAM-1): a cyclic peptide based on the domain 1 C-D loop can inhibit VCAM-1-alpha 4 integrin interaction.

Vascular cell adhesion molecule 1 (VCAM-1) represents a structurally and functionally distinct class of immunoglobulin superfamily molecules that bind leukocyte integrins and are involved in inflammatory and immune functions. X-ray crystallography defines the three-dimensional structure of the N-terminal two-domain fragment that participates in ligand binding. Residues in domain 1 important for ligand binding reside in the C-D loop, which projects markedly from one face of the molecule near the contact between domains 1 and 2. A cyclic peptide that mimics this loop inhibits binding of alpha 4 beta 1 integrin-bearing cells to VCAM-1. These data demonstrate how crystallographic structural information can be used to design a small molecule inhibitor of biological function.

Amino Acid Sequence↗
PubMed1995

Amino acid residues required for binding of lymphocyte function-associated antigen 3 (CD58) to its counter-receptor CD2.

Efficient activation and regulation of the cellular immune response requires engagement of T cell accessory molecules as well as the antigen-specific T cell receptor. The lymphocyte function-associated antigen (LFA) 3 (CD58)/CD2 accessory pathway, one of the first discovered, has been extensively characterized in terms of structure and function of the CD2 molecule, which is present on all T lymphocytes and natural killer cells of the human immune system. The binding site of human CD2 for LFA-3 has been localized to two epitopes on one face of the first immunoglobulin (Ig)-like domain of this two-domain, Ig superfamily molecule. Human LFA-3 is genetically linked and is 21% identical in amino acid sequence to CD2, suggesting that this adhesive pair may have evolved from a single ancestral molecule. We have aligned the amino acid sequences of LFA-3 and CD2 and mutagenized selected amino acids in the first domain of LFA-3 that are analogous to those implicated in the binding site of CD2. The data show that K30 and K34, in the predicted C-C' loop, and D84, in the predicted F-G loop of LFA-3, are involved in binding to CD2, suggesting that two complementary sites on one face of the first domain of each molecule bind to each other.

Amino Acid Sequence↗
PubMed1995

Expression of vascular cell adhesion molecule-1 by follicular dendritic cells.

Follicular dendritic cells are the major supporting cell of the germinal center microenvironment. The major function of follicular dendritic cells is to present antigen to B cells in secondary lymphoid tissues. Through cell-cell interactions, FDCs are hypothesized to be central to the regulation of normal B cell growth and differentiation. The major receptor-ligand pair which mediates B cell-FDC adhesion is the beta 1 integrin VLA-4, present on B cells and VCAM-1 expressed on FDCs. Follicular non-Hodgkin's lymphomas similarly employ this mechanism to bind to neoplastic germinal centers. The VCAM-1 molecule can exist as a 6 or 7 immunoglobulin domain form. The major form of VCAM-1 on activated endothelium is the 7 domain form. In this report we have determined by polymerase chain reaction of purified FDCs that they express predominantly mRNA for 7 domain VCAM-1. It is likely that the two forms of VCAM-1 are associated with distinct functions, therefore the expression of 7 domain VCAM-1 may be important in normal and neoplastic B cell-FDC interactions.

Base Sequence↗
PubMed1994

Crystallization and preliminary crystallographic analysis of the N-terminal two domain fragment of vascular cell adhesion molecule-1 (VCAM-1).

A molecular fragment comprising the first two domains of the human vascular cell adhesion molecule-1 (VCAM-1) has been crystallized by the vapor diffusion method. Two crystal forms have been examined by X-ray analysis: One crystal form belongs to the space group C2 with two molecules in the asymmetric unit and cell parameters: a = 122.1 A, b = 48.9 A, c = 73.4 A, and beta = 117.4 degrees. The other crystal form belongs to the space group P2(1) with one molecule in the asymmetric unit and cell parameters: a = 40.4 A, b = 45.7 A, c = 54.7 A, and beta = 100.5 degrees. Diffraction data up to 1.9 A resolution have been collected for the C2 crystal form.

Amino Acid Sequence↗
PubMed1994

Arrangement of domains, and amino acid residues required for binding of vascular cell adhesion molecule-1 to its counter-receptor VLA-4 (alpha 4 beta 1).

Interaction of the vascular cell adhesion molecule (VCAM-1) with its counter-receptor very late antigen-4 (VLA-4) (integrin alpha 4 beta 1) is important for a number of developmental pathways and inflammatory functions. We are investigating the molecular mechanism of this binding, in the interest of developing new anti-inflammatory drugs that block it. In a previous report, we showed that the predominant form of VCAM-1 on stimulated endothelial cells, seven-domain VCAM (VCAM-7D), is a functionally bivalent molecule. One binding site requires the first and the other requires the homologous immunoglobulin-like domain. Rotary shadowing and electron microscopy of recombinant soluble VCAM-7D molecules suggests that the seven Ig-like domains are extended in a slightly bent linear array, rather than compactly folded together. We have systematically mutagenized the first domain of VCAM-6D (a monovalent, alternately spliced version mission domain 4) by replacing 3-4 amino acids of the VCAM sequence with corresponding portions of the related ICAM-1 molecule. Specific amino acids, important for binding VLA-4 include aspartate 40 (D40), which corresponds to the acidic ICAM-1 residue glutamate 34 (E34) previously reported to be essential for binding of ICAM-1 to its integrin counter-receptor LFA-1. A small region of VCAM including D40, QIDS, can be replaced by the similar ICAM-1 sequence, GIET, without affecting function or epitopes, indicating that this region is part of a general integrin-binding structure rather than a determinant of binding specificity for a particular integrin. The VCAM-1 sequence G65NEH also appears to be involved in binding VLA-4.

Amino Acid Sequence↗
PubMed1992

Activated endothelium binds lymphocytes through a novel binding site in the alternately spliced domain of vascular cell adhesion molecule-1.

Vascular cell adhesion molecule-1 (VCAM-1) is induced on endothelial cells by inflammatory cytokines, and binds mononuclear leukocytes through the integrin very late antigen-4 (VLA-4) (alpha 4 beta 1). This adhesion pathway has been implicated in a diverse group of physiological and pathological processes, including B cell development, leukocyte activation and recruitment to sites of inflammation, atherosclerosis, and tumor cell metastasis. The major form of VCAM-1 (VCAM-7D) has seven extracellular immunoglobulin (Ig)-like domains, of which the three NH2-terminal domains (domains 1-3) are similar in amino acid sequence to domains 4-6. By functional analysis of VCAM-7D relative to VCAM-6D (a minor 6-domain form of VCAM-1 in which domain 4 is deleted because of alternative splicing), and chimeric constructs between VCAM-1 and its structural relative intercellular adhesion molecule-1 (ICAM-1), we show that either the first or the homologous fourth domain of VCAM-1 is required for VLA-4-dependent adhesion. Either of these binding sites can function in the absence of the other. When both are present, cell binding activity is increased relative to monovalent forms of the molecule. The homologous binding regions appear to have originated by internal duplication of a portion of a monovalent ancestral gene, before the mammalian radiation. Thus VCAM-1 exemplifies evolution of a functionally bivalent cell-cell adhesion molecule by intergenic duplication. We have also produced a new class of anti-VCAM-1 monoclonal antibodies that block domain 4-dependent adhesion, and demonstrate that both binding sites participate in the adhesion function of VCAM-1 on endothelial cells in vitro. Therefore both sites must be blocked in clinical, animal, or in vitro studies depending on the use of anti-VCAM-1 antibodies to inactivate the VCAM-1/VLA-4 adhesion pathway.

Amino Acid Sequence↗
PubMed1991

Expression and functional characterization of a soluble form of vascular cell adhesion molecule 1.

Vascular cell adhesion molecule 1 (VCAM1) is a leukocyte adhesion molecule induced on human endothelium in vitro and in vivo by inflammatory stimuli. A truncated cDNA for VCAM1 was constructed, stably expressed in Chinese Hamster Ovary (CHO) cells, and the secreted recombinant soluble form of VCAM1 (rsVCAM1) purified to homogeneity by immunoaffinity chromatography. Immobilized rsVCAM1 is a functional adhesion protein, and selectively binds only VLA4-expressing cells, including human B and T lymphocytes, NK cells, and certain lymphoblastoid cell lines. T cell subset analyses indicate preferential binding of CD8+ memory cells. rsVCAM1 should prove valuable for the further study of the role of VCAM1 during inflammatory and immune responses in vivo.

Amino Acid Sequence↗
PubMed1991

Activation of endothelial-leukocyte adhesion molecule 1 (ELAM-1) gene transcription.

Leukocyte adherence to endothelium is in part mediated by the transient expression of endothelial-leukocyte adhesion molecule 1 (ELAM-1) on endothelial surfaces stimulated by tumor necrosis factor alpha (TNF), interleukin (IL) 1, or bacterial lipopolysaccharide (LPS). The intracellular factors controlling induction of ELAM-1 mRNA and protein are unknown. In nuclear runoff experiments with cultured human umbilical vein endothelial cells (HUVEC), we demonstrate that transcriptional activation of the ELAM-1 gene occurs following stimulation with TNF. Sequence analysis of the 5' flanking region of the ELAM-1 gene reveals consensus DNA-binding sequences for two known transcription factors, NF-kappa B and AP-1. Gel mobility shift assays demonstrate that TNF, IL-1, or LPS (but not IL-2, IL-4, IL-6, interferon gamma, histamine, or transforming growth factor beta) induces activation of NF-kappa B-like DNA binding activity in HUVEC. In contrast, neither TNF, IL-1, nor LPS activates proteins that bind to an AP-1 consensus sequence under these experimental conditions. Phorbol 12-myristate 13-acetate, a known activator of protein kinase C (PKC), weakly induces NF-kappa B-like activity, ELAM-1 mRNA, and ELAM-1 surface expression in HUVEC. However, TNF, IL-1, and LPS do not activate PKC in HUVEC at doses that strongly induce NF-kappa B-like protein activation and ELAM-1 gene expression. PKC blockade with H7 does not inhibit activation of these NF-kappa B-like proteins but does inhibit ELAM-1 gene transcription. We conclude that PKC-independent activation of NF-kappa B in HUVEC with TNF, IL-1, or LPS is associated with, but not sufficient for, activation of ELAM-1 gene transcription.

Base Sequence↗