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Showing papers in "Annals of the New York Academy of Sciences in 1994"


Journal ArticleDOI
TL;DR: This paper presents a symmetric generalised metric for such topologies, an approach which sheds new light on how metric tools such as Banach's Theorem can be extended to non‐Hausdorff topologies.
Abstract: Metric spaces are inevitably Hausdorff and so cannot, for example, be used to study non-Hausdorff topologies such as those required in the Tarskian approach to programming language semantics. This paper presents a symmetric generalised metric for such topologies, an approach which sheds new light on how metric tools such as Banach's Theorem can be extended to non-Hausdorff topologies.

1,090 citations



Journal ArticleDOI
TL;DR: The extensive studies based on this possibility hold promise that the ALE-B can be extended to >85 years and the maximum life span increased.
Abstract: Aging is the accumulation of changes that increase the risk of death. Aging changes can be attributed to development, genetic defects, the environment, disease, and an inborn process: the aging process. The latter is the major risk factor for disease and death after age 28 in the developed countries. In these countries, average life expectancies at birth (ALE-B) now range from 76 to 79 years, 6-9 years less than the limit of approximately 85 years imposed by aging. Aging changes may be caused by free radical reactions. The extensive studies based on this possibility hold promise that the ALE-B can be extended to >85 years and the maximum life span increased.

434 citations


Journal ArticleDOI
TL;DR: The evidence is reviewed that preterm labor is a pathologic condition caused by multiple etiologies, and hence should be considered a syndrome: the Preterm Labor Syndrome.

415 citations


Journal ArticleDOI
TL;DR: This recently discovered function of melatonin establishes a role for this indole in every organism, and indeed in every cell, from the most primitive members of the animal kingdom up to and including the was shown to be a hormone produced in and secreted from the mammalian pineal gland.
Abstract: Melatonin, ~-acetyl-5-methoxytryptamine, is phylogenetically a very old molecule. Melatonin is known to exist in the dinoflagellate Gonyaulax polyedra, ' and it is perhaps produced by most if not all organisms in the animal kingdom. The conservation of this molecule during evolution may relate to its free radical scavenging ability.2 This recently discovered function of melatonin establishes a role for this indole in every organism, and indeed in every cell, from the most primitive members of the animal kingdom up to and including the was shown to be a hormone produced in and secreted from the mammalian pineal gland. In vertebrates melatonin's production in the pineal exhibits a circadian rhythm with highest blood levels of the hormone being present during the night.6 The circadian rhythm in melatonin production provides important time-of-day and time-of-year information' and, as a result, this hormonal cycle drives other 24-hour rhythms8 as well as seasonal cycles of reproduction, at least in photoperiodic mammal^.^ Although for years melatonin was thought to be exclusively produced in the pineal gland and to function only as a hormone which acted via membrane receptors located at a few discrete sites in mammals,'O~\" it was subsequently learned that in perhaps all vertebrates melatonin is found in a number of other cells and organs. l 2 , l 3 Its likely production outside the pineal gland was strongly reinforced by the observation that melatonin is even produced in unicellular organisms such as the dinoflagellate;' since they obviously lack a pineal gland, or for that matter any other organ, it is clear that individual pineal-unrelated cells can synthesize melatonin. The fact that melatonin is highly lipophilic made some investigators question Melatonin, when discovered slightly over 30 years

374 citations



Journal ArticleDOI
TL;DR: There is no reason to believe that verbal memory is truly impaired in women during phases of the menstrual cycle marked by low levels of estrogen, and there is some preliminary evidence that progesterone may enhance visual-spatial skills in women but this needs to be confirmed.
Abstract: Sufficient evidence now exists to support the contention that estrogen influences cognitive functioning in women. Moreover, the data strongly suggest that estrogen exerts a specific and not a global effect on cognitive functions. Whereas estrogen enhances and/or maintains aspects of verbal memory, it is without effect, or possibly even has a negative influence on spatial memory. Indeed, there is some preliminary evidence that progesterone may enhance visual-spatial skills in women but this needs to be confirmed. Estrogen also exerts a positive effect on sexually dimorphic cognitive skills in which females typically excel such as verbal articulation and fine motor skills. While the weight of the evidence supports the above conclusion, findings across studies are not entirely consistent. Some of the methodological problems that weaken these studies include generalizing from one or two cognitive tasks to the entire realm of cognitive functions, neglecting to assay plasma levels of estradiol to confirm cycle phase or compliance with hormone administration and neglecting to consider the differential availability to the brain of the various estrogen preparations and the effects of different routes of administration. Although, for the most part, the menstrual cycle studies and the postmenopausal studies in healthy women show that estrogen maintains verbal memory, the effect size is modest. There is no reason to believe, for example, that verbal memory is truly impaired in women during phases of the menstrual cycle marked by low levels of estrogen. Nor are 45-year-old untreated, surgically menopausal women clinically impaired to any degree that affects their daily functioning in the real world. In both cases, however, decrements in performance occur reliably in the laboratory. This raises the issue, therefore, of the clinical meaningfulness of these findings. One way to address the clinical relevance of the relationship between estrogen and memory and thus, on cognitive functioning of the brain, is to examine what is known of estrogenic effects on other physiological systems where we already have substantial information. For example, the vast majority of women experience bone loss following the menopause and many develop osteopenia (bone density more than two standard deviations below mean peak bone mass levels) which is asymptomatic. Then, with advancing age, some women with osteopenia develop osteoporosis, predisposing them to fractures following minimal trauma. It has been estimated that 40 per cent of women who live to age 80 will develop spinal fractures and 33 per cent of women who live to age 90 will experience a hip fracture.(ABSTRACT TRUNCATED AT 400 WORDS)

233 citations


Journal ArticleDOI
TL;DR: A program of study of the MMPs and TIMPs was initiated to ascertain the relation between their structure and their function, with particular emphasis on the mechanisms of biological regulation.
Abstract: Matrix metalloproteinases (MMPs) are thought to initiate the degradation of the extracellular matrix during the remodeling of connective tissues. A clear understanding of the mechanisms governing the regulation of their activity during normal physiological processes should give further insights into the uncontrolled remodeling occurring in degradative pathologies. Regulation of the MMPs occurs at the level of gene expression, with precise spatial and temporal compartmentalization of both synthesis and secretion by resident cells as well as by those cells invading the tissue. Extracellularly, MMPs are further regulated by the extent of processing of the proform to an active enzyme and by the relative production of the specific inhibitors of MMPs, the tissue inhibitors of metalloproteinases (TIMPs). Furthermore, the potential for association of MMPs with the cell surface or extracellular matrix components further constrains their relationship with substrates, activators and inhibitors, acting as a further regulator of MMP activity. We initiated a program of study of the MMPs and TIMPs to ascertain the relation between their structure and their function, with particular emphasis on the mechanisms of biological regulation. Recombinant wild-type proteins and specific mutants, including deletion and site mutations, have been prepared using a mammalian expression system.’ Aspects of our findings, which illustrate the fundamental importance of the domain structure of MMPs and TIMPs in their biology, are presented here.

233 citations


Journal ArticleDOI
TL;DR: Using this vector, the normal human CFTR cDNA has been successfully transferred to airway epithelial cells of experimental animals via the trachea, and led to the development of human gene therapy protocols for the evaluation of the safety and efficacy of adenovirus-mediated CF TR cDNA transfer to lungs of individuals with cystic fibrosis.
Abstract: Adenovirus vectors are efficient vehicles for in vivo gene transfer to many different cell types. Recombinant adenovirus vectors containing exogenous genes for transfer are derived from adenovirus type 5 and are made replication deficient by the deletion of the E1 region. Based on the observation that many natural adenovirus infections are targeted to airway epithelial cells, a replication-deficient adenovirus vector was constructed containing the cystic fibrosis transmembrane conductance regulator cDNA for the potential therapy of the respiratory manifestations of cystic fibrosis. Using this vector, the normal human CFTR cDNA has been successfully transferred to airway epithelial cells of experimental animals via the trachea. This finding has led to the development of human gene therapy protocols for the evaluation of the safety and efficacy of adenovirus-mediated CFTR cDNA transfer to lungs of individuals with cystic fibrosis. In addition to the airways, adenovirus vectors have been demonstrated to mediate in vivo gene delivery to cells of the liver, blood vessels, brain, muscle, heart, peritoneum, and salivary glands. Adenovirus vectors containing marker genes have also been demonstrated to transfer genes to human tumor cells in nude mice. Such vectors may be useful for a variety of therapeutic applications for in vivo gene transfer for the therapy of cancer and other diseases.

229 citations


Journal ArticleDOI
TL;DR: In this paper, it was shown that the hysteresis effect suggests that the water remembers its past hydrate history, presumably through the existence of subcritical sized hydrate crystal nuclei in the fluid.
Abstract: Natural gas hydrates are icelike solids in which the water molecules or “hosts” form a rigid cagelike structure enclosing voids in which light hydrocarbons or other small molecules, known as “guests,” are contained. These solids belong to a class of crystals known as clufhrutes.’ Gas hydrates are nonstoichiometric crystals. The number of water molecules per gas molecule, the hydration number, depends on the conditions in which the crystal was formed and the type of gas molecule in the hydrate. Usually, hydration numbers range from 5.75 to 19, as quoted by Sloan.2 There arc two types of well-characterized natural gas hydrate denoted as hydrate type I and hydrate type 11. The main factor deciding the type of gas hydrate formed is the diameter of the guest molecule. Propane forms the type I1 hydrate (with the larger cavity), while methane forms the type I (in which the cavity is smaller). Hydrates are important industrially since they form spontaneously in natural gas lines, even at temperatures above O’C, forming plugs that can reduce and stop the flow of gas. These plugs are difficult to remove. To avoid their formation, inhibitors like methanol are injected in the lines, increasing the cost of operation. Hence there is considerable economical incentive to try to understand how hydrates form and how to inhibit their growth. To do this, one needs to understand both the thermodynamics and the kinetics of hydrate growth and dissolution. There are extensive data on hydrate thermodynamic properties, and the phase diagram is well known. However, there are much fewer kinetic data available. Some hydrates exhibit an induction period, i.e., even when conditions are favorable for their formation, some time elapses before the hydrate forms. In contrast, if the hydrate is melted and the conditions reestablished for hydrate formation, there is essentially no induction period and the hydrate will form almost immediately.2 This hysteresis effect suggests that the water remembers its past hydrate history, presumably through the existence of subcritical sized hydrate crystal nuclei in the fluid. A hypothesis has been proposed for the existence of the induction period and the memory but this has yet to be proved.

227 citations


Journal ArticleDOI
TL;DR: Results of radioligand binding and second-messenger studies, using selected SRIF analogues, have suggested for years the existence of at least two SRIF-receptor subtypes, SSl/SRIFl and SS2/ SRIF2.
Abstract: Somatostatin (somatotropin release inhibiting factor, SRIF) was initially isolated from ovine hypothalamic extracts as a factor that inhibits growth hormone (GH) release from cultured pituitary cells.' Later it became evident that SRIF is an important regulator of endocrine and exocrine secretion and CNS functions. SRIF is derived from preprosomatostatin (116 amino acids) that is first cleaved to form prosomatostatin (92 amino acids) before being processed by tissue-specific cleavage to several shorter fragments, such as SRIF-28, SRIF-25, and SRIF-14, of which SRIF-14 was identified first. SRIF is found widely distributed throughout the intestinal tract; the D cells of the pancreas; specific endocrine cells of the thyroid, thymus, and brain; and also in neurons innervating the heart and r e t i ~ ~ a . ~ ~ SRIF not only inhibits the release of GH but also that of other hormones, such as insulin, glucagon, gastrin, and secretin, as well as exocrine secretion.2 SRIF is also present in various brain regions where it was shown to be a modulator of neural activity.@ It regulates the release of a variety of neurotransmitters, such as dopamine, 5-HT, and excitatory amino acids. In addition, SRIF and its metabolically stabilized analogues, such as octreotide (SMS 201-995), possess antiproliferative properties. Inhibitory effects on tumor-cell proliferation have been demonstrated both in vitro and in vivo.\"' All these observed regulatory effects of SRIF are mediated by specific, highaffinity membrane receptors on the target tissues, such as brain, pancreas, pituitary, gastrointestinal tract, and on tumor t i s s ~ e . ~ . ~ Results of radioligand binding and second-messenger studies, using selected SRIF analogues, have suggested for years the existence of at least two SRIF-receptor subtypes, SSl/SRIFl and SS2/SRIF2.12.13 Furthermore, various SRIF analogues differed in their inhibitory potency on the secretion of insulin, glucagon, growth hormone, and gastric acid, providing further support for the heterogeneity of SRIF re~ept0rs.l~ The final proof for SRIF receptor heterogeneity has been obtained during the last two years by the cloning of different genes coding for SRIF-receptor subtypes.

Journal ArticleDOI
TL;DR: Pituitary adenylate cyclase activating polypeptide (PACAP) was first isolated from ovine hypothalamic tissues during an attempt to isolate a novel hypophysiotropic hormone based on the ability to activate adenYLate Cyclase in rat pituitary cell cultures.
Abstract: In addition to classical neurotrophic factors, neurotransmitters and neuropeptides also exhibit neurotrophic activities.' The central nervous system (CNS) contains a variety of neuropeptides in neurons and nonneuronal cells. These peptides and their receptors appear in early developmental stages, often transiently expressed at a peak level, suggesting a possible physiological role as modulators of growth and differentiation of neurons. Neurotrophic actions of a number of neuropeptides have been reported. In particular, vasoactive intestinal peptide (VIP), which is a preganglionic neurotransmitter in the sympathetic nervous system of the adult rat,* was shown to exert multiple actions on developing sympathetic neuroblasts in culture, including stimulation of neuronal mitosis, survival, and process o~tgrowth .~ VIP also increases the survival of cultured spinal cord neurons during a critical period of de~elopment .~ .~ Pituitary adenylate cyclase activating polypeptide (PACAP) was first isolated from ovine hypothalamic tissues during an attempt to isolate a novel hypophysiotropic hormone based on the ability to activate adenylate cyclase in rat pituitary cell cultures. Two forms of PACAP, one with 38 residues (PACAP38) and a truncated form with 27 residues (PACAP27), were isolated from the ovine hypothalamic PACAP is a new member of secretin-glucagon-VIP family with 60% sequence homology with VIP, but its adenylate cyclase stimulating activity in cultured pituitary cells is 1000 times greater than Immunohistochemical

Journal ArticleDOI
TL;DR: Koch’s speculation that multiplication takes place in river water, without any assistance, has proven to be prescient, since the most recent data show that toxigenic V. cholerae 01 exist for long periods in laboratory microcosm water.
Abstract: Until the late 1970s and early 1980s, Vibrio cholerae was believed to be highly host-adapted and incapable of surviving longer than a few hours or days outside the human intestine. This view, enunciated by Felsenfeld,’ was that “some authors claimed that cholera vibrios may survive in water, particularly seawater, for as long as 2 months. This is, however, scarcely possible under natural conditions, if reinfection of the water does not take place.” This perspective of cholera ecology dominated the literature since the organism was first identified by Robert Koch in 1884.2 For V. chohae the term ‘‘survival” had been viewed to reflect a high degree of host-adaptation, ea., “cholera vibrios” being able to exist for only very short periods of time outside the human intestine. But Koch’s speculation that multiplication takes place in river water, without any assistance, has proven to be prescient, since the most recent data show that toxigenic V. cholerae 01 exist for long periods in laboratory microcosm water.’ In fact, the evidence accumulated over the ast decade shows that V. chohae is an

Journal ArticleDOI
TL;DR: Regardless of which events follow after the proPo system is activated, it is clear that it can react to foreign microbial polysaccharides and as such can be defined as a recognition system.
Abstract: Invertebrates have an open circulatory system and must therefore have rapid and immediate noninducible defence and coagulation mechanisms to entrap parasites and prevent blood loss after wounding. As in most animals, these processes are mainly carried out by the blood cells or, as they are called in arthropods, hemocytes. The hemocytes of arthropods and other invertebrates have been shown to be important in defence, since they are responsible for phagocytosis of small foreign particles such as bacteria or fungal spores and form capsules around parasites that are too large to be internalized by individual hemocytes. Because the hemocytes obviously can react to and remove a foreign particle that has succeeded in gaining entry into the body cavity of an arthropod, it appears as if these animals can differentiate non-self from self, and thus a system that can carry out this process ought to be present. Agglutinins or lectins may be one candidate for such a system.l-s Another likely candidate is the so-called prophenoloxidase (proPO) activating system: and recently evidence has accumulated mainly from work done on crustaceans that this may be the case. The prime reason why this system early was proposed to function in recognizing foreign particles was the finding that the enzyme phenoloxidase in crayfish blood was turned into its active form by fungal cell wall p-1,3-gl~cans.~~* This was later also confirmed to be the case in several insect species”” and other in~ertebrates.l~-’~ Other microbial products such as lipopolysaccharides and peptidoglycans from bacterial cell walls are also active as elicitors of the proPo system.*s.16 Thus, regardless of which events follow after the proPo system is activated, it is clear that it can react to foreign microbial polysaccharides and as such can be defined as a recognition system. Recent research has also provided clear evidence that, upon activation of the proPo system, factors are produced that will aid in the elimination of foreign particles such as parasites within the body cavity. This brief overview will report some of these studies, which have mainly been carried out on arthropods, and where

Journal ArticleDOI
TL;DR: Activity of respiratory epithelial cells in vitro as sources of cytokines and inflammatory mediators is investigated, finding that production and release of these cytokines increases substantially after exposure to specific inflammatory stimuli, such as TNF or IL-1, and after viral infection.
Abstract: Epithelial cells lining respiratory airways can participate in inflammation in a number of ways. They can act as target cells, responding to exposure to a variety of inflammatory mediators and cytokines by altering one or several of their functions, such as mucin secretion, ion transport, or ciliary beating. Aberrations in any of these functions can affect local inflammatory responses and compromise pulmonary defense. For example, oxidant stress can increase secretion of mucin and depress ciliary beating efficiency, thereby affecting the ability of the mucociliary system to clear potentially pathogenic microbial agents. Recent studies have indicated that airway epithelial cells also can act as "effector" cells, synthesizing and releasing cytokines, lipid mediators, and reactive oxygen species in response to a number of pathologically relevant stimuli, thereby contributing to inflammation. Many of these epithelial-derived substances can act locally, affecting both neighboring cells and tissues, or, via autocrine or paracrine mechanisms, affect structure and function of the epithelial cells themselves. Studies in our laboratories utilized cell cultures of both human and guinea pig tracheobronchial and nasal epithelial cells, and isolated human nasal epithelial cells, to investigate activity of respiratory epithelial cells in vitro as sources of cytokines and inflammatory mediators. Primary cultures of guinea pig and human tracheobronchial and nasal epithelial cells synthesize and secrete low levels of IL-6 and IL-8 constitutively. Production and release of these cytokines increases substantially after exposure to specific inflammatory stimuli, such as TNF or IL-1, and after viral infection.

Journal ArticleDOI
TL;DR: The key role of PMN-MMPs in periodontitis is extended, and the activities of these PMN MMPs can be inhibited directly by therapeutic levels of DOXY, providing evidence for noncompetitive inhibition.
Abstract: The characterization and regulation of matrix metalloproteinases (MMPs) have been studied to determine their role(s) in periodontal tissue destruction. Progress in elucidating the roles of MMPs in periodontal tissue destruction has led to a new concept involving the chemotherapeutic inhibition on MMPs, a therapeutic strategy which less than a decade ago was considered "a difficult and perhaps impossible task." Tetracyclines/doxycycline (DOXY) and their chemically modified nonantimicrobial derivatives (CMTs) are known to inhibit the matrix metalloproteinases, especially preferring human neutrophil collagenase (MMP-8), and prevent the oxidative activation of procollagenases. We characterized by Western blotting the molecular forms and cellular sources of gingival tissue, dental plaque, gingival crevicular fluid (GCF), and salivary MMPs associated with periodontitis. Also the molecular forms of tissue inhibitors of matrix metalloproteinases (TIMP-1 and TIMP-2) in periodontitis were studied by Western blot. Neutrophil (PMN)-derived MMPs were found to predominate in periodontitis, and phospholipase C present in increased amounts in periodontitis sites was found to be a potential inducer of PMN degranulation. We further studied the effects of DOXY on molecular forms of different latent and active MMPs purified from different cellular sources (PMNs, fibroblasts, keratinocytes) and present in vivo in oral exudates (gingival extracts, GCF, and saliva). DOXY inhibition of activated (oxidatively or proteolytically) MMPs were not associated with MMP fragmentation. Michaelis-Menten plots of initial rates of degradation of soluble type I collagen revealed an apparent Km value of 0.3-0.6 microM for MMP-8, and 75 microM DOXY inhibited MMP-8 in a manner which did not result in changes in apparent Km value but did prevent the initial degradation reaching Vmax providing evidence for noncompetitive inhibition. Treatment of patients with long-term DOXY medication results in decreased MMP-8 activities/levels in gingival tissue, crevicular fluid, and saliva, but not fragmentation of MMP-8 in vivo. These data further support and extend the key role of PMN-MMPs in periodontitis, and the activities of these PMN MMPs can be inhibited directly by therapeutic levels of DOXY.

Journal ArticleDOI
TL;DR: In this article, the formation of hydrogen bonded water molecules around different sizes of apolar molecules, and the joining of these clusters to create a hydrate nucleus, are discussed in the framework of an overall hydrate forming mechanism.
Abstract: In addition to equilibrium properties, the scope of research on natural gas hydrates now includes the rate at which they form. One motivation for this research is a hope that the rate of formation of hydrates can be predicted or significantly decreased in some way, to the extent that hydrate formation in pipelines can be avoided. This evolutionary feature of hydrate research appears in the twenty-year history of projects in our laboratory as shown in TABLE 1 and the associated references,’-?’ and in recent comprehensive reviews of the literature.2c2y Perhaps because phase behavior and other properties can be predicted for hydrate structures I and I1 (CSI for cubic structure I and CSII for cubic structure I1 in the nomenclature of Dyadin et al.)”’ with acceptable accuracy for a wide variety of gases, researchers are directing more of their efforts toward the processes of hydrate formation. There are different perspectives in the literature on the processes of hydrate formation. In the laboratory of Bishnoi, interest has focused on the mass transfer aspects of the process.” Our interest is in the molecular mechanisms and reaction kinetics of the hydrate formation process. The mechanism proposed here for the kinctics of hydrate formation is composed of two parts: (A) the formation of clusters of hydrogen bonded water molecules around different sizes of apolar molecules, and (B) the joining of these clusters to create a hydrate nucleus. The work represents an extension and a quantification of the molecular hypothesis derived from that of ice, as proposed earlier.21-23 In the discussion below, we first review the role of cavities in the structure of hydrates. Next, the ordering or clustering of water molecules around dissolved apolar molecules is described. Then, with this background, the joining of clusters to create hydrates is discussed within the framework of an overall hydrate forming mechanism. To the extent available, experimental support for hypotheses of the mechanism is presented. Finally, a brief overview of experimental efforts in our laboratory toward identifying chemical inhibitors of the kinetics of hydrate formation is given.

Journal ArticleDOI
TL;DR: It is suggested that a selective inhibitor of this isoenzyme may exhibit anti-inflammatory activity without effects on PGHS-1 of platelets and perhaps without ulcerogenic effects associated with commonly available NSAIDs.
Abstract: It is now that there are two isozymes of prostaglandin endoperoxide (PGH) synthase (cyclooxygenase) called PGH synthase-1 and -2 or COX I and II. Both isozymes catalyze the conversion of arachidonate to PGH2, the committed step in the formation of both prostacyclin and thromboxane A2. PGH synthase-1 is present in platelets and endothelial cells whereas PGH synthase-2 has been detected in endothelial cells treated with cytokines and phorbol esters. PGH synthase-1 (PGHS-1) has long been thought to be the site of action of nonsteroidal anti-inflammatory drugs (NSAIDs). However, it is now clear that the second isozyme, PGH synthase-2 (PGHS-2), is also inhibited by these compounds. Cloning of the cDNAs for murine PGHS-1 and PGHS-2 has allowed us to express these two enzymes in cos-1 cells and to compare the relative sensitivities of these enzymes in vitro using a series of common NSAIDs. NSAIDs such as indomethacin, piroxicam, and sulindac sulfide preferentially inhibit PGHS-1. Ibuprofen and meclofenamate inhibit both enzymes with comparable potencies. 6-Methoxy-2-naphthylacetic acid, the active metabolite of Relafen, inhibits murine PGHS-2 preferentially. Aspirin irreversibly inhibits PGHS-1, preventing this isozyme from forming any product; in contrast, aspirin treatment of PGHS-2 causes this enzyme to form 15-hydroxy-5c,8c,11c,13t-eicosatetraenoic acid (15-HETE) instead of PGH2. These results establish that the two mouse enzymes are pharmacologically distinct and suggest that it will be possible to identify or design compounds that are completely selective for each PGHS isozyme. Because PGHS-2 is usually only expressed in inflamed tissue or after exposure to mediators of inflammation, a selective inhibitor of this isoenzyme may exhibit anti-inflammatory activity without effects on PGHS-1 of platelets and perhaps without ulcerogenic effects associated with commonly available NSAIDs.

Journal ArticleDOI
TL;DR: The dramatic overexpression of members of the matrix-degrading metalloproteinase (MMP) family in pathological conditions characterized by connective tissue destruction, including diseases such as arthritis, periodontitis, and cancer, suggests that tight regulation of MMP genes is critical for normal tissue homeostasis.
Abstract: The dramatic overexpression of members of the matrix-degrading metalloproteinase (MMP) family in pathological conditions characterized by connective tissue destruction, including diseases such as arthritis, periodontitis, and cancer, suggests that tight regulation of MMP genes is critical for normal tissue homeostasis. An understanding of the molecular mechanisms controlling normal MMP gene expression and of the misregulation that occurs in disease processes may therefore provide leads for eventual rational therapeutic interventions.

Journal ArticleDOI
TL;DR: RICHARD E. GALARDYP MARIE E. CASSABONNE, C A R L A ” E GIESE, JAMES H. GILBERT, FRANCE LAPIERRE, HENRY LOPEZ, MARY E. SCHAEFER, ROBERT STACK, MICHAEL SULLIVAN, BRENT SUMMERS, ROB TRESSLER, DAVE TYRRELL, and JENNIFER WEEC
Abstract: RICHARD E. GALARDYP MARIE E. CASSABONNE, C A R L A ” E GIESE, JAMES H. GILBERT, FRANCE LAPIERRE, HENRY LOPEZ, MARY E. SCHAEFER, ROBERT STACK, MICHAEL SULLIVAN, BRENT SUMMERS, ROB TRESSLER, DAVE TYRRELL, AND JENNIFER WEEC; SCOTT D. ALLEN AND JOHN J. CASTELLO@; JOHN P. BARLETTA AND GREGORY S. SCHULTZe; LEONARD0 A. FERNANDEZf; SUSAN FISHER AND TIAN-YI CUF; HARALD G. FOELLMERh; DAMIAN GROBELNY’; AND WALTER M. HOLLERANJ

Journal ArticleDOI
TL;DR: Genomic and cDNA library hybridization as well as Northern and Southern hybridization studies among rat, guinea pig, and human species identifies only two members of the CCK receptor family, CCKAR and CCKBR, and does not rule out the existence of other less closely related members.
Abstract: A review of the literature encompassing numerous pharmacological, physiological, and biochemical studies indicates the presence of at least four CCK receptor types, CCKA, CCKB, gastrin, and CG-4 receptors. Multiple subtypes of the CCKAR have been postulated to account for the differences in pharmacology or affinity cross-linking of CCKARs between pancreas and gallbladder and the presence of high and low affinity CCKARs on pancreatic acini. Multiple subtypes of the CCKBR have been postulated to explain the differences in pharmacology and physiology between gastric and gallbladder smooth muscle CCKBRs. We recently cloned and functionally expressed both the CCKAR and the CCKBR from rat, guinea pig, and human. The CCKAR and CCKBR are 48% homologous and constitute a family of receptors within the guanine nucleotide-binding regulatory protein-coupled superfamily of receptors. Each receptor is highly conserved between species. A single cDNA encoding a single protein is present in both pancreas and gallbladder and can account for both high and low affinity CCKARs found on pancreatic acini when transfected into COS-7 cells. A single cDNA encoding a single CCKBR protein is present in both the central nervous system and the periphery including the gastrointestinal system. Therefore, the gastrin receptor is actually a CCKBR present on parietal cells. Genomic and cDNA library hybridization as well as Northern and Southern hybridization studies among rat, guinea pig, and human species identifies only two members of the CCK receptor family, CCKAR and CCKBR. Although these studies do not identify other closely related members of the CCK receptor family, they do not rule out the existence of other less closely related members. Furthermore, differences in tissue and species-specific posttranslational processing, receptor coupling, and associated membrane protein and lipid heterogeneity may be among some of the other factors that may account for the phenotypic expression of more receptor subtypes than molecular studies would predict.

Journal ArticleDOI
TL;DR: Engagement of PECAM-1 causes up-regulation of integrin function on leukocytes, implicating PECam-1 as a trigger molecule that may regulate leukocyte trafficking through the vessel wall.
Abstract: Platelet/Endothelial Cell Adhesion Molecule-1 (PECAM-1) is a 130-kDa integral membrane glycoprotein found on the surface of human platelets and leukocytes, and at the intercellular junctions of endothelial cells. PECAM-1 is a member of the immunoglobulin (Ig) gene superfamily, with six Ig-like loops in the extracytoplasmic domain, a 19-residue transmembrane domain, and a 118-amino acid cytoplasmic tail that contains potential sites for phosphorylation and lipid modification that could potentially modulate its adhesive properties and/or subcellular distribution. Antibodies to PECAM-1 interfere with the ability of endothelial cells to form normal cellular junctions, suggesting that PECAM-1 functions in forming or stabilizing the vascular bed. Anti-PECAM-1 antibodies also have been reported to block neutrophil and monocyte chemotaxis in response to lipopolysaccaride, suggesting that PECAM-1 may play a role in leukocyte motility. PECAM-1-transfected murine L cells, but not untransfected L cells, aggregate in a calcium- and PECAM-1-dependent manner, demonstrating directly that PECAM-1 functions as a cell-cell adhesion molecule. PECAM-1 becomes highly phosphorylated in response to cellular activation and, coincident with phosphorylation, associates with the cytoskeleton of activated, but not resting platelets. The engagement of PECAM-1 with the platelet cytoskeleton enables it to move large distances within the plane of the membrane and may similarly account for the ability of PECAM-1 to localize to the intercellular borders of endothelial cells once cell-cell contact has been achieved. Finally, engagement of PECAM-1 causes up-regulation of integrin function on leukocytes, implicating PECAM-1 as a trigger molecule that may regulate leukocyte trafficking through the vessel wall.

Journal ArticleDOI
TL;DR: The successful initiation of lactation which would lead to the potential of utilizing breastfeeding as contraceptive may require more attention to be paid to the establishment of non-stress release of oxytocin.
Abstract: Breastfeeding delays the resumption of normal ovarian cycles by disrupting the pattern of pulsatile release of GnRH from the hypothalamus and hence LH from the pituitary The plasma concentrations of FSH during lactation are sufficient to induce follicle growth, but the inadequate pulsatile LH signal results in a reduced estradiol production by these follicles When follicle growth and estradiol secretion does increase to normal, the suckling stimulus prevents the generation of a normal preovulatory LH surge and follicles either fail to rupture, or become atretic or cystic Only when the suckling stimulus declines sufficiently to allow generation of a normal preovulatory LH surge to occur will ovulation take place with the formation of a corpus luteum of variable normality Thus suckling delays the resumption of normal ovarian cyclicity by disrupting but not totally inhibiting, the normal pattern of release of GnRH by the hypothalamus The mechanism of suckling-induced disruption of GnRH release remains unknown It does not appear to involve prolactin, dopamine or opiates although a combination of these factors might be involved Prolactin is the major hormone responsible for milk production and is present in sufficient quantities in almost all women to allow the establishment of normal lactation Oxytocin is essential for milk let down and is susceptible to inhibition of release by stress The successful initiation of lactation which would lead to the potential of utilizing breastfeeding as contraceptive may require more attention to be paid to the establishment of non-stress release of oxytocin

Journal ArticleDOI
TL;DR: From these studies, it can be concluded that the clostridial neurotoxins responsible for tetanus and botulism block neuroexocytosis via the proteolytic cleavage of specific components of the neuroxocytotic machinery.
Abstract: Tetanus and botulinum neurotoxins bind to nerve cells, penetrate the cytosol, and block neurotransmitter release. Comparison of their amino-acid sequences shows the presence of the highly conserved His-Glu-x-x-His zinc-binding motif of zinc-endopeptidases (HExxH). Atomic absorption measurements of clostridial neurotoxins show the presence of one atom of zinc/toxin molecule bound to the light chain. The toxin-bound zinc ion is essential for the neurotoxins inhibition of neurotransmitter release in Aplysia neurons injected with the toxins. Phosphoramidon, a very specific inhibitor of zinc-endopeptidases, blocks the intracellular activity of the clostridial neurotoxins. Highly purified preparations of the light chain of tetanus and botulinum B and F neurotoxins cleaved specifically VAMP/synaptobrevin, an integral membrane protein of small synaptic vesicles, both in vivo and in vitro. From these studies, it can be concluded that the clostridial neurotoxins responsible for tetanus and botulism block neuroexocytosis via the proteolytic cleavage of specific components of the neuroexocytotic machinery.

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TL;DR: It is concluded that doxycycline and the chemically modified tetracyclines, in addition to inhibiting the MMP activity may also reduce the enzyme expression at the transcriptional level.
Abstract: The mechanism of tetracycline-induced inhibition of matrix metalloproteinases (MMP) was studied by measuring the MMP secretion and MMP-2 mRNA levels in unkeratinizing periodontal ligament epithelial cells and skin keratinocytes cultured in the presence of doxycycline or chemically modified tetracyclines (CMT) lacking antimicrobial activity. Doxycycline, CMT-1, and CMT-8 exerted a direct dose-dependent inhibition of porcine periodontal ligament epithelial cell medium MMP activity as assayed by gelatin enzymography. Both the 92-kDa (MMP-9) and 72-kDa (MMP-2) gelatinases were inhibited by the tetracyclines added to the conditioned medium. Culturing the cells in the presence of the tetracyclines required considerably smaller concentrations to reduce the secreted MMP activity. The drugs were not toxic to the epithelial cells at concentrations from 4 to 250 micrograms/mL up to 24 h of culture. Tetracycline effects on the MMP-2 mRNA levels were studied in human skin keratinocytes using Northern hybridization analysis with a specific cDNA probe. A marked inhibition in the MMP-2 gene expression was observed by 6 h with 5 micrograms/mL of doxycycline, CMT-1 or CMT-8. Doxycycline inhibition was somewhat stronger than the two other tetracyclines. After 24 h of culture with 50 micrograms/mL of the drugs, the total RNA levels also decreased by 33 to 40%. The 72-kDa gelatinase activity in culture medium of the keratinocytes followed roughly the pattern of inhibition of the gene expression. We conclude that doxycycline and the chemically modified tetracyclines, in addition to inhibiting the MMP activity may also reduce the enzyme expression at the transcriptional level.

Journal ArticleDOI
TL;DR: Somatostatin has been demonstrated in high concentrations in the hypothalamus, the cerebral cortex, the brain stem, the gastrointestinal tract, and the pancreas, and its hormonal activities include the inhibition of the release of growth hormone, insulin, glucagon, and gastrin.
Abstract: Somatostatin has been demonstrated in high concentrations in the hypothalamus, the cerebral cortex, the brain stem, the gastrointestinal tract, and the pancreas. In the central nervous system, it acts as a neurotransmitter, whereas its hormonal activities include the inhibition of the release of growth hormone, insulin, glucagon, and gastrin (for a review, see ref. 1). Also, antiproliferative effects have been reported, both in vitro on tumor cell lines, and in vivo on neuroendocrine human tumors. High-affinity somatostatin receptors have been identified in the brain and on many cells of neuroendocrine origin, like the somatotroph cells of the anterior pituitary and the pancreatic islet cell^.^.^ Also, cells not known classically as neuroendocrine, such as lymphocytes, may possess these receptor^.^ Besides, somatostatin receptors have been demonstrated on a variety of human tumors by classical biochemical binding techniques, as well as by in vitro autoradiography. These tumors include those with APUD (amine precursor uptake and decarboxylation) characteristics (pituitary tumors, endocrine pancreatic tumors, carcinoids, paragangliomas, small cell lung cancers, medullary thyroid carcinomas, pheochromocytomas} as well as meningiomas, well-differentiated brain tumors (astrocytomas), neuroblastomas, and some human breast cancers. Because of the short plasma half-life of somatostatin (2-4 min), analogues more suitable for medical treatment have been developed. The somatostatin analogue, octreotide, has been shown to bind to somatostatin receptors on both tumorous and nontumorous tissues. An "'In-labeled somatostatin analogue ([DTPA-D-Phe'l-octreotide] was developed for its use in scintigraphy. [DTPA-D-Phe'l-octreotide was shown to bind "'In efficiently in a single-step labeling procedure. The binding as well as the biological

Journal ArticleDOI
TL;DR: It is shown that seasonality has increased in this century in some high income, low fertility populations such as Sweden and several other populations with substantial seasonal variations in births, suggesting that other factors play an important role in birth seasonality.
Abstract: Pronounced and persistent seasonal patterns in fertility are observed in virtually all human populations. This paper presents evidence on these seasonal patterns. We note that the most pronounced seasonal patterns are in the southern United States, where births decline substantially in April and May, and in northern Europe, where births increase substantially in March and April. Although seasonal variations in fertility were more pronounced in earlier agricultural populations, we show that seasonality has increased in this century in some high income, low fertility populations such as Sweden. We use data on monthly temperature to analyze the potential role of temperature in explaining seasonal patterns. We find strong evidence that summer heat plays an important role in explaining the July-August trough in conceptions in the southern United States. We find little evidence, however, that temperature plays any role in explaining the pronounced June-July peak in conceptions in Sweden. Temperature also appears to be relatively unimportant in several other populations with substantial seasonal variations in births, suggesting that other factors play an important role in birth seasonality.


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TL;DR: In this article, two models were used to estimate the potential for biogenic methane production: (1) construction of sedimentary organic carbon budgets, and (2) depth extrapolation of modern microbial production rates.
Abstract: Potential sources of biogenic methane in the Carolina Continental Rise -- Blake Ridge sediments have been examined Two models were used to estimate the potential for biogenic methane production: (1) construction of sedimentary organic carbon budgets, and (2) depth extrapolation of modern microbial production rates While closed-system estimates predict some gas hydrate formation, it is unlikely that >3% of the sediment volume could be filled by hydrate from methane produced in situ Formation of greater amounts requires migration of methane from the underlying continental rise sediment prism Methane may be recycled from below the base of the gas hydrate stability zone by gas hydrate decomposition, upward migration of the methane gas, and recrystallization of gas hydrate within the overlying stability zone Methane bubbles may also form in the sediment column below the depth of gas hydrate stability because the methane saturation concentration of the pore fluids decreases with increasing depth Upward migration of methane bubbles from these deeper sediments can add methane to the hydrate stability zone From these models it appears that recycling and upward migration of methane is essential in forming significant gas hydrate concentrations In addition, the depth distribution profiles of methane hydrate will differ if the more » majority of the methane has migrated upward rather than having been produced in situ « less

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TL;DR: Indirect evidence suggests that estrogen interacts with NGF-related systems and that changes in circulating levels of estrogen can contribute to age-related changes in hippocampal levels of NGF.
Abstract: Estrogen replacement can significantly affect the expression of ChAT and NGF receptors in specific basal forebrain cholinergic neurons The time-course of the effects is consistent with a direct up-regulation of ChAT followed by either direct or indirect down-regulation of p75NGFR and trkA NGF receptors, possibly due to increased cholinergic activity in the hippocampal formation and cortex and a decrease in hippocampal levels of NGF Current evidence suggests ChAT, p75NGFR, trkA, and NGF all play a role in regulating cholinergic function in the hippocampal formation and cortex In addition, all have been implicated in the maintenance of normal learning and memory processes as well as in changes in cognitive function associated with aging and with neurodegenerative disease It is possible that estrogen may affect cognitive function via effects on NGF-related systems and basal forebrain cholinergic neurons Effects of estrogen on cognitive function have been reported, as has some preliminary evidence for beneficial effects of estrogen in decreasing the prevalence of and reducing some cognitive deficits associated with Alzheimer's disease Whether these effects are related to effects on NGF-related systems or basal forebrain cholinergic neurons is currently unknown Indirect evidence suggests that estrogen interacts with NGF-related systems and that changes in circulating levels of estrogen can contribute to age-related changes in hippocampal levels of NGF These findings have important implications for consideration of estrogen replacement therapy in pre- and post-menopausal women Further studies examining effects of different regimens of estrogen replacement as well as estrogen combined with progesterone on NGF and basal forebrain cholinergic neurons in young and aged animals are required Prospective studies correlating aging and estrogen replacement with numbers of basal forebrain cholinergic neurons and hippocampal and cortical levels of NGF also need to be performed to better assess the potential benefits of estrogen replacement in reducing age- and disease-related cognitive decline