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Biomedical subjects

N Platt

Publications and source records attributed to N Platt.

At least 19 recordsLinked to original sources
PubMed2004

Evaluation of an osteoporosis self-referral program to enhance management outcomes.

Osteoporosis is a common but undertreated condition. While bone density is known to predict fracture risk, there is currently no economical way of measuring general population risk. This study examined whether an economical screening technique could improve diagnosis and lead to appropriate outcomes in the management of osteoporosis. A self-referral program was established to provide women with information about osteoporosis and an individualized risk assignment. A high-risk designation was provided for postmenopausal women below the lower tertile of a calcaneal broadband ultrasound attenuation (BUA) (< or = 58 db/MHz) or those with a SCORE value > or = 6. A telephone survey was conducted 6 mo after program registration to evaluate osteoporosis management outcomes. Of 271 women surveyed, 181 (67%) were postmenopausal and thus potential candidates for estrogen replacement, and 21% and 63% were assigned a high-risk profile by either calcaneal ultrasound or SCORE, respectively. Women at higher risk were significantly more likely to discuss osteoporosis with their family physician (p < 0.001), and to undergo further testing with dual X-ray absorptiometry measurement (p < 0.005). Utilization of estrogen replacement by postmenopausal women at time of survey was significantly increased compared to registration (p = 0.01). The self-referral program positively impacted decisions women made about preventing osteoporosis, particularly if they considered themselves at higher risk.

Absorptiometry, Photon↗
PubMed2000

Apoptotic thymocyte clearance in scavenger receptor class A-deficient mice is apparently normal.

Studies of apoptotic cell uptake by phagocytes in vitro have implicated a number of different receptors capable of mediating ingestion. However, there is currently little evidence for involvement of any of these candidate receptors in vivo. Previously, we have shown by the use of a blocking mAb against the class A scavenger receptor (SR-A) and thymic macrophages prepared from SR-A null mice, that this receptor is responsible for approximately 50% of the uptake of apoptotic thymocytes in vitro. In this study we have investigated the frequency of dying cells in the thymus of mice lacking SR-A. Our inability to demonstrate increased frequencies of nonphagocytosed Annexin V+, TUNEL+, or propidium iodide+ apoptotic thymocytes suggests there is no deficiency in apoptotic thymocyte clearance in these mice. Even when the rate of thymocyte apoptosis was increased by exposure of receptor-deficient mice to gamma irradiation, we did not detect a difference in the numbers of dying cells compared with similarly treated wild-type animals. This provides the first direct evidence of redundancy in apoptotic cell clearance mechanisms in vivo.

Animals↗
PubMed2000

A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes.

This study identifies a dendritic cell (DC) subset that constitutively transports apoptotic intestinal epithelial cell remnants to T cell areas of mesenteric lymph nodes in vivo. Rat intestinal lymph contains two DC populations. Both populations have typical DC morphology, are major histocompatibility complex class II(hi), and express OX62, CD11c, and B7. CD4(+)/OX41(+) DCs are strong antigen-presenting cells (APCs). CD4(-)/OX41(-) DCs are weak APCs and contain cytoplasmic apoptotic DNA, epithelial cell-restricted cytokeratins, and nonspecific esterase (NSE)(+) inclusions, not seen in OX41(+) DCs. Identical patterns of NSE electrophoretic variants exist in CD4(-)/OX41(-) DCs, intestinal epithelial cells, and mesenteric node DCs but not in other DC populations, macrophages, or tissues. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL)-positive DCs and strongly NSE(+) DCs are present in intestinal lamina propria. Peyer's patches and mesenteric but not other lymph nodes contain many strongly NSE(+) DCs in interfollicular and T cell areas. Similar DCs are seen in the ileum and in T cell areas of mesenteric nodes in gnotobiotic rats. These results show that a distinct DC subset constitutively endocytoses and transports apoptotic cells to T cell areas and suggest a role for these DCs in inducing and maintaining peripheral self-tolerance.

Animals↗
PubMed1999

Class A scavenger receptors and the phagocytosis of apoptotic cells.

Apoptotic cells are rarely seen in situ because of rapid clearance by phagocytes. A number of receptors have been implicated in the recognition and ingestion of dying cells. Class A scavenger receptors (SRs) are multi-domained membrane glycoproteins that can endocytose modified lipoproteins and bind a wide range of ligands. There is growing evidence that they contribute to several biological processes. We present data that suggest class A SRs are involved in the phagocytosis of apoptotic cells.

Animals↗
PubMed1998

Recognizing death: the phagocytosis of apoptotic cells.

Although apoptotic cell death is widespread, dying cells are rarely seen in situ because of their rapid clearance by neighbouring phagocytes. Phagocytic recognition of apoptotic cells is less well understood than the death programme itself, but an increasing number of recent studies are highlighting its importance. This review discusses the nature of the receptors that have been implicated in apoptotic cell phagocytosis, the mechanisms of uptake and the immunological consequences of apoptotic cell ingestion.

Animals↗
PubMed1998

Scavenger receptors: diverse activities and promiscuous binding of polyanionic ligands.

Scavenger receptors are a diverse family of proteins that share a common property--the binding of modified lipoprotein--but they have recently been shown to recognise a diverse range of ligands. Understanding the molecular interaction of receptor-ligand binding should provide insight into how scavenger receptors contribute to important biological processes.

Amino Acid Sequence↗
PubMed1997

The macrophage scavenger receptor type A is expressed by activated macrophages and protects the host against lethal endotoxic shock.

During gram-negative bacterial infections, lipopolysaccharide (LPS) stimulates primed macrophages (Mphi) to release inflammatory mediators such as tumor necrosis factor (TNF)-alpha, which can cause hypotension, organ failure, and often death. Several different receptors on Mphi have been shown to bind LPS, including the type A scavenger receptor (SR-A). This receptor is able to bind a broad range of polyanionic ligands such as modified lipoproteins and lipoteichoic acid of gram-positive bacteria, which suggests that SR-A plays a role in host defense. In this study, we used mice lacking the SR-A (SRKO) to investigate the role of SR-A in acquired immunity using a viable bacillus Calmette Guérin (BCG) infection model. We show that activated Mphi express SR-A and that this molecule is functional in assays of adhesion and endocytic uptake. After BCG infection, SRKO mice are able to recruit Mphi to sites of granuloma formation where they become activated and restrict BCG replication. However, infected mice lacking the SR-A are more susceptible to endotoxic shock and produce more TNF-alpha and interleukin-6 in response to LPS. In addition, we show that an antibody which blocks TNF-alpha activity reduces LPS-induced mortality in these mice. Thus SR-A, expressed by activated Mphi, plays a protective role in host defense by scavenging LPS as well as by reducing the release by activated Mphi of proinflammatory cytokines. Modulation of SR-A may provide a novel therapeutic approach to control endotoxic shock.

Animals↗
PubMed1997

Discrimination between maintenance- and differentiation-inducing signals during initial and intermediate stages of positive selection.

As well as signaling through the alphabeta T cell receptor complex, positive selection of immature CD4+ 8+ thymocytes involves additional ill-defined accessory interactions provided by thymic epithelial cells. Here, we have isolated CD4+ 8+ thymocytes at a pre-positive selection stage of development (TCR- CD69- 4+ 8+ cells), or after initiation of positive selection (CD69+ 4+ 8+ cells), from mice where the normal lifespan of thymocytes is extended by the presence of a bcl-2 transgene, to allow us to discriminate between requirements for maintenance and differentiation signals during positive selection. We find that MHC class II+ thymic epithelial cells drive positive selection of TCR- CD69- 4+ 8+ bcl-2 tg thymocytes to the CD4+ and CD8+ stage, while no such mature subsets are observed when thymocytes are cultured alone or with major histocompatibility complex (MHC) class II+ salivary epithelial cells. However, CD4+ 8+ cells remain in such cultures in considerable numbers, and retain the potential for positive selection if re-cultured with thymic epithelium, suggesting that thymic epithelial cells provide specific differentiation-inducing signals for positive selection. In contrast, intermediate CD69+ 4+ 8+ thymocytes show some capacity for phenotypic conversion in the absence of thymic stromal cells although strikingly the single-positive CD4+ and CD8+ cells generated are not functionally competent. Finally, we show that prior culture of thymic epithelial cells under monolayer conditions abrogates their ability to support the initiation of positive selection, suggesting that the epithelial cell molecules necessary for the provision of differentiation signals during positive selection are down-regulated under such conditions.

Animals↗
PubMed1996

Role for the class A macrophage scavenger receptor in the phagocytosis of apoptotic thymocytes in vitro.

Numerous immature thymocytes undergo apoptosis and are rapidly engulfed by phagocytic thymic macrophages. The macrophage surface receptors involved in apoptotic thymocyte recognition are unknown. We have examined the role of the class A macrophage scavenger receptor (SR-A) in the engulfment of apoptotic thymocytes. Uptake of steroid-treated apoptotic thymocytes by thymic and inflammatory-elicited SR-A positive macrophages is partially inhibited by an anti-SR-A mAb and more completely by a range of scavenger receptor ligands. Thymic macrophages from mice with targeted disruption of the SR-A gene show a 50% reduction in phagocytosis of apoptotic thymocytes in vitro. These data suggest that SR-A may play a role in the clearance of dying cells in the thymus.

Animals↗
PubMed1996

Macrophage membrane molecules: markers of tissue differentiation and heterogeneity.

Monoclonal antibodies directed against murine macrophage differentiation antigens provide tools to characterize novel glycoproteins, their expression by different macrophage subpopulations in situ and regulation by cytokines and other agents in vitro. Studies are in progress to determine ligands for these molecules, and to establish possible functions. We summarize current knowledge of the following molecules: F4/80, a glycoprotein with homology to the G-protein linked transmembrane 7 hormone receptor family; macrosialin, a member of the lysosomal-associated membrane protein [lamp] family with a macrophage-specific mucin-like extracellular domain also present in its human homologue, CD68; sialoadhesin, a sialic acid binding lectin with multiple Ig superfamily domains; mannosyl receptor, a lectin-like molecule with multiple C-type lectin domains; type 3 complement receptor, a beta 2 integrin involved in cell migration and adhesion; scavenger receptor, a transmembrane homotrimer with a collagenous domain.

Animals↗
PubMed1995

Cloning and expression of the beta-N-acetylglucosaminidase gene from Streptococcus pneumoniae. Generation of truncated enzymes with modified aglycon specificity.

The gene encoding a beta-N-acetylglucosaminidase from Streptococcus pneumoniae has been obtained by screening an expression library for beta-N-acetylglucosaminidase activity. Clones of different nucleotide sizes each having arylglycoside activity were obtained, and DNA sequencing revealed a gene of 3933 base pairs possessing typical bacterial transcription initiation and termination sequences and terminating in an ochre stop codon. Computer analysis of the translated protein of 1311 amino acids (144,210 Da) identified a tandem repeat within which lies a sequence homologous with six other hexosaminidase gene products from a wide variety of species ranging from bacteria to humans. Also found were an amino-terminal putative secretion signal peptide and a carboxyl-terminal cell sorting/anchorage motif typically found in over 20 other Gram-positive surface proteins. The expression of an almost complete DNA clone in Escherichia coli produced a functional and authentic beta-N-acetylglucosaminidase with aglycon specificity identical to the wild-type enzyme. However, enzymes produced from truncated DNA clones show more restricted aglycon specificity and are unable to hydrolyze terminal beta 1-2GlcNAc residues from N-glycans containing a bisecting N-acetylglucosamine. The availability of these clones allows structural analyses to be made of catalytic and oligosaccharide recognition protein domains that enhance functional activity.

Acetylglucosaminidase↗