PubMed Health⌕ Search

Biomedical subjects

S Gordon

Publications and source records attributed to S Gordon.

At least 73 records · Page 4Linked to original sources
PubMed2001

HIV-macrophage interactions at the cellular and molecular level.

Macrophages, centrally involved in both the innate and adaptive arms of the immune system are not only the chief target of the human immunodeficiency virus (HIV), but also its main reservoir and vehicle of transmission. Macrophage-tropic (M-tropic) viruses are responsible for the initial infection, predominate in the asymptomatic phase, and persist throughout infection, even after the emergence of preferential T cell- and/or dual-tropic HIV-1 variants. Functional impairment of HIV-infected macrophages plays a role in the immune dysregulation characteristic of acquired immunodeficiency syndrome (AIDS). Efforts directed at understanding the cellular and molecular mechanisms underlying HIV-macrophage interactions remain the basis for devising novel and efficacious therapeutic strategies against HIV ant the AIDS epidemic.

AIDS-Related Opportunistic Infections↗
PubMed2000

Human EMR2, a novel EGF-TM7 molecule on chromosome 19p13.1, is closely related to CD97.

The epidermal growth factor (EGF)-TM7 proteins [EMR1, (EGF-like molecule containing mucin-like hormone receptor 1) F4/80, and CD97] constitute a recently defined class B GPCR subfamily and are predominantly expressed on leukocytes. These molecules possess N-terminal EGF-like domains coupled to a seven-span transmembrane (7TM) moiety via a mucin-like spacer domain. Genomic mapping analysis has suggested a possible EGF-TM7 gene family on the human chromosome 19p13 region. In this study, a new member of the EGF-TM7 family, EMR2, which shares strikingly similar molecular characteristics with CD97, is described. In addition to mapping closely to CD97 on human chromosome 19p13.1, EMR2 contains a total of five tandem EGF-like domains and expresses similar protein isoforms consisting of various numbers of EGF-like domains as a result of alternative RNA splicing. Furthermore, EMR2 and CD97 exhibit highly homologous EGF-like domains and share identical gene organization, indicating that both genes are the products of a recent gene duplication event. The homologous EGF-like domains enable the identification of both EMR2 and CD97 by monoclonal antibodies (mAbs) raised against the first EGF-like domain of CD97, whereas mAbs directed against the extracellular spacer domain of CD97 are able to differentiate these two proteins. Both EMR2 and CD97 are highly expressed in immune tissues; however, unlike CD97, which is ubiquitously expressed in most cell types, EMR2 expression is restricted to monocytes/Mφ and granulocytes. EMR2 fails to interact with CD55, the cellular ligand for CD97, suggesting the possibility of a different cellular ligand(s). EMR2 may therefore have a unique function in cells of monocyte/Mφ and granulocyte lineages.

Alternative Splicing↗
PubMed2000

Cellular and molecular mechanisms of action of bisphosphonates.

BACKGROUND: Bisphosphonates currently are the most important class of antiresorptive agents used in the treatment of metabolic bone diseases, including tumor-associated osteolysis and hypercalcemia, Paget's disease, and osteoporosis. These compounds have high affinity for calcium and therefore target to bone mineral, where they appear to be internalized selectively by bone-resorbing osteoclasts and inhibit osteoclast function. METHODS: This article reviews the pharmacology of bisphosphonates and the relation between the chemical structure of bisphosphonates and antiresorptive potency, and describes recent new discoveries of their molecular mechanisms of action in osteoclasts. RESULTS: Bisphosphonates can be grouped into two pharmacologic classes with distinct molecular mechanisms of action. Nitrogen-containing bisphosphonates (the most potent class) act by inhibiting the mevalonate pathway in osteoclasts, thereby preventing prenylation of small GTPase signaling proteins required for osteoclast function. Bisphosphonates that lack a nitrogen in the chemical structure do not inhibit protein prenylation and have a different mode of action that may involve the formation of cytotoxic metabolites in osteoclasts or inhibition of protein tyrosine phosphatases. CONCLUSIONS: Bisphosphonates are highly effective inhibitors of bone resorption that selectively affect osteoclasts. After more than 30 years of clinical use, their molecular mechanisms of action are only just becoming clear.

Animals↗
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

Adenovirus-mediated gene transfer of a secreted form of human macrophage scavenger receptor inhibits modified low-density lipoprotein degradation and foam-cell formation in macrophages.

BACKGROUND: Macrophage scavenger receptors (MSRs) play an important role in the pathogenesis of atherosclerosis. Therefore, local modulation of MSR activity could have a beneficial effect on atherogenesis. METHODS AND RESULTS: We cloned a secreted "decoy" MSR (sMSR) that contains an extracellular portion of the human MSR type AI and constructed an adenoviral vector that directs high-level expression of sMSR in macrophages under the control of the human CD68 promoter. Expression of the sMSR protein inhibited the degradation of (125)I-labeled acetylated LDL and oxidized LDL by murine macrophages up to 90%. sMSRs also reduced acetylated LDL degradation in MSR knockout mouse peritoneal macrophages by 60% to 80%, which suggests that the decoy construct can compete for the uptake mediated via other related scavenger receptors. In addition, sMSRs inhibited foam-cell formation in murine macrophages in the presence of cytochalasin D. The mechanism of inhibition is through ligand binding to the sMSRs, which prevents the ligand binding to MSRs on cell membranes. CONCLUSIONS: The demonstration that recombinant adenovirus-mediated gene transfer of decoy sMSRs can block foam-cell formation suggests a possible new strategy for gene therapy of atherosclerosis and for the treatment of lipid accumulation after arterial manipulations.

Adenoviridae↗
PubMed2000

Reindeer concerns

Explore the source record for details and available documents.

Journal Article↗
PubMed2000

Aldehyde-mannan antigen complexes target the MHC class I antigen-presentation pathway.

Antigens such as MUC1 coupled to oxidized mannan lead to rapid and efficient MHC class I presentation to CD8+ cells and a preferential T1 response; after reduction there is class II presentation and a T2 immune response. We now show that the selective advantage of the oxidized mannan-MUC1 is due to the presence of aldehydes and not Schiff bases, and that oxidized mannan-MUC1 binds to the mannose and not scavenger receptors and is internalized and presented by MHC class I molecules 1,000 times more efficiently than when reduced. After internalization there is rapid access to the class I pathway via endosomes but not lysosomes, proteasomal processing and transport to the endoplasmic reticulum, Golgi apparatus and cell surface. Aldehydes cause rapid entry into the class I pathway, and can therefore direct the subsequent immune response.

Aldehydes↗
PubMed2000

Role of alpha-1 adrenoceptor subtypes mediating constriction of the rabbit ear thermoregulatory microvasculature.

An acute in vivo preparation of the microvasculature of the rabbit ear was used to evaluate the functional role of alpha1 (alpha1)-adrenoceptor subtypes in thermoregulatory microcirculation. The effect of alpha1-adrenoceptor subtype blockade on phenylephrine-induced vasoconstriction was assessed with the alpha1A, alpha1B, and alpha1D-adrenoceptor-selective antagonists 5-methyl-urapidil (10(-8) M), chloroethylclonidine (10(-5) M), and 8-[2-[4(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol[4.5]deca ne-7,9-dione dihydrochloride (BMY7378) (10(-6) M), respectively. The results demonstrated that pretreatment of the ear microvasculature with 5-methyl-urapidil or BMY7378 shifted the phenylephrine concentration-response curve rightward and significantly changed the log of the phenylephrine concentration, causing half-maximum stimulation (EC50) in arterioles (p < 0.05). BMY7378 shifted the phenylephrine concentration-response curve of the arteriovenous anastomoses about 100-fold rightward (p < 0.05). All three alpha1-adrenoceptor antagonists eliminated the vasoconstrictive effects of phenylephrine on venules. The results indicate that the ear microvasculature has a heterogenous distribution of alpha1-adrenoceptor subtypes. The alpha1A and alpha1D-adrenoceptor subtypes appear to have a greater influence on constrictive function in arterioles, whereas the alpha1D-adrenoceptor is the dominant constrictor of arteriovenous anastomoses. In general, the alpha1-adrenoceptor does not play a major vasoconstrictor role in venules. Chloroethylclonidine, an irreversible alpha1B-adrenoceptor antagonist, induced contractile responses in the ear microvasculature, probably due to its alpha2-adrenoceptor agonist effects. This study extended our understanding of the adrenergic receptor control mechanisms of a cutaneous thermoregulatory end organ characterized by two parallel perfusion circuits providing nutritional and thermoregulatory functions.

Animals↗
PubMed2000

Mannose receptor and scavenger receptor: two macrophage pattern recognition receptors with diverse functions in tissue homeostasis and host defense.

In this report we have reviewed our recent data which suggest a new function for MR in antigen delivery in lymphoid organs, together with highlighting three recent discoveries from our laboratory concerning the role of SR-A in adhesion, phagocytosis of apoptotic cells and protection from endotoxic shock in mice. The diversity of functions mediated by each receptor demonstrates there is much yet to be discovered about how macrophages use their cell surface receptors to 'see' the external environment, and yet perform a wide range of strictly regulated functions.

Animals↗
PubMed2000

Biochemical responses of bone metabolism to 1,25-dihydroxyvitamin D administration in black and white women.

The basis for the racial difference in bone mass between black and white women is not known. Lower bone turnover, better renal calcium conservation, and decreased sensitivity to parathyroid hormone (PTH) have been proposed as explanations. A dynamic comparison of osteoblast function, utilizing stimulation by 1,25-dihydroxyvitamin D [1,25(OH)2D], has not been tested between these two ethnic groups. We compared well-matched black (n = 15) and white (n = 15) premenopausal women, before and during 5 days of 1,25(OH)2D administration (1.0 microgram/day) in order to assess dynamic indices of bone metabolism. As expected, at baseline, black women had lower levels of serum 25-hydroxyvitamin D and biochemical markers of bone turnover with slightly higher levels of PTH. Black women also had superior renal calcium conservation than white women at baseline. In response to 1,25(OH)2D administration, black women had a slightly greater increase in serum calcium and greater decrement in PTH. Moreover, black women showed a lesser increment in urinary calcium than white women and a more robust increase in two markers of bone formation--osteocalcin and carboxyterminal propeptide of type 1 procollagen--than white women. There were no changes in bone resorption indices in either race upon 1,25(OH)2D administration. These data provide preliminary evidence that black women conserve calcium more efficiently under both static and dynamic conditions, and also appear to have better osteoblastic functional reserve than white women.

Adult↗
PubMed2000

LNB-TM7, a group of seven-transmembrane proteins related to family-B G-protein-coupled receptors.

A number of unusual seven-transmembrane molecules have recently been characterized that have significant amino acid sequence similarity within the membrane-spanning hydrophobic regions and intervening loops to members of G-protein-coupled receptor family B. However, in contrast to the family-B G-protein-coupled receptors, these molecules have unusually large N-terminal extracellular domains that contain a number of well- characterized protein modules. The range of cell types expressing these complex molecules and their potential roles in cell adhesion and signalling have become a major focus of research in a number of biological systems.

Amino Acid Sequence↗
PubMed2000

The role of scavenger receptors in the innate immune system.

Akey aspect of the innate immune system is the ability to discriminate between self and infectious nonself. This is achieved through pattern recognition receptors which directly recognise molecular epitopes expressed by microbes. Scavenger receptors (SRs) have been studied primarily due to their ability to bind and internalise modified lipoproteins, suggesting an important role in foam cell formation and the pathogenesis of atherosclerosis. However, the ability of some SRs to function as pattern recognition receptors through their binding of a wide variety of pathogens indicates a potential role in host defence. This review will detail our current understanding of the function of SRs in innate immunity, and in the initiation of aquired immune responses.

Animals↗
PubMed2000

Macrophage lectins in host defence.

Macrophage lectins contribute to host defence by a variety of mechanisms. The best characterised, mannose receptor (MR) and complement receptor three (CR3), are both able to mediate phagocytosis of pathogenic microbes and induce intracellular killing mechanisms. The regulation of the effector functions induced via MR is complex, and may involve both host and microbial factors. Therefore, MR is likely to play a dynamic role in the response to infection; it may act as a classical pattern recognition receptor in phagocytosis, whereas other poorly characterised factors may make a more decisive contribution to its function in physiologic settings. In contrast, the lectin site of CR3 appears to lack host-derived ligands and may be a true pattern recognition receptor. Further studies are required to evaluate the roles of other macrophage lectins in recognition of and responses to microbes.

Animals↗
PubMed2000

Introduction

Explore the source record for details and available documents.

Journal Article↗
PubMed2000

An examination of psychosocial variables moderating the relationship between life stress and injury time-loss among athletes of a high standard.

Based on Williams and Andersen's model of stress and athletic injury, six psychosocial variables were assessed as possible moderators of the relationship between life stress and injury among 121 athletes (65 males, 56 females) competing in a variety of sports at state, national or international level. No significant effects of the sex of the participants were evident. Correlational analyses revealed moderator effects of several variables. Specifically, dispositional optimism and hardiness were related to decreased injury time-loss in athletes when positive life change increased, and global self-esteem was associated with decreased injury time-loss when both negative life change and total life change increased. The results indicate that athletes with more optimism, hardiness or global self-esteem may cope more effectively with life change stress, resulting in reduced injury vulnerability and recovery rates.

Adolescent↗
PubMed2000

Hodgkin's disease in primary care.

Hodgkin's disease is a common hematologic malignancy in young adults. The typical patient is a young adult male presenting with painless cervical adenopathy or a mediastinal mass on chest X-ray. If diagnosed early and aggressively treated, long-term survival rates are excellent. The subtypes of Hodgkin's disease are differentiated by pathologic examination of an affected lymph node. Chemotherapy, with or without adjuvant radiation, is the favored therapeutic regimen for most patients. A comprehensive approach to care, which incorporates psychosocial implications, can improve quality of life for Hodgkin's disease patients.

Adolescent↗