Life Glow Plus Super Life Glow Life Glow Basic Bone Dense Calcium Taheebo Life Tea Germanium Colloidal Minerals Methyl Sulfonyl Methane Transfer Factor Immune Egg	Vibrant Life Home Web All VL Products Family Of Three Chelation Formulas Oral Chelation Ingredient Comparisons The Wednesday Letter Karl Loren Viewpoints Frequently Asked Questions Testimonials Free Radicals Central Page For 18 Web Sites	Vibrant Life Home Page Shopping Cart	Separate Search Page or search below
Navigation Help	Karl Loren Background	Ingredients Technical	Write To Karl Loren	Table Of Contents

100 Studies of Free Radicals:

The Cause Of Virtually All Disease

Go To The Home Page For Free Radical Information

Go To A Page comparing the Japanese Water Machine and Microhydrin -- re:  "negative water."

Click on the image to go to the page which links to all the other pages on this web site on the subject of "oral chelation."

Click Here to see a page with links to all the other pages on free radicals.

Top Of Menu
Menu Position #20
Menu Position #40
Menu Position #60
Menu Position #80

HealthGate Documents

Record 1 from database: MEDLINE
Return To The Top

Title

Oxidative mechanisms in the toxicity of metal ions.

Author

Stohs SJ; Bagchi D

Address

School of Pharmacy, Creighton University, Omaha, NE 68178, USA.

Source

Free Radic Biol Med, 1995 Feb, 18:2, 321-36

Abstract

The role of reactive oxygen species, with the subsequent oxidative deterioration of biological macromolecules in the toxicities associated with transition metal ions, is reviewed. Recent studies have shown that metals, including iron, copper, chromium, and vanadium undergo redox cycling, while cadmium, mercury, and nickel, as well as lead, deplete glutathione and protein-bound sulfhydryl groups, resulting in the production of reactive oxygen species as superoxide ion, hydrogen peroxide, and hydroxyl radical. As a consequence, enhanced lipid peroxidation. DNA damage, and altered calcium and sulfhydryl homeostasis occur. Fenton-like reactions may be commonly associated with most membranous fractions including mitochondria, microsomes, and peroxisomes. Phagocytic cells may be another important source of reactive oxygen species in response to metal ions. Furthermore, various studies have suggested that the ability to generate reactive oxygen species by redox cycling quinones and related compounds may require metal ions. Recent studies have suggested that metal ions may enhance the production of tumor necrosis factor alpha (TNF alpha) and activate protein kinase C, as well as induce the production of stress proteins. Thus, some mechanisms associated with the toxicities of metal ions are very similar to the effects produced by many organic xenobiotics. Specific differences in the toxicities of metal ions may be related to differences in solubilities, absorbability, transport, chemical reactivity, and the complexes that are formed within the body. This review summarizes current studies that have been conducted with transition metal ions as well as lead, regarding the production of reactive oxygen species and oxidative tissue damage.

Language of Publication

English

Unique Identifier

95262971

MeSH Heading (Major)

Metals|*TO; Oxidative Stress|*

MeSH Heading

Animal; Human; Oxidation-Reduction; Reactive Oxygen Species|ME; Support, U.S. Gov't, Non-P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0891-5849

Country of Publication

UNITED STATES

Record 2 from database: MEDLINE
Return To The Top

Title

Nutrition and metal toxicity.

Author

Goyer RA

Address

National Institute of Environmental Health Sciences, Research Triangle Park, NC 27707.

Source

Am J Clin Nutr, 1995 Mar, 61:3 Suppl, 646S-650S

Abstract

Lead, cadmium, and mercury are toxic metals that are not essential for nutrition. However, the toxic effects of these metals may be mediated or enhanced by interactions or deficiencies of nutritionally essential metals. Lead competes with calcium, inhibiting the release of neurotransmitters, and interferes with the regulation of cell metabolism by binding to second-messenger calcium receptors, blocking calcium transport by calcium channels and calcium-sodium ATP pumps, and by competing for calcium-binding protein sites and uptake by mitochondria. Dietary deficiencies of calcium, iron, and zinc enhance the effects of lead on cognitive and behavioral development. Iron deficiency increases the gastrointestinal absorption of cadmium, and cadmium competes with zinc for binding sites on metallothionein, which is important in the storage and transport of zinc during development. Selenium protects from mercury and methyl mercury toxicity by preventing damage from free radicals or by forming inactive selenium mercury complexes.

Language of Publication

English

Unique Identifier

95185439

MeSH Heading (Major)

Metals|*PO; Nutrition|*

MeSH Heading

Animal; Calcium|ME; Diet; Drug Interactions; Human; Iron|DF

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0002-9165

Country of Publication

UNITED STATES

Record 3 from database: MEDLINE
Return To The Top

Title

Role of Fenton chemistry in thiol-induced toxicity and apoptosis.

Author

Held KD; Sylvester FC; Hopcia KL; Biaglow JE

Address

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, USA.

Source

Radiat Res, 1996 May, 145:5, 542-53

Abstract

Under certain conditions, many radioprotective thiols can be toxic, causing loss of colony-forming ability in cultured mammalian cells in a biphasic fashion whereby the thiols are not toxic at high or low concentrations of the drug, but cause decreased clonogenicity at intermediate (0.2-1.0 mM) drug levels. This symposium paper summarizes our studies using dithiothreitol (DTT) as a model thiol to demonstrate the role of Fenton chemistry in thiol toxicity. The toxicity of DTT in V79 cells has several characteristics: it is dependent on the medium used during exposure of cells to the drug; the toxicity is decreased or prevented by addition of catalase exogenously, but superoxide dismutase has no effect; the toxicity is increased by addition of copper, either free or derived from ceruloplasmin in serum; and the toxicity can be modified intracellularly by altering glucose availability or pentose cycle activity. Thus the data are consistent with a mechanism whereby DTT oxidation produces H2O2 in a reaction catalyzed by metals, predominantly copper, followed by reaction of H2O2 in a metal-catalyzed Fenton reaction to produce the ultimate toxic species, .OH. Studies comparing 12 thiols have shown that the magnitude of cell killing and pattern of dependence on thiol concentration vary among the different agents, with the toxicity depending on the interplay between the rates of two reactions: thiol oxidation and the reaction between the thiol and the H2O2 produced during the thiol oxidation. The addition of other metals, e.g. Zn2+, and metal chelators, e.g. EDTA, can also alter DTT toxicity by altering the rates of thiol oxidation or the Fenton reaction. Recent studies have shown that in certain cell lines thiols can also cause apoptosis in a biphasic pattern, with little apoptosis at low or high drug concentrations but greatly increased apoptosis levels at intermediate (approximately 3 mM) thiol concentrations. There appears to be a good correlation between those thiols that cause loss of clonogenicity and those that induce apoptosis, suggesting similar mechanisms may be involved in both end points. However, thiol-induced apoptosis is not prevented by addition of exogenous catalase. These observations are discussed in relation to the possible role of Fenton chemistry in induction of apoptosis by thiols.

Language of Publication

English

Unique Identifier

96198949

MeSH Heading (Major)

Apoptosis|*DE; Cell Survival|*DE; Hydrogen Peroxide|*; Iron|*; Sulfhydryl Compounds|*PD/TO

MeSH Heading

Animal; Cell Line; Chelating Agents|PD; Dithiothreitol|PD/TO; Human; Hydroxyl Radical; Metals|PD; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0033-7587

Country of Publication

UNITED STATES

Record 4 from database: MEDLINE
Return To The Top

Title

The protective role of ceruloplasmin against the activity of free radicals in brain ischaemia.

Author

I…Áecka J

Address

Katedra i Klinika Neurologii Akademii Medycznej w Lublinie.

Source

Ann Univ Mariae Curie Sklodowska [Med], 1996, 51:, 97-101

Abstract

Free radicals are atoms, groups of atoms or particles having on their last orbital at least one unpaired electron. This feature decides about their great chemical reactivity and lability (12, 16). To potentially toxic oxygen radicals belong: peroxidal anion radical, hydroxidal radical, hydrogen peroxide, hydroxylic radical, peroxidal lipid radical, singletal oxygen (12). The presence of free radicals in biological systems may play a role in etiopathogenesis of different illnesses. Overactivity of these compounds causes damage of tissues and bodily organs (3, 16, 18).

Language of Publication

English

Unique Identifier

98128307

MeSH Heading (Major)

Cerebral Ischemia|*PP; Ceruloplasmin|*PH

MeSH Heading

Biological Markers|AN; Cerebral Ischemia, Transient|PP; Free Radicals|ME; Human; Metals|ME

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0066-2240

Country of Publication

POLAND

Record 5 from database: MEDLINE
Return To The Top

Title

A site-specific mechanism for free radical induced biological damage: the essential role of redox-active transition metals.

Author

Chevion M

Address

Department of Cellular Biochemistry, Hebrew University of Jerusalem, Israel.

Source

Free Radic Biol Med, 1988, 5:1, 27-37

Abstract

The metal-mediated site-specific mechanism for free radical-induced biological damage is reviewed. According to this mechanism, cooper- or iron-binding sites on macromolecules serve as centers for repeated production of hydroxyl radicals that are generated via the Fenton reaction. The aberrations induced by superoxide, ascorbate, isouramil, and paraquat are summarized. An illustrative example is the enhancement of double-strand breaks by ascorbate/copper. Prevention of the site-specific free radical damage can be accomplished by using selective chelators for iron and copper, by displacing these redox-active metals with other redox-inactive metals such as zinc, by introducing high concentrations of hydroxyl radicals scavengers and spin trapping agents, and by applying protective enzymes that remove superoxide or hydrogen peroxide. Histidine is a special agent that can intervene in free radical reactions in variety of modes. In biological systems, there are traces of copper and iron that are at high enough levels to catalyze free-radical reactions, and account for such deleterious processes. In the human body Fe/Cu = 80/1 (w/w). Nevertheless, both (free) copper and iron are soluble enough, and the rate constants of their reduced forms with hydrogen peroxide are sufficiently high to suggest that they might be important mediators of free radical toxicity.

Language of Publication

English

Unique Identifier

89326207

MeSH Heading (Major)

DNA Damage|*; Free Radicals|*; Metals|*/ME

MeSH Heading

Animal; Human; Oxidation-Reduction; Oxygen|TO; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0891-5849

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Free Radicals); 0 (Metals); 7782-44-7 (Oxygen)

Record 6 from database: MEDLINE
Return To The Top

Title

Biochemical aspects of free radicals.

Author

Basaga HS

Address

Department of Science Education, Middle East Technical University, Ankara, Turkey.

Source

Biochem Cell Biol, 1990 Jul-Aug, 68:7-8, 989-98

Abstract

Toxic free radicals can be produced by many reactions required for the maintenance of normal metabolism and the production of energy in the cell. The reactivity of both primary and secondary radicals with biomolecules and in whole tissue systems is of interest, not only because of their importance in radiobiology but also because of the role these species play in toxicity and various disorders. Oxidant stress is known to increase the production of free radicals. In the presence of metals, especially iron, these radicals are converted into more damaging species. Trace elements play an important role in many systems that have evolved to deal with free radicals. The dietary status of the cell can affect the preventative antioxidant constituents of the cell. The chain-breaking antioxidant status can clearly be influenced by the dietary content of substances such as vitamins E and C.

Language of Publication

English

Unique Identifier

91025881

MeSH Heading (Major)

Free Radicals|*

MeSH Heading

Animal; Antioxidants|ME; Disease|ET; Human; Metals|ME; Models, Chemical; Oxidation-Reduction

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0829-8211

Country of Publication

CANADA

CAS Registry/EC Number

0 (Antioxidants); 0 (Free Radicals); 0 (Metals)

Record 7 from database: MEDLINE
Return To The Top

Title

Variability in response to D-penicillamine: pharmacokinetic insights.

Author

Joyce DA

Address

Department of Clinical Pharmacology, Queen Elizabeth II Medical Centre, University of Western Australia, Nedlands.

Source

Agents Actions Suppl, 1993, 44:, 203-7

Abstract

D-Penicillamine (D-Pen) is one of a group of chemically similar drugs which are efficacious in rheumatoid arthritis and which have similar patterns of biotransformation and similar toxicity. These similarities suggest associations between the transformations of D-Pen and it's toxicity and efficacy. Oxidation, methylation, formation of stable adducts with protein, interaction with metals and reduction of oxygen species have been shown in-vivo or in-vitro. Metabolism to a sulphoxide may occur and may be relevant to toxicity. Intracellular concentrations of D-Pen and metabolites are largely unknown.

Language of Publication

English

Unique Identifier

93383755

MeSH Heading (Major)

Penicillamine|AE/*PK

MeSH Heading

Biotransformation|PH; Comparative Study; Disulfides|ME; Free Radicals; Human; Metals|ME; Methylation; Oxygen|ME; Sulfoxides|ME; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0379-0363

Country of Publication

SWITZERLAND

CAS Registry/EC Number

0 (Disulfides); 0 (Free Radicals); 0 (Metals); 0 (Sulfoxides); 52-67-5 (Penicillamine); 7782-44-7 (Oxygen)

Record 8 from database: MEDLINE
Return To The Top

Title

Oxidants and human disease: some new concepts.

Author

Halliwell B

Address

Department of Biochemistry, University of London King's College, UK.

Source

FASEB J, 1987 Nov, 1:5, 358-64

Abstract

Oxidant species such as superoxide radical (O.2-), hydrogen peroxide (H2O2), hydroxyl radical (HO.), and lipid peroxides (LOOH) are becoming increasingly implicated in human disease. However, the question of whether such oxidants are a major cause of tissue injury in human disease or are merely produced during such injury has been difficult to answer because of inadequate experimental techniques, and possibly because of an overemphasis on lipid peroxidation as a mechanism of oxidant injury. Recent developments in methodology, in our understanding of the primary mechanism of oxidant toxicity to cells, and in concepts of antioxidant protection are reviewed. Good evidence now exists for some role of oxidant damage to tissues in the pathology of several human diseases, including rheumatoid arthritis, reperfusion injury, immune injury to lung and kidney, and cerebral trauma or ischemia. These have led to promising suggestions for new therapeutic approaches.

Language of Publication

English

Unique Identifier

88056036

MeSH Heading (Major)

Disease|*ET/ME; Oxygen|*ME

MeSH Heading

Antioxidants|TU; DNA|ME; Free Radicals; Human; Hydrogen Peroxide|AE/ME; Hydroxides|AE/ME; Ions; Lipid Peroxides|AE/ME; Metals|PD; Superoxides|AE/ME

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0892-6638

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Antioxidants); 0 (Free Radicals); 0 (Hydroxides); 0 (Ions); 0 (Lipid Peroxides); 0 (Metals); 11062-77-4 (Superoxides); 3352-57-6 (Hydroxyl Radical); 7722-84-1 (Hydrogen Peroxide); 7782-44-7 (Oxygen); 9007-49-2 (DNA)

Record 9 from database: MEDLINE
Return To The Top

Title

Transition metals as catalysts of "autoxidation" reactions.

Author

Miller DM; Buettner GR; Aust SD

Address

Department of Chemistry and Biochemistry, Utah State University, Logan 84322-0300.

Source

Free Radic Biol Med, 1990, 8:1, 95-108

Abstract

Superoxide (O2-), hydrogen peroxide (H2O2), and hydroxyl radical (.OH) produced from the "autoxidation" of biomolecules, such as ascorbate, catecholamines, or thiols, have been implicated in numerous toxicities. However, the direct reaction of dioxygen with the vast majority of biomolecules, including those listed above, is spin forbidden, a condition which imposes a severe kinetic limitation on this reaction pathway. Therefore, an alternate mechanism must be invoked to explain the "autoxidations" reactions frequently reported. Transition metals are efficient catalysts of redox reactions and their reactions with dioxygen are not spin restricted. Therefore it is likely that the "autoxidation" observed for many biomolecules is, in fact, metal catalyzed. In this paper we discuss: 1) the quantum mechanic, thermodynamic, and kinetic aspects of the reactions of dioxygen with biomolecules; 2) the involvement of transition metals in biomolecule oxidation; and 3) the biological implications of metal catalyzed oxidations. We hypothesize that true autoxidation of biomolecules does not occur in biological systems, instead the "autoxidation" of biomolecules is the result of transition metals bound by the biomolecules.

Language of Publication

English

Unique Identifier

90215326

MeSH Heading (Major)

Metals|*ME/TO; Oxygen|*ME

MeSH Heading

Animal; Catalysis; Chelating Agents; Copper|ME; Free Radicals; Human; Iron|ME; Models, Chemical; Oxidation-Reduction; Thermodynamics

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0891-5849

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Chelating Agents); 0 (Free Radicals); 0 (Metals); 12185-07-8 (dioxygen); 7439-89-6 (Iron); 7440-50-8 (Copper); 7782-44-7 (Oxygen)

Record 10 from database: MEDLINE
Return To The Top

Title

Surface reactivity in the pathogenic response to particulates.

Author

Fubini B

Address

UniversitÄa di Torino, FacoltÄa di Farmacia, Dipartimento di Chimica Inorganica, Italy. fubini@silver.ch.unito.it

Source

Environ Health Perspect, 1997 Sep, 105 Suppl 5:, 1013-20

Abstract

The peculiar characteristics of dust toxicity are discussed in relation to the processes taking place at the particle-biological medium interface. Because of surface reactivity, toxicity of solids is not merely predictable from chemical composition and molecular structure, as with water soluble compounds. With particles having the same bulk composition, micromorphology (the thermal and mechanical history of dust and adsorption from the environment) determines the kind and abundance of active surface sites, thus modulating reactivity toward cells and tissues. The quantitative evaluation of doses is discussed in comparisons of dose-response relationships obtained with different materials. Responses related to the surface of the particle are better compared on a per-unit surface than per-unit weight basis. The role of micromorphology, hydrophilicity, and reactive surface cations in determining the pathogenicity of inhaled particles is described with reference to silica and asbestos toxicity. Heating crystalline silica decreases hydrophilicity, with consequent modifications in membranolytic potential, retention, and transport. Transition metal ions exposed at the surface generate free radicals in aqueous suspensions. Continuous redox cycling of iron, with consequent activation-reactivation of the surface sites releasing free radicals, could account for the long-term pathogenicity caused by the inhalation of iron-containing fibers. In various pathogenicities caused by mixed dusts, the contact between components modifies toxicity. Hard metal lung disease is caused by exposure to mixtures of metals and carbides, typically cobalt (Co) and tungsten carbide (WC), but not to single components. Toxicity stems from reactive oxygen species generation in a mechanism involving both Co metal and WC in mutual contact. A relationship between the extent of water adsorption and biopersistence is proposed for vitreous fibers. Modifications of the surface taking place in vivo are described for ferruginous bodies and for the progressive comminution of chrysotile asbestos fibers.

Language of Publication

English

Unique Identifier

98063460

MeSH Heading (Major)

Mineral Fibers|AN/*TO

MeSH Heading

Animal; Chemistry, Physical; Dust|AE; Human; Support, Non-U.S. Gov't; Surface Properties

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0091-6765

Country of Publication

UNITED STATES

Record 11 from database: MEDLINE
Return To The Top

Title

Iron-induced tissue damage and cancer: the role of reactive oxygen species-free radicals.

Author

Okada S

Address

First Department of Pathology, Okayama University Medical School, Japan.

Source

Pathol Int, 1996 May, 46:5, 311-32

Abstract

Oxygen is poisonous, but we cannot live without it. The high oxidizing potential of oxygen molecules (dioxygen) is a valuable source of energy for the organism and its reactivity is low; that is, spin forbidden. However, the dioxygen itself is a 'free radical' and, especially in the presence of transition metals, it is a major promoter of radical reactions in the cell. Humans survive only by virtue of their elaborate defense mechanisms against oxygen toxicity. Iron is the most abundant transition metal in the human body. Because iron shows wide variation in redox potential with different co-ordination ligands, it may be used as a redox intermediate in many biological mechanism. However, it is precisely this redox activeness that makes iron a key participant in free radical production. The current research on the relationship between iron and cancer is briefly reviewed. Research results are reported here which indicate that iron, when bound to certain ligands, can cause free-radical mediated tissue damage and become carcinogenic. The present study also suggests that iron may also have a significant role in spontaneous human cancer.

Language of Publication

English

Unique Identifier

96405749

MeSH Heading (Major)

Iron|*TO; Neoplasms|*CI; Reactive Oxygen Species|*

MeSH Heading

Animal; Disease Models, Animal; Free Radicals; Human; Neoplasms, Experimental|CI; Oxidation-Reduction; Oxygen|CH; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

1320-5463

Country of Publication

AUSTRALIA

Record 12 from database: MEDLINE
Return To The Top

Title

Free radical generation by selenium compounds and their prooxidant toxicity.

Author

Spallholz JE

Address

Texas Technology University, Lubbock 79404, USA.

Source

Biomed Environ Sci, 1997 Sep, 10:2-3, 260-70

Abstract

Selenium (Se) and many of its compounds are among the most toxic of nutrients. Selenium toxicity was first described in range animals in the western United States in the 1930's which consumed "selenium accumulator" plants of the genus Astragalus, Xylorrhiza, Oonopsis, and Stanleya. Selenites and selenates from the soil accumulate in these plants primarily as methylated selenium compounds and plants evolve dimethyldiselenide and dimethylselenide. Dietary selenium, primarily as selenomethionine and selenocysteine for humans fulfill the dietary requirement for selenoenzymes and proteins. In humans and animals excessive dietary selenium may be toxic. In vitro, selenium compounds such as selenite, selenium dioxide and diselenides react with thiols, such as glutathione, producing superoxide and other reactive oxygen species. This catalytic reaction of selenium compounds with thiols likely accounts for selenium toxicity to cells ex vivo and in vivo where the major glutathione producing organ, the liver, is also the major target organ of selenium toxicity. Selenium enzymes and selenoethers that do not readily form a selenide (RSe-) anion and compounds such as Ebselen where selenium is sequestered, are not toxic. Methylation of selenium by both plants and animals serves to detoxify selenium by generating methylselenides. Alternatively, full reduction of Se to elemental selenium (Se0) as done by some bacteria and the formation of heavy metal selenides such as Ag2Se or Hg2Se, results in a non-catalytic non-toxic form of selenium. This catalytic prooxidant attribute of some selenium compounds appears to account for its toxicity when such activity exceeds plant and animal methylation reactions and antioxidant defenses. This prooxidant activity may also account for cellular apoptosis and may provide a useful pharmaceutical application for selenium compounds as antibacterial, antiviral, antifungal and anticancer agents.

Language of Publication

English

Unique Identifier

97460952

MeSH Heading (Major)

Reactive Oxygen Species|*; Selenium Compounds|*TO

MeSH Heading

Animal; Free Radicals; Human

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0895-3988

Country of Publication

UNITED STATES

Record 13 from database: MEDLINE
Return To The Top

Title

Oxygen toxicity: an introduction.

Author

Bostek CC

Address

 

Source

AANA J, 1989 Jun, 57:3, 231-7

Abstract

Although oxygen has been known to be toxic for more than 200 years, the clinical importance of oxygen toxicity was not appreciated until an epidemic of retrolental fibroplasia occurred in the early 1950s. Oxygen at high partial pressures is toxic to the respiratory, cardiovascular, nervous, and gastrointestinal systems. Toxicity results from the formation of oxygen-free radicals. These arise within mitochondria as oxygen is reduced to water, as byproducts of prostaglandin and thromboxane synthesis, and by the xanthine oxidase catalyzed reduction of xanthine or hypoxanthine. They are also produced by activated macrophages as part of the immune response. Superoxide anion is the radical most commonly produced. It dismutes to hydrogen peroxide, which is able to diffuse through lipid membranes. Hydrogen peroxide reacts with transition metals to produce the highly reactive hydroxyl radical which can initiate chain reactions of lipid peroxidation leading to cell rupture. Oxygen radical scavengers such as superoxide dismutase and catalase protect the body against normal levels of oxygen-free radicals. Oxygen toxicity can result from either reperfusion of ischemic tissue or prolonged exposure to high concentrations of oxygen. Limiting hyperoxia to maintain arterial oxygen percent saturation (SaO2) greater than or equal to 90% is recommended.

Language of Publication

English

Unique Identifier

89370953

MeSH Heading (Major)

Free Radicals|*; Oxygen|ME/*PO

MeSH Heading

Animal; Dogs; Human; Lung Diseases|CI; Oxygen Inhalation Therapy|NU; Rats; Reperfusion Injury|CI

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0094-6354

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Free Radicals); 7782-44-7 (Oxygen)

Record 14 from database: MEDLINE
Return To The Top
Return To Menu Item 20

Title

Amyloid precursor protein, copper and Alzheimer's disease.

Author

Multhaup G

Address

ZMBH Center for Molecular Biology, University of Heidelberg, Germany.

Source

Biomed Pharmacother, 1997, 51:3, 105-11

Abstract

Although a consensus that Alzheimer's disease (AD) is a single disease has not yet been reached, the involvement of the amyloid precursor protein (APP) and beta A4 (A beta) in the pathologic changes advances our understanding of the underlying molecular alterations. Increasing evidence implicates oxidative stress in the neurodegenerative process of AD. This hypothesis is based on the toxicity of beta A4 in cell cultures, and the findings that aggregation of beta A4 can be induced by metal-catalyzed oxidation and that free oxygen radicals might be involved in APP metabolism. Another neurological disorder, familial amyotrophic lateral sclerosis (FALS), supports our view that AD and FALS might be linked through a common mechanism. In FALS, SOD-Cu(I) complexes are affected by hydrogen peroxide and free radicals are produced. In AD, the reduction of Cu(II) to Cu(I) by APP involves an electron-transfer reaction and could also lead to a production of hydroxyl radicals. Thus, copper-mediated toxicity of APP-Cu(II)/(I) complexes may contribute to neurodegeneration in AD.

Language of Publication

English

Unique Identifier

97324976

MeSH Heading (Major)

Alzheimer Disease|*ME; Amyloid beta-Protein Precursor|*ME; Copper|*ME

MeSH Heading

Amyotrophic Lateral Sclerosis|GE/ME; Human; Hydroxyl Radical|ME

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0753-3322

Country of Publication

FRANCE

Record 15 from database: MEDLINE
Return To The Top
Return To Menu Item 20

Title

Use of iron chelators in preventing hydroxyl radical damage: adult respiratory distress syndrome as an experimental model for the pathophysiology and treatment of oxygen-radical-mediated tissue damage.

Author

Marx JJ; van Asbeck BS

Address

Department of Internal Medicine, University Hospital Utrecht, The Netherlands.

Source

Acta Haematol, 1996, 95:1, 49-62

Abstract

Tissue damage in many diseases is caused by hydroxyl radicals, generated during single electron reduction of oxygen. The first step is usually the formation of the superoxide radical. This radical is constantly formed in all living cells, and in particular during activation of phagocytes or during reoxygenation following ischaemia. Damage, however, only occurs in the presence of catalytic transition metals of which iron is the most important in human pathology. Oxygen-radical-mediated damage can be prevented by iron chelators, as has been demonstrated in numerous in vitro and in vivo experiments. A description is given as to how toxic oxygen products are formed in biological systems, and how organisms succeed in preventing autodestruction by scavenger molecules. The use of iron chelators to prevent oxygen radical damage is reviewed with emphasis on possible clinical applications. The adult respiratory distress syndrome is described in more detail as a model for oxygen-radical-mediated damage that can be successfully prevented with iron chelators.

Language of Publication

English

Unique Identifier

96185296

MeSH Heading (Major)

Hydroxyl Radical|*AE; Iron Chelating Agents|*TU; Respiratory Distress Syndrome, Adult|ET/*PC

MeSH Heading

Free Radical Scavengers; Free Radicals; Human; Iron|ME; Oxidation-Reduction; Reactive Oxygen Species|ME

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0001-5792

Country of Publication

SWITZERLAND

Record 16 from database: MEDLINE
Return To The Top
Return To Menu Item 20

Title

Oxygen free radicals in nephrology.

Author

Canavese C; Stratta P; Vercellone A

Address

Department of Nephrology, University of Torino, Italia.

Source

Int J Artif Organs, 1987 Nov, 10:6, 379-89

Abstract

For living creatures with an aerobic metabolism, the univalent reduction of oxygen can lead to formation within the cell of intermediate products with marked chemical instability and strong potential toxicity. These are the free radicals (FR) superoxide and hydroxyl, hydrogen peroxide and the singlet 1O2. Their toxicity is primarily expressed through the peroxidation of membrane lipids, resulting in mitochondrial, lysosomal and parietal damage. It is enhanced by the presence of metals in trace amounts. Imbalance between the production of FR and the availability of FR scavengers (superoxide dismutase, catalase, glutathione peroxidase, etc.) may underlie different human pathologies. FR have been thought to play a part in inflammation, the aging process, carcinomatous transformations, damage due to recirculation and autoimmune diseases. As far as the kidney is concerned, the intervention of FR has been demonstrated or can be postulated in various contexts in the light of what has been observed in other pathologies: immunological nephritis, toxic nephropathies, microthrombotic and microangiopathic processes, damage caused by post-ischemic reflow, and problems in the preservation and rejection of transplants. FR have also been incriminated in lung lesions following intradialytic leukostasis and some aspects of toxicity ascribable to uremia. Subject to the precautions imposed by the need for theoretical, experimental and clinical verification, FR biochemistry offers new keys to the interpretation of a variety of kidney pathologies and opens up new prospects for treatment, both through a better understanding of the mechanism of action of drugs already known and employed, and with regard to the practical possibility of using alternative or combined forms of therapy.

Language of Publication

English

Unique Identifier

88168928

MeSH Heading (Major)

Kidney Diseases|*ME; Oxygen|*ME/PH

MeSH Heading

Animal; Free Radicals; Human; Oxidation-Reduction

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0391-3988

Country of Publication

ITALY

CAS Registry/EC Number

0 (Free Radicals); 7782-44-7 (Oxygen)

Record 17 from database: MEDLINE
Return To The Top
Return To Menu Item 20

Title

Reactive oxygen species and Alzheimer's disease.

Author

Multhaup G; Ruppert T; Schlicksupp A; Hesse L; Beher D; Masters CL; Beyreuther K

Address

ZMBH-Center for Molecular Biology Heidelberg, University of Heidelberg, Germany. g.multhaup@mail.zmbh.uni-heidelberg.de

Source

Biochem Pharmacol, 1997 Sep, 54:5, 533-9

Abstract

Although a consensus that Alzheimer's disease (AD) is a single disease has not been reached yet, the involvement of the amyloid precursor protein (APP) and betaA4 (A beta) in the pathologic changes advances our understanding of the underlying molecular alterations. Increasing evidence implicates oxidative stress in the neurodegenerative process of AD. This hypothesis is based on the toxicity of betaA4 in cell cultures, and the findings that aggregation of betaA4 can be induced by metal-catalyzed oxidation and that free oxygen radicals may be involved in APP metabolism. Another neurological disorder, familial amyotrophic lateral sclerosis (FALS), supports our view that AD and FALS may be linked through a common mechanism. In FALS, SOD-Cu(I) complexes are affected by hydrogen peroxide and free radicals are produced. In AD, the reduction of Cu(II) to Cu(I) by APP involves an electron-transfer reaction and could also lead to a production of hydroxyl radicals. Thus, copper-mediated toxicity of APP-Cu(II)/(I) complexes may contribute to neurodegeneration in AD.

Language of Publication

English

Unique Identifier

97477005

MeSH Heading (Major)

Alzheimer Disease|GE/*ME/PA; Amyloid beta-Protein|*ME; Amyloid beta-Protein Precursor|*ME; Reactive Oxygen Species|*

MeSH Heading

Aging; Amyotrophic Lateral Sclerosis|ME/PA; Brain|ME/PA; Human; Oxidative Stress; Superoxide Dismutase|ME

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0006-2952

Country of Publication

ENGLAND

Record 18 from database: MEDLINE
Return To The Top
Return To Menu Item 20

Title

Therapeutic iron chelators and their potential side-effects.

Author

Singh S; Khodr H; Taylor MI; Hider RC

Address

Department of Pharmacy, King's College, University of London, U.K.

Source

Biochem Soc Symp, 1995, 61:, 127-37

Abstract

A number of iron-chelating agents are currently being considered as orally active alternatives to desferrioxamine (DFO), the therapeutic agent for the treatment of body iron overload that is available at present. These include bidentate hydroxypyridinones (HPO), tridentate desferrithiocin (DFT) analogues and hexadentate aminocarboxylate (HBED) chelators. All chelating agents have the potential to induce toxic effects when iron homoeostasis is affected within the body. This can arise when the absorption, distribution and utilization of iron is affected. Alternatively, chelating agents can induce toxicity by directly interfering with iron-dependent metalloenzymes located within the body. These effects are, however, mainly localized to non-haem enzymes such as ribonucleotide reductase and lipoxygenase. The resultant iron complexes also have the ability to induce toxicity. Depending on the coordination geometry and donor atoms associated with the metal centre, redox cycling of the iron centre with the corresponding generation of free radicals can result.

Language of Publication

English

Unique Identifier

96232729

MeSH Heading (Major)

beta-Thalassemia|*DT; Iron Chelating Agents|AD/AE/*TU

MeSH Heading

Administration, Oral; Human; Oxidation-Reduction

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0067-8694

Country of Publication

ENGLAND

Record 19 from database: MEDLINE
Return To The Top
Return To Menu Item 20

Title

Metal ion-catalyzed oxidation of proteins: biochemical mechanism and biological consequences [published erratum appears in Free Radic Biol Med 1991;10(3-4):249]

Author

Stadtman ER

Address

Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.

Source

Free Radic Biol Med, 1990, 9:4, 315-25

Abstract

In the presence of O2, Fe(III) or Cu(II), and an appropriate electron donor, a number of enzymic and nonenzymic oxygen free radical-generating systems are able to catalyze the oxidative modification of proteins. Whereas random, global modification of many different amino acid residues and extensive fragmentation occurs when proteins are exposed to oxygen radicals produced by high energy radiation, only one or a few amino acid residues are modified and relatively little peptide bond cleavage occurs when proteins are exposed to metal-catalyzed oxidation (MCO) systems. The available evidence indicates that the MCO systems catalyze the reduction of Fe(III) to Fe(II) and of O2 to H2O2 and that these products react at metal-binding sites on the protein to produce active oxygen (free radical?) species (viz; OH, ferryl ion) which attack the side chains of amino acid residues at the metal-binding site. Among other modifications, carbonyl derivatives of some amino acid residues are formed; prolyl and arginyl residues are converted to glutamylsemialdehyde residues, lysyl residues are likely converted to 2-amino-adipylsemialdehyde residues; histidyl residues are converted to asparagine and/or aspartyl residues; prolyl residues are converted to glutamyl or pyroglutamyl residues; methionyl residues are converted to methionylsulfoxide residues; and cysteinyl residues to mixed-disulfide derivatives. The biological significance of these metal ion-catalyzed reactions is highlighted by the demonstration: (i) that oxidative modification of proteins "marks" them for degradation by most common proteases and especially by the cytosolic multicatalytic proteinase from mammalian cells; (ii) protein oxidation contributes substantially to the intracellular pool of catalytically inactive and less active, thermolabile forms of enzymes which accumulate in cells during aging, oxidative stress, and in various pathological states, including premature aging diseases (progeria, Werner's syndrome), muscular dystrophy, rheumatoid arthritis, cataractogenesis, chronic alcohol toxicity, pulmonary emphysema, and during tissue injury provoked by ischemia-reperfusion. Furthermore, the metal ion-catalyzed protein oxidation is the basis of biological mechanisms for regulating changes in enzyme levels in response to shifts from anaerobic to aerobic metabolism, and probably from one nutritional state to another. It is also involved in the killing of bacteria by neutrophils and in the loss of neutrophil function following repeated cycles of respiratory burst activity.

Language of Publication

English

Unique Identifier

91131022

MeSH Heading (Major)

Copper|*ME; Ferrous Compounds|*ME; Oxygen|*ME; Proteins|*ME

MeSH Heading

Aging; Animal; Free Radicals; Human; Oxidation-Reduction

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0891-5849

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Ferrous Compounds); 0 (Free Radicals); 7440-50-8 (Copper); 7782-44-7 (Oxygen)

Record 20 from database: MEDLINE
Return To The Top
Return To Menu Item 20

Title

Involvement of iron and iron-catalyzed free radical production in ethanol metabolism and toxicity.

Author

Nordmann R; Ribière C; Rouach H

Address

 

Source

Enzyme, 1987, 37:1-2, 57-69

Abstract

Lipoperoxidation, a degradative process of membranous polyunsaturated fatty acids, has been suggested to represent an important mechanism in the pathogenesis of ethanol toxicity on the liver and possibly also on the brain. Catalysis by transition metals, especially iron, is involved in the biosynthesis of free radicals contributing to lipid peroxidation. Although the exact nature of the redox-active iron implicated in this catalysis is still unknown, it has been well established that lipid peroxidation can be prevented in vitro by iron chelators such as desferrioxamine. Deprivation of redox-active iron through desferrioxamine inhibits by about 50% the microsomal oxidation of ethanol in vitro and reduces very significantly in vivo the overall ethanol elimination rate in rats. Administration of desferrioxamine together with ethanol also reduces the ethanol-induced disturbances in the antioxidant defense mechanisms of the hepatocyte. It also reduces in mice both the severity of physical dependence on ethanol and lethality following the acute administration of a narcotic dose of ethanol. Chronic overloading of rats with iron results, on the opposite, in an increased rate of ethanol elimination, although alcohol dehydrogenase and catalase activities are reduced and cytochrome P-450 depleted in the liver of such iron-overloaded animals. The magnitude of the ethanol-induced increase in lipid peroxidation and decrease in the major membranous antioxidant, alpha-tocopherol, is exacerbated in iron-overloaded rats. Several disturbances of iron metabolism have been reported in human alcoholics. Their contribution to ethanol toxicity appears very likely in the case of hepatic siderosis associated with alcohol abuse. Ethanol could however disturb iron metabolism even in the absence of gross abnormalities of the total iron stores. It is suggested that ethanol intoxication could increase cellular redox-active iron, thus contributing to an enhanced steady-state concentration of reactive-free radicals. This oxidative stress would lead to lipoperoxidative damage and cellular injury.

Language of Publication

English

Unique Identifier

87190272

MeSH Heading (Major)

Alcohol, Ethyl|*ME; Alcoholic Intoxication|*ME; Iron|*ME

MeSH Heading

Animal; Brain|DE; Catalase|ME; Deferoxamine|PD; Free Radicals; Human; Hydroxides; Lipid Peroxides|ME; Liver|DE/EN; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE; REVIEW

ISSN

0013-9432

Country of Publication

SWITZERLAND

CAS Registry/EC Number

EC 1.11.1.6 (Catalase); 0 (Free Radicals); 0 (Hydroxides); 0 (Lipid Peroxides); 3352-57-6 (Hydroxyl Radical); 64-17-5 (Alcohol, Ethyl); 70-51-9 (Deferoxamine); 7439-89-6 (Iron)

Record 21 from database: MEDLINE
Return To The Top
Return To Menu Item 20

Title

Free radicals in toxicology.

Author

Aust SD; Chignell CF; Bray TM; Kalyanaraman B; Mason RP

Address

Biotechnology Center, Utah State University, Logan 84322.

Source

Toxicol Appl Pharmacol, 1993 Jun, 120:2, 168-78

Abstract

Free radicals are recognized more and more frequently as being involved in the mechanism of toxicity of chemicals. In some cases, the organic radicals are involved, but often oxygen radicals result from redox cycling chemicals. Free radicals are usually very reactive, which, in addition to causing toxicities, can make them difficult to detect. Electron spin resonance (ESR) techniques are frequently used, but generally the radicals must be trapped to form a more stable radical for detection. Quantitation is therefore often very difficult. Free radicals of many xenobiotics are formed during their metabolism by enzymes such as cytochrome P450 or peroxidases. In some cases, chemicals can redox cycle using reductases, such as cytochrome P450 reductase, which can catalyze one-electron reductions. Some redox cycling xenobiotics reduce molecular oxygen by one electron to generate superoxide. Superoxide can cause toxicities against which superoxide dismutase is protective. However, in the presence of transition metals such as iron, superoxide can generate the very reactive hydroxyl radical by the iron-catalyzed Haber-Weiss reaction. Iron is therefore normally tightly controlled by transport and storage proteins. Chemicals that can release iron from these proteins can be very toxic, causing lipid, protein, and nucleic acid oxidation. The oxidation of these species, such as a low-density lipoprotein, is generally protected by a complex antioxidant system involving glutathione and glutathione peroxidase, vitamin E, ascorbic acid, etc.

Language of Publication

English

Unique Identifier

93289584

MeSH Heading (Major)

Toxicology|*MT; Xenobiotics|ME/*TO

MeSH Heading

Animal; Ferritin|ME; Free Radicals|ME/TO; Human; Iron|TO; Oxidation-Reduction; Skatole|ME/TO

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0041-008X

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Free Radicals); 0 (Xenobiotics); 7439-89-6 (Iron); 83-34-1 (Skatole); 9007-73-2 (Ferritin)

Record 22 from database: MEDLINE
Return To The Top
Return To Menu Item 20

Title

Free radicals and environmental toxins.

Author

Thomas CE; Aust SD

Address

 

Source

Ann Emerg Med, 1986 Sep, 15:9, 1075-83

Abstract

Some chemicals that contaminate our environment exert their toxic effects by virtue of their ability to form free radicals. In the absence of sufficient quenching reactions, these reactive radicals can attack biomolecules, resulting in their oxidative degradation. Biological membranes which contain polyunsaturated fatty acids are most susceptible to oxidative degradation (lipid peroxidation), although oxidation of DNA may have more severe biological consequences. Free radicals species can be generated by at least two mechanisms in vivo. The first, of which carbon tetrachloride (CCl4) is the classic example, is the biotransformation of the chemical to a free radical species. Metabolism of CCl4 to the trichloromethyl radical by the hepatic mixed-function oxidase system results in the initiation of lipid peroxidation, protein-lipid cross linkages, and trichloromethyl adducts with DNA, protein, and lipid. The second mechanism for forming free radicals involves their reduction to less stable free radical intermediates which are oxidized by molecular oxygen to give superoxide (O2-.). In the presence of transition metals, such as iron, O2-. can be converted to other oxygen radical species, such as the hydroxyl radical (.OH), an extremely powerful oxidant capable of cleaving DNA, oxidizing protein, and initiating lipid peroxidation. Under many conditions, lipid peroxidation appears not to be initiated by .OH, but rather by an iron-oxygen complex. Regardless of the identity of the initiating species, transition metals are required for most of the deleterious reactions of oxygen. Superoxide and certain organic radicals have been found to release iron from ferritin.

Language of Publication

English

Unique Identifier

86293892

MeSH Heading (Major)

Air Pollutants, Environmental|*PO; Free Radicals|*

MeSH Heading

Carbon Tetrachloride|ME; Chemistry; Human; Iron|ME; Lipid Peroxides|ME; Mixed Function Oxidases|ME; Oxidation-Reduction

Publication Type

JOURNAL ARTICLE; REVIEW

ISSN

0196-0644

Country of Publication

UNITED STATES

CAS Registry/EC Number

EC 1.13.12. (Mixed Function Oxidases); 0 (Air Pollutants, Environmental); 0 (Free Radicals); 0 (Lipid Peroxides); 56-23-5 (Carbon Tetrachloride); 7439-89-6 (Iron)

Record 23 from database: MEDLINE
Return To The Top
Return To Menu Item 20

Title

Free radicals derived from oxygen, and medicine.

Author

Duracková Z; Bergendi L; Liptáková A; Muchová J

Address

Ustav lekárskej chémie, biochémie a klinickej biochémie LFUK, Bratislava, Slovakia.

Source

Bratisl Lek Listy, 1993 Aug, 94:8, 419-34

Abstract

Toxic free radicals may be produced by many reactions, which are necessary for the maintenance of normal metabolism, and the production of energy in cells. The origin, reactivity with other molecules and removal of free radicals, is in the foreground of interest since their effect is mostly toxic and result in a whole series of pathological states of cells, organs and whole organisms. Production of these radicals increases in oxidative stress and in the presence of ions of metals (chiefly iron), leads to the creation of more reactive metabolites. The generally accepted view is that the main biological actor in damaged tissues is the hydroxyl radical (OH), which is created in the iron catalyzed Haber-Weiss reaction. The balance between the increased creation of free radicals in various pathological states, or unfavourable conditions in the environment, and natural antioxidants of a low-molecular (vitamin C, E, glutathione etc.) or enzyme character (superoxide dismutase, glutathione peroxidase, glutathione reductase, catalase, etc.), plays the chief role in damage which is the cause of many diseases and ageing. (Fig. 3, Tab. 5, Ref. 62.).

Language of Publication

ENG LA=SLO

Unique Identifier

94272980

MeSH Heading (Major)

Free Radicals|*/CH/ME

MeSH Heading

Human

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0006-9248

Country of Publication

SLOVAKIA

CAS Registry/EC Number

0 (Free Radicals)

Record 24 from database: MEDLINE
Return To The Top
Return To Menu Item 20

Title

Liver copper storage and transport during development: implications for cytotoxicity.

Author

Luza SC; Speisky HC

Address

Biochemical Pharmacology and Lipids Unit, Nutrition and Food Technology Institute, University of Chile, Santiago.

Source

Am J Clin Nutr, 1996 May, 63:5, 812S-20S

Abstract

Copper is an essential trace element for many biological processes. Its functions range from influencing specific gene expression to serving as a cofactor or prosthetic group for several enzymes. Intakes of copper at doses that exceed physiologic demands are normally met with efficient homeostatic mechanisms. Ceruloplasmin, albumin, and transcuprein, and to a lesser extent certain amino acids, are major copper-transporting constituents in circulating plasma. After its hepatic uptake, copper may be stored within hepatocytes, secreted into plasma, or excreted in bile. The biliary route represents the major excretory pathway of copper and largely accounts for its hepatic turnover. Copper retained by hepatocytes is mostly bound to specific metal-binding proteins, primarily metallothionein, or incorporated into several cuproenzymes. Copper incorporation into metallothionein and certain cuproproteins appears to require prior binding of copper to glutathione, thus defining a relation between copper metabolism and the intracellular availability of glutathione. Hepatic metallothionein concentrations can be modulated by dietary copper; changes in metallothionein and in copper status are significant throughout development. Binding of copper to metallothionein provides a temporary storage for cytoplasmic copper, preventing it from occurring as (potentially toxic) free ionic metal. In its unbound form, copper can generate hydroxyl radicals. Because metallothionein exhibits a high reactivity toward these radicals, it is increasingly recognized to play a protective role against copper-induced cytotoxicity. We discuss some of the possible toxicologic implications that may arise from changes in hepatic copper and metallothionein status during development.

Language of Publication

English

Unique Identifier

96204963

MeSH Heading (Major)

Copper|AN/*ME/TO; Liver|CH/*DE/*ME

MeSH Heading

Animal; Bile|ME; Biological Transport|PH; Ceruloplasmin|ME/PH; Glutathione|ME/PH; Human; Metallothionein|ME/PH

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0002-9165

Country of Publication

UNITED STATES

Record 25 from database: MEDLINE
Return To The Top
Return To Menu Item 20

Title

Radiation and aging: free radical damage, biological response and possible antioxidant intervention.

Author

Greenstock CL

Address

Radiation Biology Branch, AECL Research, Chalk River, Ontario, Canada.

Source

Med Hypotheses, 1993 Nov, 41:5, 473-82

Abstract

In this review, the basic processes responsible for radiation-induced changes in critical cell components and their biological consequences will be discussed. The chemical and physical alterations in biomolecules are mediated by free radicals and other reactive intermediates formed, following absorption of radiant energy, by ionization of proximal targets or the surrounding water molecules. Accumulation of free radical damage and its catalysis by various oxidants including quinones and other age pigments, metal ions, lipid peroxides, prostaglandins and components released from cells, increase with age. A cell's response to such damage depends upon environmental and inherited factors. DNA repair is an effective way to protect against radiation damage, but other constitutive or inducible defence mechanisms can also modify biological response, and these processes generally become less effective with age. Loss of fidelity with age of bio-feedback mechanisms including homeostasis, redox control, ion and metabolic regulation, which in turn affects cell growth and differentiation, energy efficiency, the immune system and general health, can be associated with free radical pathology. Current theories of aging will be examined including those involving wear-and-tear, genetic, metabolic, immunologic and biochemical factors. Ionizing radiation, as with other external stresses including UV, heat, chemotherapeutic agents, chemical carcinogens and tumor promoters, interact with nucleic acids, proteins and membrane phospholipids facilitating free radical-mediated oxidative damage. Appropriate antioxidant intervention, by inhibiting or reducing free radical toxicity, may offer protection against radiation, and alleviate or delay symptoms of aging and chronic disease.

Language of Publication

English

Unique Identifier

94195133

MeSH Heading (Major)

Aging|DE/ME/*RE

MeSH Heading

Animal; Antioxidants|PD; DNA Damage; Free Radicals; Human; Models, Biological; Radiation Injuries|ET/ME

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0306-9877

Country of Publication

ENGLAND

CAS Registry/EC Number

0 (Antioxidants); 0 (Free Radicals)

Record 26 from database: MEDLINE
Return To The Top
Return To Menu Item 20

Title

Role of oxygen free radicals in carcinogenesis and brain ischemia.

Author

Floyd RA

Address

Molecular Toxicology Research Group, Oklahoma Medical Research Foundation, Oklahoma City 73104.

Source

FASEB J, 1990 Jun, 4:9, 2587-97

Abstract

Even though oxygen is necessary for aerobic life, it can also participate in potentially toxic reactions involving oxygen free radicals and transition metals such as Fe that damage membranes, proteins, and nucleic acids. Oxygen free radical reactions and oxidative damage are in most cases held in check by antioxidant defense mechanisms, but where an excessive amount of oxygen free radicals are produced or defense mechanisms are impaired, oxidative damage may occur and this appears to be important in contributing to several pathological conditions including aging, carcinogenesis, and stroke. Several newer methods, such as in vivo spin-trapping, have become available to monitor oxygen free radical flux and quantitate oxidative damage. Using a combination of these newer methods collectively focused on one model, recent results show that oxidative damage plays a key role in brain injury that occurs in stroke. Subtle changes, such as oxidative damage-induced loss of glutamine synthetase activity, may be a key event in stroke-induced brain injury. Oxygen free radicals may play a key role in carcinogenesis by mediating formation of base adducts, such as 8-hydroxyguanine, which can now be quantitated to very low levels. Evidence is presented that a new class of free radical blocking agents, nitrone spin-traps, may help not only to clarify if free radical events are involved, but may help prevent the development of injury in certain pathological conditions.

Language of Publication

English

Unique Identifier

90269543

MeSH Heading (Major)

Carcinogens|*/ME; Cerebral Ischemia|*CI; Free Radicals|*; Oxygen|*AE

MeSH Heading

Animal; Human; Lipid Peroxidation; Proteins|ME; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0892-6638

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Carcinogens); 0 (Free Radicals); 7782-44-7 (Oxygen)

Record 27 from database: MEDLINE
Return To The Top
Return To Menu Item 20

Title

Protein glycation and oxidative stress in diabetes mellitus and ageing.

Author

Wolff SP; Jiang ZY; Hunt JV

Address

Department of Clinical Pharmacology, University College London, UK.

Source

Free Radic Biol Med, 1991, 10:5, 339-52

Abstract

Hyperglycemia is increasingly regarded as the cause of the diabetic complications, in particular via the ability of glucose to glycate proteins and generate Maillard browning products which cross-link proteins and render them brown and fluorescent in vitro. Similar changes occur in vivo to long-lived proteins in diabetes mellitus as well as in ageing. The evidence supporting this route of glucose toxicity is discussed in the context of the ability of glucose to oxidize in vitro (catalyzed by trace amounts of transition metal) generating hydrogen peroxide, highly reactive oxidants, and protein-reactive ketoaldehyde compounds. It is suggested that protein browning in vivo may not result from the reactions of glucose with protein but from the transition metal-catalyzed reactions of other small autoxidisable substrates, such as ascorbate, with protein. Overall, studies of glycation and protein browning suggest a critical role for oxidative processes perhaps involving decompartmentalized transition metals and a variety of low molecular weight reducing agents in diabetes mellitus and ageing.

Language of Publication

English

Unique Identifier

91309904

MeSH Heading (Major)

Aging|*; Diabetes Mellitus|ET/*ME/PP; Glucose|*TO; Proteins|*ME

MeSH Heading

Free Radicals; Glycosylation; Human; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0891-5849

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Free Radicals); 50-99-7 (Glucose)

Record 28 from database: MEDLINE
Return To The Top
Return To Menu Item 20

Title

Active oxygen in neuromuscular disorders.

Author

Davison A; Tibbits G; Shi ZG; Moon J

Address

Faculty of Applied Sciences, School of Kinesiology, Simon Fraser University, Burnaby, Canada.

Source

Mol Cell Biochem, 1988 Dec, 84:2, 199-216

Abstract

Although muscle and nerve are reasonably well protected against active oxygen and related free radicals, environmental or inherited malfunctions can overpower their defences. Active oxygen is involved in many neuropathies and myopathies. In every case the damage is caused by agents which exert effects disproportionately greater than the quantities encountered, through a variety of amplification mechanisms. We can categorize these amplification mechanisms as follows: (a) non-replacement of targets (e.g. loss of genetic information, ataxia telangectasia being an hereditary ataxia in which an oxygen mediated chromosomal instability is apparent), (b) non-removal of unwanted materials (e.g. lipofuscin accumulation in brain and heart), (c) redox cycling, usually involving catalysis by trace-metal ions (e.g. some forms of Parkinsonism), (d) non-redox catalysis (e.g. toxicity in cardiac muscle or brain due to vanadium or aluminium respectively), (e) modification of ion transport (e.g. calcium ionophore or acrylamide induce histopathological changes in muscle, similar in some respects to those seen in Duchenne muscular dystrophy), (f) compromised defences (e.g. muscle and nerve become particularly susceptible to free radical damage after loss of the protective actions of vitamin E), and (g) amplification by inflammatory and immune responses (e.g. multiple sclerosis, reperfusion injury to brain and heart, and traumatic injury to nervous tissue). Unfortunately, a variety of therapeutic agents which might be expected to protect against almost every conceivable form of oxygen mediated damage have proved clinically ineffective in most of these disorders. The reasons for this will be explored with an emphasis on common features, differences, mechanisms, and potential therapeutic approaches.

Language of Publication

English

Unique Identifier

89159172

MeSH Heading (Major)

Neuromuscular Diseases|*PP; Oxygen|*PH

MeSH Heading

Human; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0300-8177

Country of Publication

NETHERLANDS

CAS Registry/EC Number

7782-44-7 (Oxygen)

Record 29 from database: MEDLINE
Return To The Top
Return To Menu Item 20

Title

The role of iron in oxygen-mediated toxicities.

Author

Ryan TP; Aust SD

Address

Biotechnology Center, Utah State University, Logan 84322-4705.

Source

Crit Rev Toxicol, 1992, 22:2, 119-41

Abstract

The transition metal iron is capable of catalyzing redox reactions between biomolecules and oxygen that would not occur if catalytically active iron were not present. Although these biological oxidations (which are known collectively as "oxidative stress") have been implicated in numerous toxicities, the exact role of the iron catalyst remains to be elucidated. This review focuses on our current understanding of the role of iron in oxidative stress, discussing biologically relevant sources, biochemical forms, and reaction mechanisms of iron as a catalyst of biomolecular oxidations. Specific toxicities in which alterations in normal iron metabolism is thought to overwhelm the body's antioxidant defense system are presented, and future treatment regimens involving novel antioxidant drugs are discussed.

Language of Publication

English

Unique Identifier

92378771

MeSH Heading (Major)

Iron|*ME/TO; Oxygen|*ME

MeSH Heading

Atherosclerosis|ME; Biological Availability; Free Radicals; Human; Neoplasms|ME; Oxidation-Reduction; Reperfusion Injury|ME; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

1040-8444

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Free Radicals); 7439-89-6 (Iron); 7782-44-7 (Oxygen)

Record 30 from database: MEDLINE
Return To The Top
Return To Menu Item 20
Return To Menu Item 40

Title

Oxidative stress: a role in the pathogenesis of Parkinson's disease.

Author

Götz ME; Freyberger A; Riederer P

Address

Klinische Neurochemie, Universitäts-Nervenklinik Würzburg, Federal Republic of Germany.

Source

J Neural Transm Suppl, 1990, 29:, 241-9

Abstract

The degeneration of nigro-striatal dopaminergic neurons is considered to be a predominant pathogenetic factor of Parkinson's disease (PD). However, the etiology of this degeneration is not known. Hypotheses assume accumulation of endogenous and/or exogenous toxins as trigger of the disease. An increase in the concentration of free radicals has been suggested to be toxic to cells, especially when combined with certain metals like free iron or copper. The role of melanin in the degenerative process is not clear, but autoxidative reactions such as the oxidation of dopamine (DA) to melanin generating radicals and toxic metabolites seem to enhance the vulnerability of neurons in the substantia nigra (SN). Disappearance of melanin in the SN, increase of total iron and ferric iron, extreme decrease of glutathione (GSH) levels, reduced activity of enzymes involved in the detoxification of hydrogen peroxide, hydroxyl and superoxide radicals (peroxidases, catalase, glutathione peroxidase), an increase of monoamine oxidase B (MAO B) activity and the substantial increase of malondialdehyde, a marker of lipid peroxidation, in the SN seem to indicate a role of an oxidative stress syndrome in the SN causing or aggravating PD.

Language of Publication

English

Unique Identifier

90293750

MeSH Heading (Major)

Brain|*ME/PP; Dopamine|*ME; Melanins|*ME; Monoamine Oxidase|*ME; Parkinson Disease|*ME/PP

MeSH Heading

Aged; Aged, 80 and over; Glutathione|ME; Human; Middle Age

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0303-6995

Country of Publication

AUSTRIA

CAS Registry/EC Number

EC 1.4.3.4 (Monoamine Oxidase); 0 (Melanins); 51-61-6 (Dopamine); 70-18-8 (Glutathione)

Record 31 from database: MEDLINE
Return To The Top
Return To Menu Item 20
Return To Menu Item 40

Title

Bleomycin pharmacology: mechanism of action and resistance, and clinical pharmacokinetics.

Author

Dorr RT

Address

Department of Internal Medicine and Pharmacology, University of Arizona, College of Medicine, Tucson.

Source

Semin Oncol, 1992 Apr, 19:2 Suppl 5, 3-8

Abstract

Bleomycin is a glycopeptide antibiotic with a unique mechanism of antitumor activity. The drug binds to guanosine-cytosine-rich portions of DNA via association of the "S" tripeptide and by partial intercalation of the bithiazole rings. A group of five nitrogen atoms arranged in a square-pyramidal conformation binds divalent metals including iron, the active ligand, and copper, an inactive ligand. Molecular oxygen, bound by the iron, can produce highly reactive free radicals and Fe(III). The free radicals produce DNA single-strand breaks at 3'-4' bonds in deoxyribose. This yields free base propenals, especially of thymine: cytotoxicity is cell-cycle-phase specific for G2 phase. In humans, bleomycin is rapidly eliminated primarily by renal excretion. This accounts for approximately half of a dose. In patients with renal compromise or extensive prior cisplatin therapy, the drug half-life can extend from 2 to 4 hours up to 21 hours. Thus, dose adjustments are needed when creatinine clearance is less than or equal to 3N mL/min. Finally, resistance to bleomycin in normal tissues can be correlated with the presence of a bleomycin hydrolase enzyme, which is in the cysteine proteinase family. The enzyme replaces a terminal amine with a hydroxyl, thereby inhibiting iron binding and cytotoxic activity. The low concentration of enzyme in the skin and lung may explain the unique sensitivity of these tissues to bleomycin toxicity. However, correlation of hydrolase levels with tumor cell sensitivity has thus far been negative.

Language of Publication

English

Unique Identifier

93030884

MeSH Heading (Major)

Bleomycin|AI/CH/*PD/PK

MeSH Heading

Glycoside Hydrolases|PD; Human; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0093-7754

Country of Publication

UNITED STATES

CAS Registry/EC Number

EC 3.2.1. (Glycoside Hydrolases); EC 3.4.22.- (bleomycin hydrolase); 11056-06-7 (Bleomycin)

Record 32 from database: MEDLINE
Return To The Top
Return To Menu Item 20
Return To Menu Item 40

Title

Ferritin and ceruloplasmin in oxidative damage: review and recent findings.

Author

de Silva DM; Aust SD

Address

Biotechnology Center, Utah State University, Logan 84322-4705.

Source

Can J Physiol Pharmacol, 1993 Sep, 71:9, 715-20

Abstract

The oxidation of biomolecules such as lipid, protein, and DNA is associated with a variety of toxicities and pathologies. In an all-encompassing definition these oxidative processes have been referred to as "oxidative stress." Although the direct reaction between molecular oxygen and most biomolecules is spin forbidden, this reaction can be efficiently catalyzed by transition metals such as iron and copper. Iron especially has been demonstrated to be a potent catalyst of biological oxidations. This review focuses on the relationship between iron and copper with respect to the copper protein ceruloplasmin, which may play a role in iron homeostasis by catalyzing the oxidation of iron as it is placed in ferritin.

Language of Publication

English

Unique Identifier

94147244

MeSH Heading (Major)

Ceruloplasmin|*PH; Ferritin|*PH

MeSH Heading

Animal; Copper|ME; Free Radicals|AE; Human; Iron|ME; Oxidation-Reduction; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0008-4212

Country of Publication

CANADA

CAS Registry/EC Number

EC 1.16.3.1 (Ceruloplasmin); 0 (Free Radicals); 7439-89-6 (Iron); 7440-50-8 (Copper); 9007-73-2 (Ferritin)

Record 33 from database: MEDLINE
Return To The Top
Return To Menu Item 20
Return To Menu Item 40

Title

Ferritin as a source of iron for oxidative damage [see comments]

Author

Reif DW

Address

Biology Department, Fisons Pharmaceuticals, Rochester, NY 14603.

Source

Free Radic Biol Med, 1992, 12:5, 417-27

Abstract

The generation of deleterious activated oxygen species capable of damaging DNA, lipids, and proteins requires a catalyst such as iron. Once released, ferritin iron is capable of catalyzing these reactions. Thus, agents that promote iron release may lead to increased oxidative damage. The superoxide anion formed enzymatically, radiolytically, via metal-catalyzed oxidations, or by redox cycling xenobiotics reductively mobilizes ferritin iron and promotes oxidative damage. In addition, a growing list of compounds capable of undergoing single electron oxidation/reduction reactions exemplified by paraquat, adriamycin, and alloxan have been reported to release iron from ferritin. Because the rapid removal of iron from ferritin requires reduction of the iron core, it is not surprising that the reduction potential of a compound is a primary factor that determines whether a compound will mobilize ferritin iron. The reduction potential does not, however, predict the rate of iron release. Therefore, ferritin-dependent oxidative damage may be involved in the pathogenesis of diseases where increased superoxide formation occurs and the toxicity of chemicals that increase superoxide production or have an adequate reduction potential to mobilize ferritin iron.

Language of Publication

English

Unique Identifier

92275421

MeSH Heading (Major)

Ferritin|*ME; Iron|*ME; Lipid Peroxidation|*; Oxygen|*ME

MeSH Heading

Animal; Human; Nitric Oxide|ME; Oxidation-Reduction; Superoxides|ME; Xenobiotics|ME

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0891-5849

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Xenobiotics); 10102-43-9 (Nitric Oxide); 11062-77-4 (Superoxides); 7439-89-6 (Iron); 7782-44-7 (Oxygen); 9007-73-2 (Ferritin)

Record 34 from database: MEDLINE
Return To The Top
Return To Menu Item 20
Return To Menu Item 40

Title

Involvement of metallothionein and copper in cell proliferation.

Author

W…ostowski T

Address

Institute of Biology, Warsaw University, Bia…ystok, Poland.

Source

Biometals, 1993 Summer, 6:2, 71-6

Abstract

Metallothionein is a low-molecular weight, cysteine-rich, metal-binding protein which has been implicated in the detoxification of toxic metals (cadmium, mercury), metabolism of zinc and copper, as well as in the scavenging of free radicals. Recent evidence suggests that the protein may also be involved in cell proliferation. Based on the experiments carried out so far, it is assumed that the fundamental role of metallothionein in cell proliferation may be to detoxify and/or transfer copper ions from the cytoplasm to the nucleus at the G1/S phase, which in turn participate in some way in nuclear DNA synthesis.

Language of Publication

English

Unique Identifier

93364161

MeSH Heading (Major)

Cell Division|*; Copper|*ME; Metallothionein|*ME

MeSH Heading

Amino Acid Sequence; Animal; Cell Cycle; Conserved Sequence; Evolution; Human

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0966-0844

Country of Publication

ENGLAND

CAS Registry/EC Number

7440-50-8 (Copper); 9038-94-2 (Metallothionein)

Record 35 from database: MEDLINE
Return To The Top
Return To Menu Item 20
Return To Menu Item 40

Title

Emergent issues in the genetics of intestinal neoplasia.

Author

Dove WF; Gould KA; Luongo C; Moser AR; Shoemaker AR

Address

McArdle Laboratory for Cancer Research, University of Wisconsin, Madison 53706, USA.

Source

Cancer Surv, 1995, 25:, 335-55

Abstract

Mutation of the APC gene may be a common denominator of all human colon cancer--polypoid and non-polypoid familial cancer as well as sporadic occurrences. Fearon and Vogelstein (1990) have described a series of molecular changes during the progression of human colon cancer, beginning with mutations in APC. Min is a strain of the laboratory mouse carrying a nonsense mutation in Apc, the mouse homologue of APC. The Min strain has been used to test the effect of germline alterations in certain genes identified in the progression pathway of Fearon and Vogelstein. A deficiency in DNA cytosine methylase leads to a reduction in the tumour multiplicity of Min mice contrary to the a priori expectation based on the global hypomethylation of the DNA of early colonic neoplasms. Alterations in Kras had no perceptible effect on the tumour multiplicity of Min mice but may not have been successfully directed to the proliferative cell population. Constitutional mutation of p53 did not influence the multiplicity or histopathology of early Min induced intestinal tumours. The cause and effect analysis of the genetics of colon cancer is clearly in an early phase. An unlinked genetic factor interacting with Min in controlling intestinal tumour multiplicity is Mom1. A central goal for the near future is to identify the Mom1 gene product and to identify other loci that can interact with the Min mutation and affect tumour multiplicity or progression. Mouse chimaeras will permit an analysis of the clonality and cell autonomy of Min induced neoplasms and also of the action of Mom1. The results of these analyses will inform investigators as to what modes of prevention and therapy might be designed for particular tumour types. The Min strain thereby presents an opportunity to discover protective factors against human colon cancer.

Language of Publication

English

Unique Identifier

96351364

MeSH Heading (Major)

Adenomatous Polyposis Coli|*GE; Colorectal Neoplasms|*GE; Genes, APC|*; Intestinal Neoplasms|*GE

MeSH Heading

Alleles; Animal; Genes, p53; Heterozygote; Homozygote; Human; Mice; Neoplasms, Experimental|GE; Phenotype; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0261-2429

Country of Publication

UNITED STATES

Record 36 from database: MEDLINE
Return To The Top
Return To Menu Item 20
Return To Menu Item 40

Title

Role of oxygen in phagocyte microbicidal action.

Author

Allen RC

Address

Research and Development Division, ExOxEmis, Inc., Little Rock, Arkansas.

Source

Environ Health Perspect, 1994 Dec, 102 Suppl 10:, 201-8

Abstract

Immune information in the form of inflammatory mediators directs phagocyte locomotion and increases expression of opsonin receptors such that contact with an opsonized microbe results in receptor ligation and activation of microbicidal metabolism. Carbohydrate dehydrogenation and O2 consumption feed reactions that effectively lower the spin quantum number (S) of O2 from 1 to 1/2 and finally to 0. Oxidase-catalyzed univalent reduction of O2 (S = 1; triplet multiplicity) yields hydrodioxylic acid (HO2) and its conjugate base superoxide, O2- (S = 1/2; doublet multiplicity). Acid or enzymatic disproportionation of superoxide yields H2O2 (S = 0; singlet multiplicity). Haloperoxidase catalyzes H2O2-dependent oxidation of Cl- yielding HOCl (S = 0), and reaction of HOCl with H2O2 yields singlet molecular oxygen, 1O2 (S = 0; singlet multiplicity). The Wigner spin conservation rule restricts direct reaction of S = 1 O2 with S = 0 organic molecules. Lowering the S of O2 overcomes this spin restriction and allows microbicidal combustion. High exergonicity dioxygenation reactions yield electronically excited carbonyl products that relax by photon emission, i.e., phagocyte luminescence. Addition of high quantum yield substrates susceptible to spin allowed dioxygenation, i.e., chemiluminigenic substrates, greatly increases detection sensitivity and defines the nature of the oxygenating agent. Measurement of luminescence allows high sensitivity, real-time, and substrate-specific differential analysis of phagocyte dioxygenating activities. Under assay conditions where immune mediator and opsonin exposure are controlled, luminescence analysis of the initial phase of opsonin-stimulated oxygenation activity allows functional assessment of the opsonin receptor expression per circulating phagocyte and can be used to gauge the in vivo state of immune activation.

Language of Publication

English

Unique Identifier

95220302

MeSH Heading (Major)

Antibiosis|*; Oxygen|ME/*PH; Phagocytes|ME/*PH

MeSH Heading

Animal; Human; Models, Biological; Oxidation-Reduction; Receptors, Immunologic|ME

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0091-6765

Country of Publication

UNITED STATES

Record 37 from database: MEDLINE
Return To The Top
Return To Menu Item 20
Return To Menu Item 40

Title

Pharmacogenetics in biological perspective.

Author

Kalow W

Address

Department of Pharmacology, University of Toronto, Ontario, Canada.

Source

Pharmacol Rev, 1997 Dec, 49:4, 369-79

Abstract

What have we learned? Pharmacogenetics, heritable variation in response to xenobiotics, is present in all forms of life. Initially, human data perhaps have created the most excitement, and they provide much biochemical detail. However, if we look at pharmacogenetic variation of insects and bacteria, we see it as a characteristic of populations; individuals with inborn resistance to various toxicants can cause the survival of a population by the process of Darwinian selection. Diversity of a population and Darwinian selection are different milestones serving population survival. Variation of drug response may represent variation of drug targets, drug metabolism, and probably drug transport. Metabolic variation appears to be the most prominent; at present, it is not clear whether this prominence has historical or biological causes. It is an interesting exercise to compare pharmacogenetic resistance with intoxication and resistance to infection by invasion of disease-carrying bacteria or other pathogens. The big difference is that pathogens tend to show variabilities that drugs do not have. The immune system is made to deal with the genetic variabilities linked to the short life span of most pathogens. However, there are, besides the immune system, several cases of genetic host resistance associated with the long life span of mammalian hosts. Such genetic host resistances are factors equivalent to pharmacogenetic variation. Current data pertain to resistance against malaria, tuberculosis, cholera, and AIDS. Most pharmacogenetic variants within a population are preadaptive, that is, they are established before xenobiotic exposure. Hence, one must postulate a multiplicity of variants in a population capable of resisting a multiplicity of drugs. The persistence of this multiplicity suggests that most variants are either present in heterozygous form and are thereby advantageous for their carriers, or they are selectively neutral mutants. It means that the biological cost of pharmacogenetic diversity, measured in terms of reduced fertility, should be low in a population. The frequencies of variant genes are usually not the same in different populations. Also the nucleotide substitutions in a variable gene often differ between populations. In other words, pharmacogenetic differences between populations are typical events. Pharmacogenetics is usually thought of as the study of a situation in which a single gene product exerts control over a given drug response so that a failure to respond, or an excessive response, may result. However, one should not forget that random variation is always present, probably reflecting the randomness of mutations plus variation of any environmental factors that might contribute. This underlying randomness of variation will always affect the picture of any all-or-none variation. Future pharmacogenetics must deal with both random and monogenic variation.

Language of Publication

English

Unique Identifier

98105374

MeSH Heading (Major)

Pharmacogenetics|SN/*TD; Pharmacokinetics|*; Xenobiotics|*TO

MeSH Heading

Animal; Arthropods|DE; Bacteria|DE; Comparative Study; Cytochrome P-450 CYP2D6|DF; Drug Resistance|GE; Evolution; Gene Frequency; Human; Variation (Genetics)

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0031-6997

Country of Publication

UNITED STATES

Record 38 from database: MEDLINE
Return To The Top
Return To Menu Item 20
Return To Menu Item 40

Title

Multiple identity enactments and multiple personality disorder: a sociocognitive perspective [see comments]

Author

Spanos NP

Address

Department of Psychology, Carleton University, Ottawa, Ontario, Canada.

Source

Psychol Bull, 1994 Jul, 116:1, 143-65

Abstract

People who enact multiple identities behave as if they possess 2 or more selves, each with its own characteristic moods, memories, and behavioral repertoire. Under different names, this phenomenon occurs in many cultures; in North American culture, it is frequently labeled multiple personality disorder (MPD). This article reviews experimental, cross-cultural, historical, and clinical findings concerning multiplicity and examines the implications of these findings for an understanding of MPD. Multiplicity is viewed from a sociocognitive perspective, and it is concluded that MPD, like other forms of multiplicity, is socially constructed. It is context bounded, goal-directed, social behavior geared to the expectations of significant others, and its characteristics have changed over time to meet changing expectations.

Language of Publication

English

Unique Identifier

94360026

MeSH Heading (Major)

Multiple Personality Disorder|*PX

MeSH Heading

Amnesia|PX; Consciousness; Cross-Cultural Comparison; Human; Hypnosis; Religion and Psychology; Social Behavior; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0033-2909

Country of Publication

UNITED STATES

Record 39 from database: MEDLINE
Return To The Top
Return To Menu Item 20
Return To Menu Item 40

Title

Modulation of mitogenesis by liver fatty acid binding protein.

Author

Sorof S

Address

Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

Source

Cancer Metastasis Rev, 1994 Dec, 13:3-4, 317-36

Abstract

Liver fatty acid binding protein (L-FABP), a cytoplasmic 14 kDa protein previously termed Z protein, is conventionally considered to be an intracellular carrier of fatty acids in rat hepatocytes. The following evidence now indicates that L-FABP is also a specific mediator of mitogenesis of rat hepatocytes: a. the synergy between the action of L-FABP and unsaturated fatty acids, especially linoleic acid, in the promotion of cell proliferation; b. the specific requirement for L-FABP in induction of mitogenesis by two classes of nongenotoxic hepatocarcinogenic peroxisome proliferators (amphipathic carboxylates and tetrazole-substituted acetophenones); c. the direct correlation between the binding avidities of different prostaglandins for L-FABP and their relative growth inhibitory activities toward cultured rat hepatocytes; d. the temporal coincidences between the covalent binding to L-FABP by chemically reactive metabolites of the genotoxic carcinogens, 2-acetylaminofluorene and aminoazo dyes, and their growth inhibitions of hepatocytes during liver carcinogenesis in rats; e. and f. the marked elevations of L-FABP in rat liver during mitosis in normal and regenerating hepatocytes, and during the entire cell cycle in the hyperplastic and malignant hepatocytes that are produced by the genotoxic carcinogens, 2-acetylaminofluorene and aminoazo dyes. These actions of L-FABP are consistent with those of a protein involved in regulation of hepatocyte multiplication. Discovery that L-FABP, the target protein of the two types of genotoxic carcinogens, is required for the mitogenesis induced by two classes of nongenotoxic carcinogens points to a common process by which both groups of carcinogens promote hepatocyte multiplication. The implication is that during tumor promotion of liver carcinogenesis, these genotoxic and nongenotoxic carcinogens modify the normal process by which L-FABP, functioning as a specific receptor of unsaturated fatty acids or their metabolites, promotes the multiplication of hepatocytes.

Language of Publication

English

Unique Identifier

95228178

MeSH Heading (Major)

Carrier Proteins|*PH; Cell Division|*DE/PH; Liver|*CY

MeSH Heading

Animal; Fatty Acids|PH; Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0891-9992

Country of Publication

UNITED STATES

Record 40 from database: MEDLINE
Return To The Top
Return To Menu Item 40

Title

The rise and fall in information-processing rates over the life span.

Author

Cerella J; Hale S

Address

Veterans Administration Outpatient Clinic, Boston, MA 02114.

Source

Acta Psychol (Amst), 1994 Aug, 86:2-3, 109-97

Abstract

We surveyed studies that measured information-processing durations in groups of experimental subjects (children or elderly adults) and a group of college-aged control subjects. Some studies varied the type of processing while keeping the age of a subject group fixed. Process-durations in experimental subjects could be described by a multiplicative function of the control durations, regardless of the type of processing. Other studies varied the age of the subject groups while keeping the type of processing fixed. Process-durations declined during childhood, in a manner that could be described by a negative exponential function of age. Process-durations increased throughout middle- and old-age, in a manner that could be described by a positive exponential function of age. The sum of the two exponentials defined a U-shaped function that described process-durations over the life span. The most important studies varied both the type of processing and the age of the subject groups. An array of measurements of this kind could be described by a two-dimensional function that combined the multiplicative effect of process-duration and the exponential effects of age. The multiplicative effect of process-duration suggested that the execution of a processing sequence was conditioned by a single developmental parameter in both the experimental subject and the control subject. The exponential components determined the magnitude of the developmental parameter as the age of the subject changed. Given the global character of these effects, it seemed to us that the developmental mechanism may operate at a more elementary level than the information-processing stages conceived by cognitive theories. In a developmental framework, information processing may be reducible to a large number of small steps of a homogeneous duration or reliability, such as might be realized on a neural network. The exponential rate constants may be related to constant-probability hazards that act on one or another population of neural elements to create minute defects or incremental improvements. Their cumulative effects alter the functioning of the network over its lifetime, in a way that parallels the observed changes in process-durations.

Language of Publication

English

Unique Identifier

95066978

MeSH Heading (Major)

Aging|PH/*PX; Cognition|*/PH; Human Development|*

MeSH Heading

Adolescence; Adult; Aged; Brain|PH; Child; Child, Preschool; Female; Human; Male; Middle Age; Models, Neurological; Models, Psychological; Psychomotor Performance; Reaction Time; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.; Time Factors

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0001-6918

Country of Publication

NETHERLANDS

Record 41 from database: MEDLINE
Return To The Top
Return To Menu Item 40

Title

Molecular and genetic epidemiology of hepatocellular carcinoma: studies in China and Senegal.

Author

London WT; Evans AA; Buetow K; Litwin S; McGlynn K; Zhou T; Clapper M; Ross E; Wild C; Shen FM; et al

Address

Division of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.

Source

Princess Takamatsu Symp, 1995, 25:, 51-60

Abstract

To identify environmental, viral, and genetic factors that may influence the risk of developing hepatocellular carcinoma (HCC), large prospective studies are being conducted in Haimen City, China and Senegal, and a case-control study of genetic variation in the detoxification of aflatoxin-B1 was carried out in Shanghai, China. Analysis of 78 HCCs that have occurred among 51,020 men enrolled in a large prospective study in Haimen City, China showed a strong association of HCC with chronic hepatitis B virus (HBV) infection. There were also significant associations of HCC risk with occupation (farming), history of a clinical episode of hepatitis in adulthood, and a family history of HCC. Study of 52 HCC cases and 116 controls for genetic polymorphisms and HCC risk showed a significant association with epoxide hydrolase (EPHX) mutant alleles (1/2, 2/2) and a borderline association with homozygous deletion of the glutathione-S-transferase mu (GSTM1) gene. There was a multiplicative interaction of these polymorphisms with chronic HBV infection such that HBsAg-positive persons who were GSTM1 null and were EPHX 1/2 or 2/2 had 135 times the risk of HCC as HBsAg-negative persons with the wild type genotypes for GSTM1 and EPHX. The risk of HCC is not uniform among persons with chronic HBV or HCV infections. Studies of genetic, viral, and environmental interactions may permit identification of those individuals at highest risk within groups at increased risk of HCC. Prevention strategies could then be targeted at those individuals.

Language of Publication

English

Unique Identifier

97029599

MeSH Heading (Major)

Carcinoma, Hepatocellular|*ET/GE; Liver Neoplasms|*ET/GE

MeSH Heading

Aflatoxin B1|TO; China; Hepatitis, Viral, Human|CO; Human; Male; Senegal

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

Country of Publication

UNITED STATES

Record 42 from database: MEDLINE
Return To The Top
Return To Menu Item 40

Title

The inflammatory response and tissue damage. The example of renal scars following acute renal infection.

Author

Glauser MP; Meylan P; Bille J

Address

Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

Source

Pediatr Nephrol, 1987 Oct, 1:4, 615-22

Abstract

Most clinical and experimental evidence suggests that renal scarring occurs following urinary tract infections in those patients with an abnormality of the urinary tract or kidney function. Experimentally, bacterial multiplication within the kidney occurs only in the presence of obstruction, leading rapidly to acute exudative pyelonephritis and invariably to kidney scars within weeks. Various manipulations of the bacterial load and/or of the inflammatory response during acute pyelonephritis have demonstrated that the inflammatory processes, not the bacterial component of pyelonephritis, are responsible for permanent renal tissue damage. Polymorphonuclear leucocytes (PMNLs) infiltrating the kidney tissue during acute pyelonephritis appear to release metabolites that are toxic to the parenchyma. Indeed, both the prevention of PMNL influx into renal tissue, by means of colchicine or cyclophosphamide, and the inactivation of some of their toxic metabolites, by means of dapsone, have led to the prevention of tissue damage and kidney scars. However, the most potent protective activity was observed with early antibiotic treatment, which stopped bacterial multiplication and prevented the early influx of PMNLs, thus preventing tissue damage and scar formation. Similar observations have been made in children with acute pyelonephritic episodes, in whom early and aggressive antibiotic treatment prevented subsequent kidney scars, while delayed treatment did not.

Language of Publication

English

Unique Identifier

91027241

MeSH Heading (Major)

Cicatrix|*ET/PA; Nephritis|*ET/PA; Urinary Tract Infections|*CO

MeSH Heading

Human; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0931-041X

Country of Publication

GERMANY

Record 43 from database: MEDLINE
Return To The Top
Return To Menu Item 40

Title

Pituitary-thyroid relationships in hypothyroidism.

Author

Silva JE

Address

 

Source

Baillieres Clin Endocrinol Metab, 1988 Aug, 2:3, 541-65

Abstract

The pituitary gland is undoubtedly a target for thyroid hormone. It is the tissue with the highest density of T3 receptors and contains Type II T4 5' deiodinase which are involved in the secretion of TSH and other pituitary hormones. In the case of TSH, this knowledge has resulted in a better understanding of a number of conditions such as the adaptation to reduced thyroid reserve, and in an improvement in the way we treat hypothyroidism. But the pituitary being a target tissue for thyroid hormones has additional consequences. A direct effect of T3 on various secretions of the gland has been documented, and in the case of other pituitary hormones, directly or indirectly, thyroid hormone has some effect. T3 has a broad spectrum of metabolic and physiological effects that may, by themselves, account for a large proportion of the variability of the clinical presentation of hypothyroidism. The multiplicity of pituitary hormones and the multiplicative action of these various hormones through their target glands make the pituitary gland another key element in the variability of clinical manifestations of hypothyroidism. While this variability poses a diagnostic challenge in that hypothyroidism should be considered in a large number of conditions, the abnormalities resulting from the lack of thyroid hormone in the pituitary are equally challenging from a therapeutic point of view, since they respond promptly to the correction of the hypothyroidism. We should try to identify and treat those that are both life-threatening and not corrected rapidly by the administration of thyroid hormone.

Language of Publication

English

Unique Identifier

89133986

MeSH Heading (Major)

Hypothyroidism|*PP; Pituitary Gland, Anterior|*PP; Pituitary Hormones, Anterior|*PH; Thyroid Hormones|*PH

MeSH Heading

Adrenal Cortex|PP; Human

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0950-351X

Country of Publication

ENGLAND

CAS Registry/EC Number

0 (Pituitary Hormones, Anterior); 0 (Thyroid Hormones)

Record 44 from database: MEDLINE
Return To The Top
Return To Menu Item 40

Title

Regulation of new fat cell formation.

Author

Sypniewska G

Address

Department of Clinical Nutrition, National Institute of Food and Nutrition, Warsaw.

Source

Acta Physiol Pol, 1989 Mar-Apr, 40:2, 156-63

Abstract

The formation of new adipocytes occurs either at the stage of multiplication or differentiation or both. It seems possible that the formation of new fat cells is dependent on the average cell weight in a given adipose tissue depot, but there may also be other regional, local regulatory factors. Multiplication of fat cells has been suggested to be stimulated by 17-beta-oestradiol while the differentiation of adipocytes is stimulated by growth hormone, glucocorticoids, insulin, insulin-like growth factor and female sex hormones. There are, probably, other factors acting in circulation or locally. The factors promoting growth of new fat cells with overfeeding are at present unknown. Some hypothetical possibilities are discussed.

Language of Publication

English

Unique Identifier

90358051

MeSH Heading (Major)

Adipose Tissue|*CY/DE/GD

MeSH Heading

Animal; Cell Differentiation|DE; Cell Division|DE; Estradiol|PD/PH; Growth Substances|PD/PH; Hormones|PD/PH; Human; Stem Cells|CY/DE

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0044-6033

Country of Publication

POLAND

CAS Registry/EC Number

0 (Growth Substances); 0 (Hormones); 50-28-2 (Estradiol)

Record 45 from database: MEDLINE
Return To The Top
Return To Menu Item 40

Title

Future prospects in antiviral therapy.

Author

Wiltink EH

Address

Medical Centre, Department of Pharmacy, Amsterdam, The Netherlands.

Source

Pharm Weekbl Sci, 1992 Aug 21, 14:4A, 268-74

Abstract

Two important stumbling blocks to the development of effective and nontoxic antiviral drugs are the intracellular localization of the virus and the fact that a virus uses host cell functions to multiply. Therefore, new antiviral drugs must act on a virus-specific function. Most currently available useful antiviral drugs are the result of compound screening of large numbers of possible agents. Advances in our understanding of the molecular biology and biochemistry of the viral multiplication cycle and new laboratory techniques for determining the molecular sites of action have now made it possible to develop and screen new antiviral drugs in a more purposeful manner. Another possible option in antiviral therapy is combination therapy using drugs that enhance the therapeutic effect or diminish side-effects. The most promising new antiviral drugs are discussed according to the different steps they affect in the viral multiplication process. Combination therapy is also reviewed.

Language of Publication

English

Unique Identifier

93065136

MeSH Heading (Major)

Antiviral Agents|*PD

MeSH Heading

Drug Therapy|TD; Forecasting; Human; Virus Replication|DE/PH

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0167-6555

Country of Publication

NETHERLANDS

CAS Registry/EC Number

0 (Antiviral Agents)

Record 46 from database: MEDLINE
Return To The Top
Return To Menu Item 40

Title

The traditional toxicologic paradigm is correct: dose influences mechanism.

Author

Goodman JI

Address

Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824, USA. goodman3@pilot.msu.edu

Source

Environ Health Perspect, 1998 Feb, 106 Suppl 1:, 285-8

Abstract

Dose influences mechanism; and over a wide range of doses, one can envision that mechanism will change with changing dose. This basic concept in toxicology is juxtaposed with the biologic importance of maintaining normal DNA methylation status to provide the focus of this paper. The idea that altered DNA methylation plays a variety of roles in carcinogenesis is compatible with three key features of this multistage process: clonal selection of abnormal cells in a progressive fashion, the reversibility of tumor promotion, and the multiplicity of tumor phenotypes. A relatively low capacity to maintain normal methylation status appears to explain, in part, the high propensity of the B6C3F1 mouse to develop liver tumors. This observation supports the view that a mouse liver tumor response is not an appropriate end point for human risk assessment. Additionally, it is suggested that altered DNA methylation can be viewed as a secondary mechanism underlying carcinogenesis. The knowledge that a chemical is acting by a mode of action involving a secondary mechanism can be used to support a safety factor or multiplicity of exposure approach to risk assessment.

Language of Publication

English

Unique Identifier

98199847

MeSH Heading (Major)

Carcinogens|*TO

MeSH Heading

Animal; Dose-Response Relationship, Drug; DNA Methylation; Human; Liver Neoplasms, Experimental|CI; Mice; Mutagens|TO; Risk Assessment; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0091-6765

Country of Publication

UNITED STATES

Record 47 from database: MEDLINE
Return To The Top
Return To Menu Item 40

Title

Role played by vasopressin (and of an adrenalpostpituitary imbalance) in the development of cancerous diseases.

Author

Bernard-Weil E

Address

83, Bd. de l'Hôpital, Paris, France.

Source

Med Hypotheses, 1992 Mar, 37:3, 127-36

Abstract

Several authors have demonstrated that vasopressin (VP) plays a role in the metabolism of various cell lines, cancerous or not, and in particular acts upon the growth and the multiplication of cell cultures. Less known are the data concerning the existence of an adrenal-postpituitary imbalance in favour of VP in cancerous patients. Seeing that adreno-cortical hormones (ACH) are able to exert an inhibiting action on cell multiplication in vitor, a similar effect being very moderate or even absent in vivo, one can see the advantage of taking such effects into account. They allowed us to explain the discrepancy between the in vivo and in vitro effects of ACH, since VP is able to counteract the expected effects of ACH. A model, first empirical, then mathematical, of the so-called adrenal-postpituitary system, was proposed for this purpose. It enables us to propose some hypotheses in the fight to escape the action of ACH in cancer. Paradoxically, it seems that a bipolar therapy, using ACH and VP, would be useful in reaching this goal.

Language of Publication

English

Unique Identifier

92261416

MeSH Heading (Major)

Neoplasms|*ET/TH; Vasopressins|*PH

MeSH Heading

Animal; Human; Models, Biological; Pituitary-Adrenal System|PP

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0306-9877

Country of Publication

ENGLAND

CAS Registry/EC Number

0 (Vasopressins)

Record 48 from database: MEDLINE
Return To The Top
Return To Menu Item 40

Title

Prognostic factors in nasopharyngeal carcinoma investigated by computer tomography--an analysis of 659 patients [see comments]

Author

Teo P; Shiu W; Leung SF; Lee WY

Address

Department of Clinical Oncology, Prince of Wales Hospital, Shatin, N.T., Hong Kong.

Source

Radiother Oncol, 1992 Feb, 23:2, 79-93

Abstract

A total of 659 freshly diagnosed nasopharyngeal carcinoma (NPC) (1984-1987), were investigated by computed tomography (CT), treated with locoregional radiotherapy to radical dose, and given neoadjuvant chemotherapy (CHEMO) with 2-3 courses of cisplatinum and 5-fluorouracil for bulky (greater than or equal to 4 cm) cervical nodal metastasis and booster radiotherapy (PPB) for parapharyngeal disease. All except 15 patients were fully evaluable with complete data entry till death or to the last follow-up (minimum 2 years). The data have been analysed extensively to identify variables of potential prognostic significance. The assessed factors include patients' sex and age, nasal involvement (NAS), oropharyngeal involvement (ORO), parapharyngeal involvement (PAR), muscle involvement (MU), skull base involvement (BS), cranial nerves (II-VIII) palsy (CN1), cranial nerves (IX-XII) palsy (CN2), intracranial extension (IC), laryngopharyngeal extension (HYP), confinement to nasopharynx (NP), Ho's N-stage (Nho), maximal nodal size (Nmax), nodal mobility (Nf- fixed, Npf- doubt in mobility, Nm- mobile), nodal laterality (unilateral, contralateral, bilateral), nodal multiplicity (single, multiple), and presentation with distant metastasis (M1). These factors have been assessed as to their interdependence and correlation with the clinical course (study endpoints) using both monovariate analyses and Cox's Regression model. Significant association among Ho's T2 and T3 features was identified. Advanced Ho's N-stage correlated significantly with bulky nodes, multiple nodes, fixed nodes, and, contralateral and bilateral nodes. Poor prognostic factors found to be significant by both monovariate analyses and Cox's Regression model included the M1, Nho (advanced), CN1, BS, and CN2 for the actuarial survival (ASR) for all patients (659), the Nho (advanced), CN1, CN2, and BS for the ASR for the non-metastatic patients (628), the absence of NP and the male sex for the local failure rate (628), the Nho (advanced), CN2, and BS for the distant metastasis rate (628), and the Nho (advanced), CN1, and BS for the disease-free survival (DFS) (628). In addition, old age, male sex, and the presence of parapharyngeal disease were probably significant in predicting poor survival (ASR); CN1 was probably significant in predicting more local failures, and, the parapharyngeal disease and the intracranial extension for more distant metastases. The Ho's N-staging is superior to the other N-stage classifications, because once the Ho's N-stage has been determined, other nodal characteristics including nodal size, multiplicity, laterality, and fixity, are prognostically insignificant.

Language of Publication

English

Unique Identifier

92187923

MeSH Heading (Major)

Nasopharyngeal Neoplasms|MO/PA/*RA

MeSH Heading

Age Factors; Aged; Female; Human; Male; Middle Age; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Sex Factors; Survival Rate; Tomography, X-Ray Computed

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0167-8140

Country of Publication

NETHERLANDS

Record 49 from database: MEDLINE
Return To The Top
Return To Menu Item 40

Title

A reviewer's perspective on multiple endpoint issues in clinical trials.

Author

Huque MF; Sankoh AJ

Address

Division of Biometrics III, Food and Drug Administration, Rockville, Maryland 20857, USA.

Source

J Biopharm Stat, 1997 Nov, 7:4, 545-64

Abstract

Multiplicity issues due to clinical endpoints frequently arise in clinical trials. Conducting tests of significance separately for each endpoint in a univariate manner, or ignoring the issue, could lead to inflation of the type 1 error probability in making treatment effect claims. This is of concern because inflation of the type I error probability could lead to approval of inefficacious therapies. Therefore, one generally requires that this error probability be controlled at some prespecified alpha-level. At the same time the method employed for this purpose should be one with optimal efficiency so as to be able to detect clinically meaningful treatment effect with high probability. In this presentation, we give a clinical and statistical background to the problem with a few examples and show some simulation results that illustrate the impact of ignoring multiplicity due to multiple endpoints on the type I error probability. This is then followed by an overview and discussion of some global methods in the literature and how they can be used to make endpoint specific tests of significance. Finally, we will introduce a Monte-Carlo simulation and resampling approach (with examples using real data) for controlling the type I error probability.

Language of Publication

English

Unique Identifier

98023165

MeSH Heading (Major)

Clinical Trials|*MT; Statistics|*MT

MeSH Heading

Human; Monte Carlo Method; Multivariate Analysis; Research Design

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

1054-3406

Country of Publication

UNITED STATES

Record 50 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

Analyzing the functional consequences of transmitter complexity.

Author

Brezina V; Weiss KR

Address

Dept of Physiology and Biophysics, Mount Sinai School of Medicine, New York, NY 10029, USA.

Source

Trends Neurosci, 1997 Nov, 20:11, 538-43

Abstract

Neurons and other cells are regulated by a great multiplicity of neurotransmitters, modulators, hormones and other chemical messengers, which, through complex networks of extensively diverging and converging pathways, exert a multiplicity of effects. How do we analyze the functioning of such a complex network? If the effects of a transmitter depend on the presence of many other transmitters, how can we predict what they will be? If multiple transmitters act through the same network, how can their actions be specific? If they converge on the same effects, are some of the transmitters redundant? Why are there so many transmitters? Such questions can be addressed using an analytical approach that examines, qualitatively or quantitatively, how the operation of the network globally maps a multidimensional input space of transmitters to a multidimensional output space of effects.

Language of Publication

English

Unique Identifier

98031252

MeSH Heading (Major)

Nervous System Physiology|*; Neurons|*PH; Neurotransmitters|*PH

MeSH Heading

Animal; Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0166-2236

Country of Publication

ENGLAND

Record 51 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

Constrictive and restrictive pulmonary hypertension in the newborn and infant.

Author

Reid LM

Address

Department of Pathology, Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Source

Am J Cardiovasc Pathol, 1987, 1:2, 287-99

Abstract

The normal pulmonary circulation is constricted at birth and, as judged by its low arterial density, is relatively more restricted than in the older infant and child. During adaptation to air breathing, pulmonary arterial dilatation occurs rapidly, but also the compliance of the resistance arterial segment increases. In the fetus and newborn, the resistance segment is proximal to the respiratory or alveolar surface. Further expansion of the pulmonary vascular bed occurs by growth in size of lumen diameter of existing arteries and growth of new ones. Multiplication of alveoli and arteries is relatively dissociated--alveolar density can increase normally without normal vascular multiplication. Persistent pulmonary hypertension of the newborn occurs because of (1) lung hypoplasia associated with hypoplasia of the vascular bed, usually affecting both size and number of units, (2) abnormal muscularization of intraacinar arteries before birth, causing restriction of vascular volume, (3) failure of the adaptation programs, and (4) hyperreactivity. Immaturity of the circulation is apparent as hyperreactivity or "twitchiness": this can be superimposed on each of the other types. A hyperirritable vascular bed can cause a labile and then a fixed pulmonary hypertension that does not respond to dilators.

Language of Publication

English

Unique Identifier

89087682

MeSH Heading (Major)

Hypertension, Pulmonary|*PA; Infant, Newborn, Diseases|*PA

MeSH Heading

Comparative Study; Human; Infant; Infant, Newborn; Persistent Fetal Circulation Syndrome|PA; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0887-8005

Country of Publication

UNITED STATES

Record 52 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

The nature of the mineral component of bone and the mechanism of calcification.

Author

Glimcher MJ

Address

 

Source

Instr Course Lect, 1987, 36:, 49-69

Abstract

From the physical chemical standpoint, the formation of a solid phase of Ca-P in bone represents a phase transformation, a process exemplified by the formation of ice from water. Considering the structural complexity and abundance of highly organized macromolecules in the cells and extracellular tissue spaces of mineralized tissues generally and in bone particularly, it is inconceivable that this phase transformation occurs by homogeneous nucleation, i.e., without the active participation of an organic component acting as a nucleator. This is almost surely true in biologic mineralization in general. Electron micrographs and low-angle neutron and X-ray diffraction studies clearly show that calcification of collagen fibrils occurs in an extremely intimate and highly organized fashion: initiation of crystal formation within the collagen fibrils in the hole zone region, with the long axes (c-axis) of the crystals aligned roughly parallel to the long axis of the fibril within which they are located. Crystals are initially formed in hole zone regions within individual fibrils separated by unmineralized regions. Calcification is initiated in spatially distinct nucleation sites. This indicates that such regions within a single, undirectional fibril represents independent sites for heterogeneous nucleation. Clearly, sites where mineralization is initiated in adjacent collagen fibrils are even further separated, emphasizing even more clearly that the process of progressive calcification of the collagen fibrils and therefore of the tissue is characterized principally by the presence of increasing numbers of independent nucleation sites within additional hole zone regions of the collagen fibrils. The increase in the mass of Ca-P apatite accrues principally by multiplication of more crystals, mostly by secondary nucleation from the crystals initially deposited in the hole zone region. Very little additional growth of the crystals occurs with time, the additional increase in mineral mass being principally the result of increase in the number of crystals (multiplication), not size of the crystals (crystal growth). The crystals within the collagen fibers grow in number and possibly in size to extend into the overlap zone of the collagen fibrils ("pores") so that all of the available space within the fibrils, which has possibly expanded in volume from its uncalcified level, is eventually occupied by the mineral crystals. It must be recognized that the calcification of separate tissue components and compartments (collagen, mitochondria, matrix vesicles) must be an independent physical chemical event.(ABSTRACT TRUNCATED AT 400 WORDS)

Language of Publication

English

Unique Identifier

88140353

MeSH Heading (Major)

Bone and Bones|*ME; Calcification, Physiologic|*; Minerals|*ME

MeSH Heading

Animal; Calcium Phosphates|ME; Collagen|ME; Human; Phosphorus|ME; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0065-6895

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Calcium Phosphates); 0 (Minerals); 7723-14-0 (Phosphorus); 9007-34-5 (Collagen)

Record 53 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

Molecular biology of serotonin (5-HT) receptors.

Author

Peroutka SJ

Address

Palo Alto Institute for Molecular Medicine, Burlingame, California 94010.

Source

Synapse, 1994 Nov, 18:3, 241-60

Abstract

The hypothesis that multiple serotonin (5-hydroxytryptamine; 5-HT) receptors exist was first developed in the 1950s. However, unequivocal proof of 5-HT receptor multiplicity required the availability of molecular biological technologies. Indeed, the multiplicity of 5-HT receptor subtypes, both within and between species, has far exceeded most of the predictions that might have been made on the basis of pharmacological data. Over the past few years, and especially in 1992 and 1993, numerous "new" 5-HT receptors were reported. In this review, the extensive data generated in the past few years are summarized in an evolutionary context.

Language of Publication

English

Unique Identifier

95159019

MeSH Heading (Major)

Receptors, Serotonin|*GE

MeSH Heading

Animal; Biological Transport; Dogs; Drosophila; Guinea Pigs; Hamsters; Human; Mice; Opossums; Rats; Snails; Species Specificity; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW LITERATURE

ISSN

0887-4476

Country of Publication

UNITED STATES

Record 54 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

On cancer risk estimation of urban air pollution.

Author

Törnqvist M; Ehrenberg L

Address

Department of Radiobiology, Stockholm University, Sweden.

Source

Environ Health Perspect, 1994 Oct, 102 Suppl 4:, 173-82

Abstract

The usefulness of data from various sources for a cancer risk estimation of urban air pollution is discussed. Considering the irreversibility of initiations, a multiplicative model is preferred for solid tumors. As has been concluded for exposure to ionizing radiation, the multiplicative model, in comparison with the additive model, predicts a relatively larger number of cases at high ages, with enhanced underestimation of risks by short follow-up times in disease-epidemiological studies. For related reasons, the extrapolation of risk from animal tests on the basis of daily absorbed dose per kilogram body weight or per square meter surface area without considering differences in life span may lead to an underestimation, and agreements with epidemiologically determined values may be fortuitous. Considering these possibilities, the most likely lifetime risks of cancer death at the average exposure levels in Sweden were estimated for certain pollution fractions or indicator compounds in urban air. The risks amount to approximately 50 deaths per 100,000 for inhaled particulate organic material (POM), with a contribution from ingested POM about three times larger, and alkenes, and butadiene cause 20 deaths, respectively, per 100,000 individuals. Also, benzene and formaldehyde are expected to be associated with considerable risk increments. Comparative potency methods were applied for POM and alkenes. Due to incompleteness of the list of compounds considered and the uncertainties of the above estimates, the total risk calculation from urban air has not been attempted here.

Language of Publication

English

Unique Identifier

95121305

MeSH Heading (Major)

Air Pollution|*AE; Neoplasms|*CI

MeSH Heading

Aldehydes|AE; Alkenes|AE; Animal; Benzene|AE; Human; Models, Biological; Polycyclic Hydrocarbons|AE; Risk Assessment; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Urban Health

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0091-6765

Country of Publication

UNITED STATES

Record 55 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

The control of hematopoiesis and leukemia: from basic biology to the clinic.

Author

Sachs L

Address

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

Source

Proc Natl Acad Sci U S A, 1996 May, 93:10, 4742-9

Abstract

Hematopoiesis gives rise to blood cells of different lineages throughout normal life. Abnormalities in this developmental program lead to blood cell diseases including leukemia. The establishment of a cell culture system for the clonal development of hematopoietic cells made it possible to discover proteins that regulate cell viability, multiplication and differentiation of different hematopoietic cell lineages, and the molecular basis of normal and abnormal blood cell development. These regulators include cytokines now called colony-stimulating factors (CSFs) and interleukins (ILs). There is a network of cytokine interactions, which has positive regulators such as CSFs and ILs and negative regulators such as transforming growth factor beta and tumor necrosis factor (TNF). This multigene cytokine network provides flexibility depending on which part of the network is activated and allows amplification of response to a particular stimulus. Malignancy can be suppressed in certain types of leukemic cells by inducing differentiation with cytokines that regulate normal hematopoiesis or with other compounds that use alternative differentiation pathways. This created the basis for the clinical use of differentiation therapy. The suppression of malignancy by inducing differentiation can bypass genetic abnormalities that give rise to malignancy. Different CSFs and ILs suppress programmed cell death (apoptosis) and induce cell multiplication and differentiation, and these processes of development are separately regulated. The same cytokines suppress apoptosis in normal and leukemic cells, including apoptosis induced by irradiation and cytotoxic cancer chemotherapeutic compounds. An excess of cytokines can increase leukemic cell resistance to cytotoxic therapy. The tumor suppressor gene wild-type p53 induces apoptosis that can also be suppressed by cytokines. The oncogene mutant p53 suppresses apoptosis. Hematopoietic cytokines such as granulocyte CSF are now used clinically to correct defects in hematopoiesis, including repair of chemotherapy-associated suppression of normal hematopoiesis in cancer patients, stimulation of normal granulocyte development in patients with infantile congenital agranulocytosis, and increase of hematopoietic precursors for blood cell transplantation. Treatments that decrease the level of apoptosis-suppressing cytokines and downregulate expression of mutant p53 and other apoptosis suppressing genes in cancer cells could improve cytotoxic cancer therapy. The basic studies on hematopoiesis and leukemia have thus provided new approaches to therapy.

Language of Publication

English

Unique Identifier

96209802

MeSH Heading (Major)

Hematopoiesis|*PH; Leukemia|*ET/PA/TH

MeSH Heading

Animal; Apoptosis|PH; Colony-Forming Units Assay; Colony-Stimulating Factors; Cytokines|PH/TU; Human; Mutation; Protein p53|GE/PH; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0027-8424

Country of Publication

UNITED STATES

Record 56 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

Physiopathology of primary periodontitis associated with plaque. Microbial and host factors. A review. Part 1.

Author

Liébana J; Castillo A

Address

Department of Microbiology, School of Odontology, University of Granada.

Source

Aust Dent J, 1994 Aug, 39:4, 228-32

Abstract

Microbial factors involved in the genesis of periodontitis include colonization, bacterial penetration of the epithelium, multiplication and invasive-destructive capacity. Colonization of the gingival sulcus is related, to a certain extent, to supragingival plaque. Bacterial multiplication is induced by nutrients in the gingival fluid, and nutrients produced by degradative and excretory microbial activity. Invasion and destruction are mediated by exotoxins, structural elements of the bacteria, enzymes, metabolites, polyclonal lymphocyte activity, fibroblastic cytotoxicity, and leukocyte chemotactic inhibition.

Language of Publication

English

Unique Identifier

95031758

MeSH Heading (Major)

Dental Plaque|*CO/IM/MI; Periodontitis|IM/MI/*PP

MeSH Heading

Bacteria|IM/ME/PH; Human; Leukocytes|IM

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0045-0421

Country of Publication

AUSTRALIA

Record 57 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

Multiple serotonin receptor subtypes: molecular cloning and functional expression.

Author

Teitler M; Herrick Davis K

Address

Department of Pharmacology and Toxicology, Albany Medical College, New York 12208.

Source

Crit Rev Neurobiol, 1994, 8:3, 175-88

Abstract

The field of serotonin (5HT) receptor pharmacology has been at least as dramatically altered by the advent of molecular neurobiology and recombinant DNA techniques as has any other neurotransmitter receptor field. The principal reason for this is the unforeseen multitude of genes expressing different types of 5HT receptors. Classic pharmacological studies as well as radioligand binding studies convinced workers in the field that there were multiple 5HT receptors. The extent of that multiplicity was not generally foreseen. At the time of this writing, no less than 13 5HT receptor genes have been cloned and functionally expressed. In addition, a fourteenth receptor has been well studied and will undoubtedly be cloned in the near future. These novel 5HT receptor clones are appearing at an astonishing rate. All 13 receptors have been cloned between the years 1987 to 1993, with more than half of the clones appearing in the literature in the last 18 months. Furthermore, there is no indication that all of the 5HT receptors present in the mammalian genome have been cloned. In fact, there are classic pharmacological data as well as radioligand binding data that implicate the existence of additional 5HT receptor subtypes not yet fully defined or cloned. Bringing order to this rapid outpouring of information at this time is a very difficult task. Not only is there a great multiplicity of receptor subtypes, each with a unique pharmacology and distribution, but there are species variants of 5HT receptors. In order to provide a concise and timely review, this article focuses on the strategies used to clone and express multiple 5HT receptors. Unique properties of the various receptors are emphasized.

Language of Publication

English

Unique Identifier

95007802

MeSH Heading (Major)

Receptors, Serotonin|*BI/CH

MeSH Heading

Amino Acid Sequence; Animal; Cloning, Molecular; Human; Molecular Sequence Data

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0892-0915

Country of Publication

UNITED STATES

Record 58 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

Turning point in the design of linkage studies of schizophrenia.

Author

Cloninger CR

Address

Department of Psychiatry, Washington University Medical School, St. Louis, Missouri 63110.

Source

Am J Med Genet, 1994 Jun, 54:2, 83-92

Abstract

Despite extensive genomic scans, linkage studies of multiplex pedigrees have been unable to produce replicable evidence of genes predisposing to schizophrenia. This indicates that it is unlikely that a single gene accounts for a majority of cases of schizophrenia, even in multiplex pedigrees. It is most likely that schizophrenia is caused by the nonlinear interaction of multiple genetic and environmental factors influencing brain development and function. This conclusion has strong implications for the design of linkage and association studies. Recently designed linkage studies involve several improvements to deal with extensive locus heterogeneity and multiplicative interaction. These improvements include much larger samples of pedigrees, systematic ascertainment and sequential extension rules, and standardized procedures at multiple sites to facilitate collaboration and replication. Future improvements are likely to require advances in the assessment of clinical and neurobiological variability in multiplex pedigrees, more systematic environmental assessment, and advances in analytic methods to deal with multiplicative interaction. Rather than focusing only on schizophrenia as one or more discrete disorders, future linkage efforts should also consider the etiology of individual clinical syndromes or dimensional components of risk that interact to cause the complex pattern of syndromal comorbidity observed within schizophrenics and their families.

Language of Publication

English

Unique Identifier

94354247

MeSH Heading (Major)

Linkage (Genetics)|*; Schizophrenia|*GE

MeSH Heading

Chromosome Mapping; Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0148-7299

Country of Publication

UNITED STATES

Record 59 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

Analysis of the molecular basis of neuropathogenesis of RNA viruses in experimental animals: relevance for human disease?

Author

Atkins GJ; Balluz IM; Glasgow GM; Mabruk MJ; Natale VA; Smyth JM; Sheahan BJ

Address

Department of Microbiology, Moyne Institute, Trinity College, Dublin, Ireland.

Source

Neuropathol Appl Neurobiol, 1994 Apr, 20:2, 91-102

Abstract

RNA viruses with segmented genomes were the first model used for molecular analysis of viral neuropathogenesis, since they could be analysed genetically by reassortment. Four viruses with non-segmented genomes have been used as models of neurovirulence and demyelinating disease: JHM coronavirus, Theiler's virus, Sindbis virus and Semliki Forest virus (SFV). Virus gene expression in the central nervous system of infected animals has been measured by in situ hybridization and immunocytochemistry. Cell tropism has been analysed by neural cell culture. Infectious clones have been constructed for Theiler's virus, Sindbis virus and SFV, and these allow analysis of the sequences involved in the determination of neuropathogenesis, through the construction of chimeric viruses and site-specific mutagenesis. Measles and rubella viruses have been studied in animal systems because of their importance for human disease. The importance of two recently discovered mechanisms of neuropathogenesis, antibody-induced modulation of virus multiplication, and persistence of virus in the absence of multiplication, remains to be assessed.

Language of Publication

English

Unique Identifier

94352554

MeSH Heading (Major)

Nervous System Diseases|*MI/PA; RNA Viruses|*; Virus Diseases|*MI/PA

MeSH Heading

Animal; Human; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0305-1846

Country of Publication

ENGLAND

Record 60 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

Antiviral drugs: present status and future prospects.

Author

van der Sijs IH; Wiltink EH

Address

Academic Medical Centre, Department of Pharmacy, Amsterdam, The Netherlands.

Source

Int J Biochem, 1994 May, 26:5, 621-30

Abstract

1. There is a limited number of antiviral drugs available for therapy. Many investigations and new analytical techniques have unraveled the development and progression of a viral infection. Nowadays there is a good understanding of the multiplication cycle of viruses, including the human immunodeficiency virus. 2. In this article the currently available antiviral drugs are presented arranged by their mode of action that can be understood by the multiplication cycle of the virus. 3. Clinical use and side-effects are discussed as well as place in current therapy. Some attention is paid on promising investigational antivirals.

Language of Publication

English

Unique Identifier

94273928

MeSH Heading (Major)

Antiviral Agents|*/AE/PD/SD/TU

MeSH Heading

Drugs, Investigational; Human; Viral Proteins|BI; Virus Diseases|DT/IM; Viruses|DE/GD/GE

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0020-711X

Country of Publication

ENGLAND

Record 61 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

Culpability and pain management/control in peripheral vascular disease using the ethics of principles and care.

Author

Omery A

Address

 

Source

Crit Care Nurs Clin North Am, 1991 Sep, 3:3, 551-8

Abstract

The purposes of this article were to provide insight into the process of ethics and ethical inquiry and to explore the ethical issues of culpability and pain management/control. Critical care nurses who currently care for vascular patients identified these issues as occurring frequently in their practice. Authors in critical care nursing generally have limited the process of ethical inquiry to a theoretical framework built around an ethic of principles. The message many critical care nurses heard was that this one type of theoretical ethical framework was the totality of ethics. The application of these principles was ethical inquiry. For some nurses, the ethic of principles is sufficient. For others, an ethic of principles is either incomplete or foreign. This second group of nurses may believe that they have no moral voice if the language of ethics is only the language of principles. The language of principles, however, is not the only theoretical framework available. There is also the ethic of care, and ethical inquiry can include the application of that framework. Indeed, the language of the ethic of care may give a voice to nurses who previously felt morally mute. In fact, these two theoretical frameworks are not the only frameworks available to nurses. There is also virtue ethics, a framework not discussed in this article. A multiplicity of ethical frameworks is available for nurses to use in analyzing their professional and personal dilemmas. Recognizing that multiplicity, nurses can analyze their ethical dilemmas more comprehensively and effectively. Applying differing ethical frameworks can result in the same conclusions. This was the case for the issue of culpability.(ABSTRACT TRUNCATED AT 250 WORDS)

Language of Publication

English

Unique Identifier

91354617

MeSH Heading (Major)

Ethics, Nursing|*; Pain|DT/ET/*NU; Vascular Diseases|*CO/EP

MeSH Heading

Attitude of Health Personnel; Critical Care; Guilt; Human; Life Style; Nursing Staff, Hospital|PX

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0899-5885

Country of Publication

UNITED STATES

Record 62 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

Biologic synergism and parallelism.

Author

Darroch J

Address

Department of Mathematics and Statistics, Faculty of Science and Engineering, Flinders University of South Australia.

Source

Am J Epidemiol, 1997 Apr, 145:7, 661-8

Abstract

In epidemiologic studies of two binary exposure factors, much attention has been given to the concept of synergism of the factors. The leading dictionary of epidemiology offers two definitions of synergism, one of which this author labels statistical and the other biologic. The epidemiologic literature has been largely concerned with statistical synergism, which is typically measured using additive or multiplicative interaction. This paper focuses on biologic synergism, on the related concept of biologic parallelism, and on the question of how much information can be gleaned about population amounts of biologic synergism and parallelism--information which is of vital interest to epidemiologists. A fundamental identity equates the difference between the amounts of biologic synergism and parallelism to the additive interaction. Two biologic models, the multistage model and the no-hit or immunity model, enhance the interpretation of multiplicative interaction as a measure of statistical synergism, but it is pointed out here that, unfortunately, both models incorporate the strong assumption that there is no parallelism. A third model, the single-hit or vulnerability model, makes the even stronger assumption that there is no biologic synergism and consequently that the additive interaction is equal to minus the amount of parallelism. A consequence of this fact is that a link which has been perceived in the literature to exist between the single-hit model and the additive interaction is false.

Language of Publication

English

Unique Identifier

97252726

MeSH Heading (Major)

Epidemiologic Methods|*

MeSH Heading

Epidemiology|CL/SN; Human; Models, Biological; Nomenclature

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0002-9262

Country of Publication

UNITED STATES

Record 63 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

A multifactorial approach to the study of gender characteristics.

Author

Koestner R; Aube J

Address

Department of Psychology, McGill University, Montreal, Quebec, Canada.

Source

J Pers, 1995 Sep, 63:3, 681-710

Abstract

The present article reviews some of the central conceptual issues confronted by gender researchers as they have tried to forge a theory of gender identity that can account for the complexity and diversity of gender-related characteristics displayed by women and men. An emerging consensus suggests that gender is incorporated into an individual's self-concept in multiple and loosely connected ways. We review one example of this emerging multiplicity perspective, Spence's (1993) multifactorial gender identity theory, and describe three recent studies testing its usefulness. We also discuss ways in which multiplicity models of gender could benefit from considering parallel developments in the general personality literature regarding the problem of levels or domains. In particular, it is argued that McAdams's (this issue) integrative three-level model of the structure of personality offers a helpful framework for guiding future test construction and theory development in gender research.

Language of Publication

English

Unique Identifier

96029000

MeSH Heading (Major)

Gender Identity|*; Personality Development|*; Psychosexual Development|*

MeSH Heading

Adolescence; Adult; Child; Child, Preschool; Female; Follow-Up Studies; Human; Individuality; Male; Personality Assessment; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0022-3506

Country of Publication

UNITED STATES

Record 64 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

Cell types involved in replication and distribution of human cytomegalovirus.

Author

Plachter B; Sinzger C; Jahn G

Address

Institut fÂur Klinische und Molekulare Virologie, UniversitÂat Erlangen-NÂurnberg, Germany.

Source

Adv Virus Res, 1996, 46:, 195-261

Abstract

As the number of patients suffering from severe HCMV infections has steadily increased, there is a growing need to understand the molecular mechanisms by which the virus causes disease. The factors that control infection at one time and the events leading to virus multiplication at another time are only beginning to be understood. The interaction of HCMV with different host cells is one key for elucidating these processes. Through modern techniques, much has been learned about the biology of HCMV infections in culture systems. In addition to endothelial cells, epithelial cells, and smooth muscle cells, fibroblasts are one cell population preferentially infected in solid tissues in vivo. From these sites of multiplication, the virus may be carried by peripheral monocytes and circulating endothelial cells to reach distant sites of the body. This would explain the multiorgan involvement in acute HCMV infection and the modes of viral transmission. From what has been learned mainly from human fibroblast culture systems, future studies will focus on how HCMV regulates the expression of its putative 200 genes in different host cells at different stages of cell differentiation and activation to result in viral latency and pathogenesis.

Language of Publication

English

Unique Identifier

96422084

MeSH Heading (Major)

Cytomegalovirus|GE/*PH; Virus Replication|*PH

MeSH Heading

Acute Disease; Animal; Cells, Cultured; Cytomegalovirus Infections|ME; Human; Organizations; Species Specificity; Support, Non-U.S. Gov't; Tissue Distribution; Virus Latency

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0065-3527

Country of Publication

UNITED STATES

Record 65 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60f

Title

Interaction between human carcinogens.

Author

Kaldor JM; L'Abbé KA

Address

International Agency for Research on Cancer, Lyon, France.

Source

IARC Sci Publ, 1990, :104, 35-43

Abstract

In the absence of direct information on the carcinogenicity of a complex mixture, assessment of its risk requires not only knowledge of the risks due to the separate components, but also assumptions about the interaction between the components. A formal definition of interaction is given, followed by a discussion of the theoretical basis for different kinds of interactions. Epidemiological studies which have considered the simultaneous effect of two chemical carcinogens are reviewed, and shown to provide examples of additivity, multiplicativity and interaction both intermediate between the two and greater than multiplicative. Finally, implications for the risk assessment of mixtures are discussed.

Language of Publication

English

Unique Identifier

91034043

MeSH Heading (Major)

Carcinogens, Environmental|CH/*TO; Neoplasms|*CI

MeSH Heading

Drug Interactions; Human; Risk; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0300-5038

Country of Publication

FRANCE

CAS Registry/EC Number

0 (Carcinogens, Environmental)

Record 66 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

Risk ratios and risk differences in estimating the effect of risk factors for cardiovascular disease in the elderly.

Author

Psaty BM; Koepsell TD; Manolio TA; Longstreth WT Jr; Wagner EH; Wahl PW; Kronmal RA

Address

Department of Medicine, University of Washington, Seattle.

Source

J Clin Epidemiol, 1990, 43:9, 961-70

Abstract

This article reviews the nature of the effects of hypertension, smoking and cholesterol on the incidence of cardiovascular disease and emphasizes how these effects vary by age. In the Methods section, we discuss briefly the concepts of additive and multiplicative statistical models as tools for summarizing data. In the results section, we summarize available data on the association between incident stroke and coronary heart disease in the elderly and each of these major risk factors. The traditional multiplicative model parsimoniously characterizes the individual and joint effects of age and high blood pressure in terms of risk ratios; but, for smoking and cholesterol, an additive model appears to be the most parsimonious. We discuss the consequences of these observations for the study and prevention of cardiovascular disease in the elderly.

Language of Publication

English

Unique Identifier

91011495

MeSH Heading (Major)

Cardiovascular Diseases|*EP/ET; Models, Statistical|*

MeSH Heading

Adult; Aged; Data Interpretation, Statistical; Human; Middle Age; Odds Ratio; Risk Factors; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0895-4356

Country of Publication

ENGLAND

Record 67 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

Genetics of coeliac disease.

Author

Houlston RS; Ford D

Address

Section of Epidemiology, Institute of Cancer Research, Sutton, UK.

Source

QJM, 1996 Oct, 89:10, 737-43

Abstract

Coeliac disease is one of the most common gastrointestinal disorders. The clinical features of the disease are protean, possibly due to heterogeneity. A familial basis for coeliac disease is well recognized, and although a strong HLA association is seen, this cannot entirely account for the increased risk seen in relatives of affected cases. A gene (or genes) at an HLA-unlinked locus also participates in causing coeliac disease and is likely to be a stronger determinant of disease susceptibility than the HLA locus. Such a gene (or genes) could theoretically act either additively or multiplicatively in conjunction with HLA. However, the familial risks seen in siblings and monozygotic twins are most parsimonious with a multiplicative model. Without evidence for a particular HLA-unlinked gene, and because no genetic model can be reliably ascribed to the non-HLA-linked locus, identifying causative non-linked HLA genes is likely to be through a genome-wide linkage search using non-parametric methods.

Language of Publication

English

Unique Identifier

97099660

MeSH Heading (Major)

Celiac Disease|*GE

MeSH Heading

Disease Susceptibility; Human; Linkage (Genetics); Major Histocompatibility Complex; Risk Factors

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

Country of Publication

ENGLAND

Record 68 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

Perspectives in antiviral chemotherapy.

Author

Huraux JM; Ingrand D; Agut H

Address

Groupe Hospitalier Pitié-Salpêtrière, Laboratoire de Bactériologie-Virologie, Paris, France.

Source

Fundam Clin Pharmacol, 1990, 4:4, 357-72

Abstract

The current progress in antiviral therapy is related to our better understanding of the viral multiplication, with potential targets for specific antiviral action at each step of the multiplication cycle inside the infected cell. Amantadine and Rimantadine are anti-influenza A drugs interfering with the penetration and the release of the virus. Most of the other antiviral drugs which are clinically available have the same target in common, namely the viral DNA polymerase. This holds true for modified nucleosides such as Acycloguanosine (Acyclovir), DHPG, Adenine-Arabinoside, Azidothymidine as well as pyrophosphate derivatives such as phosphonoformic acid. Unfortunately the antiviral chemotherapy must confront 3 obstacles: 1) a possible interference with the normal cellular metabolism, leading to residual cytotoxic side effects; 2) the genetic variability of the viruses, producing drug-resistant mutants and 3) the inability of any antiviral chemotherapeutic agent known to date to eradicate latent viral infection. A new approach of the control of latent infection is suggested with anti sense oligonucleotides of hybridons.

Language of Publication

English

Unique Identifier

91007566

MeSH Heading (Major)

Antiviral Agents|*TU; Virus Diseases|*DT/MI

MeSH Heading

Animal; Human

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0767-3981

Country of Publication

FRANCE

CAS Registry/EC Number

0 (Antiviral Agents)

Record 69 from database: MEDLINE
Return To The Top
Return To Menu Item 40
Return To Menu Item 60

Title

Approaches to interferon combination therapy in the treatment of AIDS.

Author

Krown SE

Address

Memorial Sloan-Kettering Cancer Center, New York, NY 10021.

Source

Semin Oncol, 1990 Feb, 17:1 Suppl 1, 11-5; discussion 38-41

Abstract

High-dose interferon alfa (IFN alfa) therapy induces an overall response rate of 25% to 30% in unselected patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma. Up to 50% of patients with relatively preserved immune reactivity respond to treatment. However, when dosages of 20 x 10(6) units or more per day are used to induce responses, constitutional and hematologic side effects may be significant. Therefore, efforts are being made to lower the effective dose of IFN alfa. One effort involves combining IFN alfa with zidovudine (AZT; Retrovir; Burroughs Wellcome, Research Triangle Park, NC). These agents act synergistically to block the multiplication of human immunodeficiency virus (HIV) in vitro. The drugs act at different points in the HIV multiplication cycle, which may explain their synergistic interaction. In addition, AZT enhances certain immune functions that have been correlated with a positive IFN alfa response. Preliminary clinical trials indicate that antitumor responses in Kaposi's sarcoma are seen with dosages of IFN alfa as low as 4.5 x 10(6) units per day when combined with AZT. However, the combination of IFN alfa and AZT may also produce dose-limiting hematologic side effects; these effects may limit the usefulness of the drug combination. Strategies for ameliorating these toxicities through the use of additional agents are discussed.

Language of Publication

English

Unique Identifier

90140742

MeSH Heading (Major)

Acquired Immunodeficiency Syndrome|*TH; Interferon Alfa, Recombinant|AE/*TU

MeSH Heading

Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination|MT; Human; Sarcoma, Kaposi's|TH; Skin Neoplasms|TH; Zidovudine|AE/TU

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0093-7754

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Interferon Alfa, Recombinant); 30516-87-1 (Zidovudine)

Record 70 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Adherence & colonization properties of Vibrio cholerae & diarrhoeagenic Escherichia coli.

Author

Ghose AC

Address

Department of Microbiology, Bose Institute, Calcutta.

Source

Indian J Med Res, 1996 Jul, 104:, 38-51

Abstract

Bacterial adherence to host cells is the initial key step towards colonization and establishment of infection within the host. The adherence process requires the participation of two components: an 'adhesin' (adherence or colonization factor) of bacteria and a 'receptor' on the host (eucaryotic) cell surface. Many bacteria express several distinct and alternative mechanisms of cell adherence depending on the environmental conditions and nature of the adhesins as well as receptors. Bacteria causing gastrointestinal infection need to penetrate the mucous layer before attaching themselves to epithelial and other absorptive cells in the intestine. This attachment is usually mediated by fimbriae or pilus structures although other cell surface components of bacteria may also take part in the process. Adherent bacteria colonize intestinal epithelium by multiplication and initiation of a series of biochemical reactions inside the target cell through signal transduction mechanisms (with or without the help of toxins). Alternatively, adherent bacteria induce extensive rearrangement of the cytoskeletal structure of the epithelial cell thereby making more intimate contact with the cell or even forcing their entry into it. This is followed by bacterial multiplication and intercellular spread leading to eventual death of the target cell. Available information on the adherence and colonization properties of V. cholerae and E. coli, the two important causative agents of gastrointestinal illness in man, is discussed and summarized in this article.

Language of Publication

English

Unique Identifier

96377684

MeSH Heading (Major)

Bacterial Adhesion|*; Diarrhea|*ET; Escherichia coli|*PY; Intestines|*MI; Vibrio cholerae|*PY

MeSH Heading

Animal; Human

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0971-5916

Country of Publication

INDIA

Record 71 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Recent advances in carrier-mediated hepatic uptake and biliary excretion of xenobiotics.

Author

Yamazaki M; Suzuki H; Sugiyama Y

Address

Department of Pharmacokinetics & Biopharmaceutics, Toho University School of Pharmaceutical Sciences, Chiba, Japan.

Source

Pharm Res, 1996 Apr, 13:4, 497-513

Abstract

PURPOSE. Besides renal excretion, hepatic metabolism and biliary excretion are the major pathways involved in the removal of xenobiotics. Recently, for many endogenous and exogenous compounds (including drugs), it has been reported that carrier-mediated transport contributes to hepatic uptake and/or biliary excretion. In particular, primary active transport mechanisms have been shown to be responsible for the biliary excretion of anticancer drugs, endogenous bile acids and organic anions including glutathione and glucuronic acid conjugates. Primary active excretion into bile means the positive removal of xenobiotics from the body, and this elimination process is now designated as "Phase III" (T. Ishikawa, Trends Biochem. Sci., 17, 1992) in the detoxification mechanisms for xenobiotics in addition to Phase I by P-450 and Phase II by conjugation. METHODS. The transporters, which have been called P-glycoprotein (MDR), multidrug resistance related protein (MRP) and GS-X pump and which are believed to be involved in the primary active pumping of xenobiotics from the cells, are now known as the ATP-binding cassette (ABC) transporters. In this review, we first describe the HMG-CoA reductase inhibitor, pravastatin, as a typical case of a carrier-mediated active transport system that contributes to the liver-specific distribution in the body. RESULTS. Regarding biliary excretion, we have summarized recent results suggesting the possible contribution of the ABC transporters to the biliary excretion of xenobiotics. We also focus on the multiplicities in both hepatic uptake and biliary excretion mechanisms. Analyzing these multiplicities in transport is necessary not only from a biochemical point of view, but also for our understanding of the physiological adaptability of the living body in terms of the removal (detoxification) of xenobiotics. CONCLUSIONS. Clarification of these transport mechanism may provide important information for studying the pharmacokinetics of new therapeutic drugs and furthermore, leads to the development of the drug delivery systems.

Language of Publication

English

Unique Identifier

96267491

MeSH Heading (Major)

Biliary Tract|*ME; Liver|*ME; Xenobiotics|*PK

MeSH Heading

Amino Acid Sequence; Animal; ABC Transporters|CH/GE; Base Sequence; Bile Acids and Salts|ME; Biological Transport, Active; Dose-Response Relationship, Drug; Drug Delivery Systems|TD; Drug Resistance, Multiple|GE; Enzyme Inhibitors|ME; Human; Hydroxymethylglutaryl CoA Reductases|AI; Molecular Sequence Data; P-Glycoprotein|PH; Pravastatin|ME; Rats

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0724-8741

Country of Publication

UNITED STATES

Record 72 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

The thyrotropin receptor.

Author

Kohn LD; Shimura H; Shimura Y; Hidaka A; Giuliani C; Napolitano G; Ohmori M; Laglia G; Saji M

Address

Laboratory of Biochemistry and Metabolism, National Institute of Diabetes, Digestive, and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892.

Source

Vitam Horm, 1995, 50:, 287-384

Abstract

This chapter has outlined the complex process required for thyroid growth and function. Both events are regulated by TSHR via a multiplicity of signals, with the aid of and requirement for a multiplicity of hormones that regulate the TSHR via receptor cross-talk: insulin, IGF-I, adrenergic receptors, and purinergic receptors. Cross-talk appears to regulate G-protein interactions or activities induced by TSH as well as TSHR gene expression. The TSHR structure and its mechanism of signal transduction is being rapidly unraveled in several laboratories, since the recent cloning of the receptor. In addition, the epitopes for autoantibodies against the receptor that can subvert the normal regulated synthesis and secretion of thyroid hormones, causing hyper- or hypofunction, have been defined. Studies of regulation of the TSHR minimal promotor have uncovered a better understanding of the mechanisms by which TSH regulates both growth and function of the thyroid cell. A key novel component of this phenomenon involves TSH AMP positive and negative regulation of the TSHR. Negative transcriptional regulation is a common feature of MHC class I genes in the thyroid. Subversion of negative regulation or too little negative regulation is suggested to result in autoimmune disease. Methimazole and iodide at autoregulatory levels may be important in reversing this process and returning thyroid function to normal. Their action appears to involve factors that react with the IREs on both the TSHR and the TG promoter. Too much negative regulation, as in the case of ras transformation, results in abnormal growth without function. TTF-1 is implicated as a critical autoregulatory component in both positive and negative regulation of the TSHR and appears to be the link between TSH, the TSHR, TSHR-mediated signals, TG and TPO biosynthesis, and thyroid hormone formation. Differentially regulated expression of the TSHR and TG by cAMP and insulin depend on differences in the specificity of the TTF-1 site, that is, the lack of Pax-8 interactions with the TSHR, and the IRE sites. Single-strand binding proteins will become important in determining how TSHR transcription is controlled mechanistically.

Language of Publication

English

Unique Identifier

95224946

MeSH Heading (Major)

Receptors, Thyrotropin|CH/GE/*PH

MeSH Heading

Amino Acid Sequence; Animal; Base Sequence; Human; Molecular Sequence Data; Molecular Structure; Protein Conformation

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0083-6729

Country of Publication

UNITED STATES

Record 73 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Nontraditional epidemiologic approaches in the analysis of gene-environment interaction: case-control studies with no controls!

Author

Khoury MJ; Flanders WD

Address

Division of Birth Defects and Developmental Disabilities, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA 30341-3724, USA.

Source

Am J Epidemiol, 1996 Aug, 144:3, 207-13

Abstract

Although case-control studies are suitable for assessing gene-environment interactions, choosing appropriate control subjects is a valid concern in these studies. The authors review three nontraditional study designs that do not include a control group: 1) the case-only study, 2) the case-parental control study, and 3) the affected relative-pair method. In case-only studies, one can examine the association between an exposure and a genotype among case subjects only. Odds ratios are interpreted as a synergy index on a multiplicative scale, with independence assumed between the exposure and the genotype. In case-parental control studies, one can compare the genotypic distribution of case subjects with the expected distribution based on parental genotypes when there is no association between genotype and disease; the effect of a genotype can be stratified according to case subjects' exposure status. In affected relative-pair studies, the distribution of alleles identical by descent between pairs of affected relatives is compared with the expected distribution based on the absence of genetic linkage between the locus and the disease; the analysis can be stratified according to exposure status. Some or all of these methods have certain limitations, including linkage disequilibrium, confounding, assumptions of Mendelian transmission, an inability to measure exposure effects directly, and the use of a multiplicative scale to test for interaction. Nevertheless, they provide important tools to assess gene-environment interaction in disease etiology.

Language of Publication

English

Unique Identifier

96302140

MeSH Heading (Major)

Environmental Illness|*EP/GE

MeSH Heading

Case-Control Studies; Epidemiology, Molecular|MT/SN; Female; Genotype; Human; Male; Odds Ratio

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0002-9262

Country of Publication

UNITED STATES

Record 74 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Molecular aspects of insulin-like growth factors, their binding proteins and receptors.

Author

Roberts CT Jr; Leroith D

Address

 

Source

Baillieres Clin Endocrinol Metab, 1988 Nov, 2:4, 1069-85

Abstract

As we have tried to illustrate in the preceding brief review of some of the current research on the molecular biology of the IGF system, the physiological function of these important and pluripotent molecules will undoubtedly prove to be extraordinarily complex. This prediction is based upon the extensive heterogeneity of the IGF-I and IGF-II ligands themselves, the multiplicity of BPs which may influence IGF action either positively or negatively at numerous levels, and the ability of these hormones/growth factors (and possibly their BPs) to interact with disparate receptor moieties, both singly and in concert, in order to elicit their various effects.

Language of Publication

English

Unique Identifier

90026114

MeSH Heading (Major)

Receptors, Cell Surface|*GE; Somatomedins|*GE

MeSH Heading

Amino Acid Sequence; Animal; DNA|GE; Gene Expression; Human; Insulin-Like Growth Factor I|GE; Insulin-Like Growth Factor II|GE; Molecular Sequence Data

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0950-351X

Country of Publication

ENGLAND

CAS Registry/EC Number

0 (Receptors, Cell Surface); 0 (Receptors, Somatomedin); 0 (Somatomedins); 67763-96-6 (Insulin-Like Growth Factor I); 67763-97-7 (Insulin-Like Growth Factor II); 9007-49-2 (DNA)

Record 75 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Platelet-derived growth factor: a multifunctional regulator of normal and abnormal cell growth.

Author

Deuel TF; Silverman NJ; Kawahara RS

Address

Department of Medicine and Biological Chemistry, Jewish Hospital, Washington University Medical Center, St Louis, MO 63110.

Source

Biofactors, 1988 Oct, 1:3, 213-7

Abstract

Polypeptide growth factors, which are synthesized and secreted both by normal and transformed cells, have a multiplicity of roles in normal and abnormal cell growth. Platelet-derived growth factor (PDGF) is nearly identical to the transforming gene (oncogene) product of simian sarcoma virus p28v-sis. Binding of PDGF to high-affinity cell surface PDGF receptors stimulates the intrinsic autophosphorylating protein tyrosine kinase activity of these receptors and sets off a cascade of metabolic events. Among these events are induction of otherwise quiescent genes which regulate synthesis of transcriptional factors and thus are critical in cell division, differentiation and development.

Language of Publication

English

Unique Identifier

89374668

MeSH Heading (Major)

Platelet-Derived Growth Factor|AN/GE/*PH

MeSH Heading

Animal; Base Sequence; Blood Platelets|AN; Cell Division; Cell Line, Transformed; Gene Expression Regulation; Hamsters; Human; Receptors, Cell Surface|GE/PH; Sequence Homology, Nucleic Acid

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0951-6433

Country of Publication

ENGLAND

CAS Registry/EC Number

0 (Platelet-Derived Growth Factor); 0 (Receptors, Cell Surface); 0 (Receptors, Platelet-Derived Growth Factor)

Record 76 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Biology and molecular biology of epidermal cell-derived thymocyte activating factor.

Author

Sauder DN; Arsenault T; McKenzie RC; Stetsko DK; Harley CB

Address

Department of Medicine, McMaster University Medical Centre, Hamilton, Ontario, Canada.

Source

Ann N Y Acad Sci, 1988, 548:, 241-52

Abstract

ETAF/IL-1 has a multiplicity of divergent biological effects: enhancement of thymocyte proliferation, stimulation of cells in the hypothalamus to mediate fever, leukocyte chemotaxis, stimulation of hepatic synthesis of acute-phase proteins, augmentation of IL-2 production and keratinocyte proliferation. Until recently, it has not been possible to determine whether these divergent activities are mediated by closely related cytokines or separate cytokines. Now with the identification of IL-1 alpha, IL-1 beta and IL-1k from keratinocytes, these studies will become possible. In either case, it is likely that ETAF/IL-1 plays an important role in local cutaneous and systemic inflammatory and immunological events.

Language of Publication

English

Unique Identifier

89245661

MeSH Heading (Major)

Interleukin-1|GE/ME/*PH

MeSH Heading

Animal; Base Sequence; Cloning, Molecular; DNA|GE; Human; Immune System|PH; Inflammation|ET; Lymphoma|ME; Oligonucleotide Probes; Receptors, Cell Surface|ME; Receptors, Immunologic|ME; Skin Neoplasms|ME; Support, Non-U.S. Gov't; T-Lymphocytes|LYMPHOCYTES J

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0077-8923

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Interleukin-1); 0 (Oligonucleotide Probes); 0 (Receptors, Cell Surface); 0 (Receptors, Immunologic); 0 (Receptors, Interleukin-1); 9007-49-2 (DNA)

Record 77 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Should we expand the TORCH complex? A description of clinical and diagnostic aspects of selected old and new agents.

Author

Kinney JS; Kumar ML

Address

Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland.

Source

Clin Perinatol, 1988 Dec, 15:4, 727-44

Abstract

Physicians faced with a newborn infant with signs and symptoms of perinatal infection must consider a multitude of diseases, and may need to embark on a complex differential diagnosis. As stated by Alford in 1967, "neonatal diagnoses of infections acquired in utero, natally and postnatally, are inherently difficult." Twenty years later, this statement is still true. In this review, the diagnostic problems encountered in the evaluation of a suspected perinatal infection have been discussed, as have the complexities of the evaluation process for the original four TORCH agents, as well as for three additional agents. From our point of view, the usefulness of the TORCH acronym has been to focus attention on perinatal infections. Its main drawback has been the resultant overuse of TORCH titers ignoring the complexity of the diagnostic process. Ideally, the TORCH concept serves two functions. It continues to remind us of the multiplicity of pathogens that can cause perinatal infection, and it underscores the need for thorough diagnostic evaluation for these challenging infections. We believe that this is an appropriate expansion of the TORCH complex, and we anticipate that this expanded TORCH complex will continue to grow.

Language of Publication

English

Unique Identifier

89090352

MeSH Heading (Major)

Cytomegalovirus Infections|*CN; Herpes Simplex|*CN; Rubella|*DI; Rubella Syndrome, Congenital|*DI; Toxoplasmosis, Congenital|*DI

MeSH Heading

Acquired Immunodeficiency Syndrome|CN; Antibodies, Viral|AN; Diagnosis, Differential; Female; Herpesviridae Infections|CN; Herpesvirus 4, Human|IM; Human; Infant, Newborn; Parvoviridae Infections|CN; Pregnancy; Pregnancy Complications, Infectious|DI

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0095-5108

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Antibodies, Viral)

Record 78 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Treatment of persistent active herpesvirus infections.

Author

Straus SE

Address

Medical Virology Section, National Institutes of Allergy and Infectious Diseases, Bethesda, Maryland 20892.

Source

J Virol Methods, 1988 Sep, 21:1-4, 305-13

Abstract

All human herpesviruses cause chronic infections in which latent virus is periodically reactivated. Persistently active infections are uncommon, however, and occur exclusively in individuals whose immune systems fail to control virus multiplication and spread. This paper summarizes the management of these unusual infections.

Language of Publication

English

Unique Identifier

89034589

MeSH Heading (Major)

Antiviral Agents|*TU; Cytomegalovirus Infections|*DT; Herpes Simplex|*DT; Herpes Zoster|*DT; Herpesviridae Infections|*DT

MeSH Heading

Chronic Disease; Herpesvirus 4, Human|HERPESVIRUS HUMAN 04; Human; Recurrence

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0166-0934

Country of Publication

NETHERLANDS

CAS Registry/EC Number

0 (Antiviral Agents)

Record 79 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Thromboxane A2 and leukotrienes are eicosanoid mediators of shock and ischemic disorders.

Author

Lefer AM

Address

Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Phila., PA 19107.

Source

Prog Clin Biol Res, 1988, 264:, 101-14

Abstract

Several important eicosanoids are produced during ischemic and shock states that may mediate much of the pathogenesis of these disorders. The primary substances of interest are the thromboxanes (e.g., TxA2), and the peptide leukotrienes (e.g., LTC4 and LTD4). TxA2 and the peptide leukotrienes fulfill all the criteria for a mediator in ischemia and shock. They are potent agents that exhibit a multiplicity of serious pathogenic actions. Moreover, inhibition of the formation or actions of TxA2 and the LTs is salutary in shock. TxA2 and the peptide leukotrienes therefore should be considered as important mediators of ischemia and shock, and probably as potent mediators as any known humoral substances in shock.

Language of Publication

English

Unique Identifier

88248152

MeSH Heading (Major)

Ischemia|*PP; Leukotriene B4|*PH; Shock|*PP; SRS-A|*PH; Thromboxane A2|*PH

MeSH Heading

Animal; Fatty Acids|PH; Human

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0361-7742

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Fatty Acids); 0 (SRS-A); 57576-52-0 (Thromboxane A2); 71160-24-2 (Leukotriene B4)

Record 80 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

PDGF-like growth factors in autocrine stimulation of growth.

Author

Heldin CH; Westermark B

Address

Ludwig Institute for Cancer Research, Uppsala Branch, Sweden.

Source

J Cell Physiol Suppl, 1987, Suppl 5:, 31-4

Abstract

PDGF is a dimeric molecule consisting of A chains and B chains. All three dimeric combinations have been found in platelets, or produced by certain normal or transformed cell types; whether functional differences occur between different dimers is currently under investigation. Production of PDGF-like factors by cells carrying PDGF receptors may establish an autocrine loop, driving cell multiplication.

Language of Publication

English

Unique Identifier

88059283

MeSH Heading (Major)

Cell Division|*DE; Platelet-Derived Growth Factor|GE/*PD

MeSH Heading

Cell Transformation, Neoplastic|DE; Cell Transformation, Viral|DE; Gene Expression Regulation; Human; Mitosis|DE; Sarcoma Viruses, Simian|GE; Structure-Activity Relationship; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0737-1462

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Platelet-Derived Growth Factor)

Record 81 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

The heart in hypertension: unresolved conceptual challenges. Special lecture.

Author

Frohlich ED

Address

Alton Ochsner Medical Foundation, New Orleans, LA 70121.

Source

Hypertension, 1988 Feb, 11:2 Pt 2, I19-24

Abstract

Much has been learned over the past 25 years concerning the role of the heart in hypertension. In a multiplicity of areas a great deal has been clarified but a number of issues remain unresolved. This personal overview outlines some of these challenging areas for investigation, including questions relating to the cardiogenic reflexes, mechanisms underlying total body autoregulation that may involve not only the adaptation of arterioles but also venoconstriction in hypertension, postcapillary constriction also involving the efferent glomerular arterioles, the mechanisms underlying the development and regression of hypertrophy as well as the function of the hypertrophied and "regressed hypertrophy" heart, and the precise hemodynamic actions of atrial natriuretic factor.

Language of Publication

English

Unique Identifier

88152969

MeSH Heading (Major)

Heart|*PP; Hemodynamics|*; Hypertension|CO/*PP

MeSH Heading

Atrial Natriuretic Factor|PH; Heart Hypertrophy|ET; Human; Vascular Resistance

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0194-911X

Country of Publication

UNITED STATES

CAS Registry/EC Number

85637-73-6 (Atrial Natriuretic Factor)

Record 82 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Function of dietary polyunsaturated fatty acids in the nervous system.

Author

Bourre JM; Bonneil M; Clément M; Dumont O; Durand G; Lafont H; Nalbone G; Piciotti M

Address

INSERM Unité 26, Hôpital Fernand Widal, Paris, France.

Source

Prostaglandins Leukot Essent Fatty Acids, 1993 Jan, 48:1, 5-15

Abstract

The brain is the organ with the second greatest concentration of lipids; they are directly involved in the functioning of membranes. Brain development is genetically programmed; it is therefore necessary to ensure that nerve cells receive an adequate supply of lipids during their differentiation and multiplication. Indeed the effects of polyunsaturated fatty acid (PUFA) deficiency have been extensively studied; prolonged deficiency leads to death in animals. Linoleic acid (LA) is now universally recognized to be an essential nutrient. On the other hand, alpha-linolenic acid (ALNA) was considered non-essential until recently, and its role needs further studies. In our experiments, feeding animals with oils that have a low alpha-linolenic content results in all brain cells and organelles and various organs in reduced amounts of 22:6(n-3), compensated by an increase in 22:5(n-6). The speed of recuperation from these anomalies is extremely slow for brain cells, organelles and microvessels, in contrast with other organs. A decrease in alpha-linolenic series acids in the membranes results in a 40% reduction in the Na-K-ATPase of nerve terminals and a 20% reduction in 5'-nucleotidase. Some other enzymatic activities are not affected, although membrane fluidity is altered. A diet low in ALNA induces alterations in the electroretinogram which disappear with age: motor function and activity are little affected but learning behaviour is markedly altered. The presence of ALNA in the diet confers a greater resistance to certain neurotoxic agents, i.e. triethyl-lead. We have shown that during the period of cerebral development, there is a linear relationship between brain content of (n-3) acids and the (n-3) content of the diet up to the point where alpha-linolenic levels reach 200 mg for 100 g food intake. Beyond that level there is a plateau. For the other organs, such as the liver, the relationship is also linear up to 200 mg/100 g, but then there is merely an abrupt change in slope and not a plateau. By varying the dietary 18:2(n-6) content, it was noted that 20:4(n-6) optimum values were obtained at 150 mg/100 g for all nerve structures, at 300 mg for testicle and muscle, 800 mg for the kidney, and 1200 mg for the liver, lung and heart. A deficiency in ALNA or an excess of LA has the same main effect: an increase in 22:5(n-6) levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Language of Publication

English

Unique Identifier

93141651

MeSH Heading (Major)

Dietary Fats|*/AD/PD; Fatty Acids, Unsaturated|AD/PD/*PH; Nervous System|EM/*PH

MeSH Heading

Animal; Brain Chemistry; Cells, Cultured; Fatty Acid Desaturases|ME; Fish Oils|AD/PD; Human; Linolenic Acids|AD/PD/PH; Lipid Peroxidation; Liver|ME; Membrane Lipids|PH; Nutritional Requirements; Rats; Signal Transduction; Species Specificity; Vitamin E|ME

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0952-3278

Country of Publication

SCOTLAND

CAS Registry/EC Number

EC 1.14.99.- (Fatty Acid Desaturases); EC 1.14.99.25 (linoleoyl-CoA desaturase); 0 (Dietary Fats); 0 (Fatty Acids, Unsaturated); 0 (Fish Oils); 0 (Linolenic Acids); 0 (Membrane Lipids); 1406-18-4 (Vitamin E); 463-40-1 (alpha-Linolenic Acid)

Record 83 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

The complexity of dopamine receptors and psychopharmacotherapy in children.

Author

Guérin P; Barthélémy C; Garreau B; Héraut J; Muh JP; Lelord G

Address

Département de Psychopathologie de l'Enfant et de Neurophysiologie du Développement, INSERM U316-CHU Bretonneau, Tours, France.

Source

Acta Paedopsychiatr, 1993, 56:2, 139-51

Abstract

The efficacy of dopaminergic antagonists, which are neuroleptics, has been shown in children in varied clinical situations. Five dopaminergic receptors (D1, D2, D3, D4, D5) have thus far been cloned: their existence has thus been confirmed, but their functional significance remains to be determined. This publication reviews their main characteristics. The multiplicity of cerebral dopamine receptors is consistent with the future development of new, more selective and discriminating psychotropic drugs. The diversity of interactions of dopaminergic receptors, among themselves and with receptors for other neurotransmitters, however, explains the difficulty in understanding the mechanism of action of neuroleptics and defining their more rational use in children.

Language of Publication

English

Unique Identifier

94182450

MeSH Heading (Major)

Antipsychotic Agents|*PD; Brain|DE/ME/*PP; Developmental Disabilities|ME/*PP; Receptors, Dopamine|*DE/PH

MeSH Heading

Adolescence; Binding Sites; Cell Communication|DE; Child; Child, Preschool; Dopamine|ME; DNA-Binding Protein, Cyclic AMP-Responsive|PH; Female; Guanosine Triphosphate|ME; Human; Male; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0936-7012

Country of Publication

GERMANY

CAS Registry/EC Number

0 (Antipsychotic Agents); 0 (DNA-Binding Protein, Cyclic AMP-Responsive); 0 (Receptors, Dopamine); 51-61-6 (Dopamine); 86-01-1 (Guanosine Triphosphate)

Record 84 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Mx proteins: GTPases involved in the interferon-induced antiviral state.

Author

Pavlovic J; Schröder A; Blank A; Pitossi F; Staeheli P

Address

Department of Virology, University of Freiburg, Germany.

Source

Ciba Found Symp, 1993, 176:, 233-43; discussion 243-7

Abstract

Mx proteins have molecular masses between 70 and 80 kDa and their synthesis is tightly regulated by interferons in mammalian and non-mammalian vertebrates. Some Mx proteins function as intracellular mediators of the interferon-induced antiviral state. When suitable cDNA constructs were constitutively expressed in mouse 3T3 cells the mouse nuclear Mx1 protein conferred selective resistance to influenza virus. The human cytoplasmic MxA protein conferred resistance to influenza virus and vesicular stomatitis virus but not to other viruses. Mx1 blocks influenza virus mRNA synthesis within the nucleus of infected cells. Mx1 presumably interacts with the influenza virus polymerase subunit PB2, because overexpression of PB2 titrates out the Mx1 block. MxA does not inhibit mRNA synthesis of influenza virus; it inhibits a subsequent cytoplasmic viral multiplication step. A possible target is the transport of newly synthesized influenza virus polymerase proteins back to the nucleus. Inhibition by MxA of vesicular stomatitis virus, which replicates in the cytoplasm, is at the transcriptional level. Parts of the N-terminal halves of all known Mx proteins are highly conserved. They contain the typical GTP-binding motif and show significant homology to other members of a new family of GTPases that includes rat dynamin, Drosophila Shibire and the yeast proteins Vps1/Spo15 and Mgm1. Purified Mx1 and MxA proteins possess GTPase activity. The GTP/GDP conversion rates are about 40 per min, and Km values about 700 microM. Mx1 and MxA variants with mutations in the GTP-binding sequences that violate the consensus are unable to confer virus resistance in vivo or to hydrolyse GTP in vitro, suggesting that GTPase activity is necessary for antiviral activity of Mx proteins. We hypothesize that the antivirally active Mx proteins (directly or indirectly) bind to polymerase proteins of susceptible viruses, thereby abolishing normal viral polymerase function. Interaction of Mx with viral targets is probably a GTP-dependent process.

Language of Publication

English

Unique Identifier

94130612

MeSH Heading (Major)

G-Proteins|*PH; GTP Phosphohydrolase|*PH; Interferons|*PD; Proteins|*PH

MeSH Heading

Amino Acid Sequence; Animal; Human; Molecular Sequence Data; Molecular Structure; Orthomyxoviridae|GD; Support, Non-U.S. Gov't; Viral Proteins|ME

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0300-5208

Country of Publication

NETHERLANDS

CAS Registry/EC Number

EC 3.6.1.- (GTP Phosphohydrolase); 0 (protein Mx); 0 (protein PB-2, viral); 0 (G-Proteins); 0 (Proteins); 0 (Viral Proteins); 9008-11-1 (Interferons)

Record 85 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

T cell adhesion, avidity regulation and signaling: a molecular analysis of CD2.

Author

Bierer BE; Hahn WC

Address

Division of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.

Source

Semin Immunol, 1993 Aug, 5:4, 249-61

Abstract

While the T cell receptor (TcR) recognizes cell bound, peptide antigens embedded within major histocompatibility complex (MHC) proteins, this interaction is not sufficient for T cell activation and function. A number of other cell surface molecules, termed co-receptors or accessory molecules, cooperate with the TcR by participating in T cell adhesion to antigen presenting cells (APC) and/or by contributing to T cell signaling. In addition, recent evidence suggests that T cell activation can, in turn, increase the avidity of several of these co-receptors for their ligands. One such co-receptor molecule is CD2, a T cell glycoprotein that not only participates in T cell activation but also provides the T cell with a major adhesion pathway whose avidity is regulated by TcR triggering. Using both cellular and molecular biological approaches, we have mapped the portions of CD2 involved in CD2-dependent signaling and in the regulation of avidity for its ligand CD58 (lymphocyte function associated antigen-3, LFA-3) to structurally distinct portions of the cytoplasmic domain. This delineation of function has allowed us to analyze the contribution of co-receptor basal adhesion, signaling, and avidity regulation in antigen-dependent T cell interactions. The signal transduction pathways recruited for the regulation of CD2 avidity for its ligand differ from those used by other co-receptors such as LFA-1 and CD8 for their respective ligands. Taken together, the multiplicity of co-receptors, their interplay, and their differential regulation contribute to the control and the sensitivity of antigen-dependent immune responses.

Language of Publication

English

Unique Identifier

94033393

MeSH Heading (Major)

Antigens, Differentiation, T-Lymphocyte|CH/*PH; Lymphocyte Transformation|*; Receptors, Immunologic|CH/*PH; Signal Transduction|*; T-Lymphocytes|IM/*PH

MeSH Heading

Animal; Antigens, CD|ME; Cell Adhesion; Cytoskeleton|PH; Human; Membrane Glycoproteins|ME; Receptor-CD3 Complex, Antigen, T-Cell|PH; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

1044-5323

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Antigens, CD); 0 (Antigens, CD2); 0 (Antigens, CD58); 0 (Antigens, Differentiation, T-Lymphocyte); 0 (Membrane Glycoproteins); 0 (Receptor-CD3 Complex, Antigen, T-Cell); 0 (Receptors, Immunologic)

Record 86 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

The GABAA receptor channel mediated chloride ion translocation through the plasma membrane: new insights from 36Cl- ion flux measurements.

Author

Kardos J

Address

Department of Pharmacodynamics, Central Research Institute for Chemistry, Hungarian Academy of Sciences, Budapest.

Source

Synapse, 1993 Jan, 13:1, 74-93

Abstract

GABAA receptors in plasma membranes of neurons are integral oligomers which form chloride channels. The binding of GABA molecules at recognition sites for channel opening triggers a transient increase in transmembrane chloride ion flux. The multiplicity and drug specificity of GABAA receptor, kinetics of channel opening, and desensitization of GABAA receptor and its short- and long-term regulation have been investigated by the use of tracer amounts of the radioactive chloride isotope, 36Cl- ion. Results and new insights from 36Cl- ion flux measurements have been reviewed.

Language of Publication

English

Unique Identifier

93150470

MeSH Heading (Major)

Chlorides|*ME; Ion Channels|*PH; Neurons|*ME; Receptors, GABA-A|*PH

MeSH Heading

Animal; Cell Membrane|ME; Chlorine; Human; Radioisotopes; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0887-4476

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Chlorides); 0 (Ion Channels); 0 (Radioisotopes); 0 (Receptors, GABA-A); 7782-50-5 (Chlorine)

Record 87 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

The influence of chemical structure on the extent and sites of carcinogenesis for 522 rodent carcinogens and 55 different human carcinogen exposures.

Author

Ashby J; Paton D

Address

ICI Central Toxicological Laboratory, Macclesfield, Ches., UK.

Source

Mutat Res, 1993 Mar, 286:1, 3-74

Abstract

Gold and her colleagues have tabulated the results of rodent bioassays on 522 chemicals and have analysed the data. The present study complements those analyses by providing a perspective from the viewpoint of the chemical structure of the carcinogens. The chemical structure of each of the carcinogens is displayed and the Gold database is represented with the test agents as the primary variable. The carcinogens are gathered into six chemical classes and each chemical is assessed for structural alerts to DNA reactivity. The database is then analysed using an integration of the following parameters: bioassay in rat, mouse or both; structural alert status; chemical class; sites and multiplicity of carcinogenesis, and trans-species carcinogenicity. A series of Figures is presented that enables rapid acquaintance with what represents the core database of rodent carcinogenicity. The several analyses presented combine in endorsing the reality of two broad classes of rodent carcinogen--presumed DNA-reactive and others (putative genotoxic and non-genotoxic carcinogens, but semantics have been largely avoided). Vainio and his colleagues have tabulated 55 situations in which humans have succumbed to chemically induced cancer, and have listed the tissues affected. This database of human carcinogens has been analysed in the present study as done for the rodent carcinogen database, and comparisons made between the two. The predominance of putative genotoxic carcinogens in the human database was confirmed, as was the reality of putative non-genotoxic carcinogenicity in humans. It is concluded that putative genotoxic rodent carcinogenesis can be correlated both with chemical structure and the extent and nature of the induced effect, and that it is of clear relevance to humans. In contrast, it is concluded that putative non-genotoxic rodent carcinogenesis is more closely related to the test species than to the test chemical, and that it is essentially unpredictable in the absence of mechanistic models. In the absence of such models nongenotoxic carcinogenic effects should be extrapolated to humans with caution. Progress in the accurate prediction and extrapolation of rodent carcinogenicity will be helped by a common, if only temporary, enabling acceptance that not all carcinogens are intrinsically genotoxic.

Language of Publication

English

Unique Identifier

93149182

MeSH Heading (Major)

Carcinogens|*CH/TO; Muridae|*; Mutagens|*CH/*TO

MeSH Heading

Alkylating Agents|TO; Animal; Benzene|TO; Biological Assay; Carcinogenicity Tests; Databases, Factual; DNA|DE; Human; Hydrazines|TO; Mice; Molecular Structure; Mutagenicity Tests; Nitrosamines|TO; Organ Specificity; Rats; Salmonella typhimurium|DE/GE; Species Specificity; Structure-Activity Relationship

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0027-5107

Country of Publication

NETHERLANDS

CAS Registry/EC Number

0 (Alkylating Agents); 0 (Carcinogens); 0 (Hydrazines); 0 (Mutagens); 0 (Nitrosamines); 71-43-2 (Benzene); 9007-49-2 (DNA)

Record 88 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

GABA receptor molecules of insects.

Author

Anthony NM; Harrison JB; Sattelle DB

Address

AFRC Laboratory of Molecular Signalling, Department of Zoology, University of Cambridge, England.

Source

EXS, 1993, 63:, 172-209

Abstract

Receptors for 4-aminobutyric acid (GABA) have been identified in both central and peripheral nervous systems of several invertebrate phyla. To date, much of the information derived from physiological and biochemical studies on insect GABA receptors relates to GABA-gated chloride channels that show some similarities with vertebrate GABAA receptors. Like their vertebrate central nervous system (CNS) counterparts, agonist activation of such insect GABA receptors leads to a rapid, picrotoxin-sensitive increase in chloride ion conductance across the cell membrane. In insects, responses to GABA can be modulated by certain benzodiazepines and barbiturates. However, recent studies have detected a number of striking pharmacological differences between GABA-gated chloride channels of insects and vertebrates. Receptor binding, electrophysiological and 36Cl- flux assays have indicated that many insect receptors of this type are insensitive to the vertebrate GABAA antagonists bicuculline and pitrazepin. Benzodiazepine binding sites coupled to insect GABA receptors display a pharmacological profile distinct from that of corresponding sites in vertebrate CNS. Receptor binding studies have also demonstrated differences between convulsant binding sites of insect and vertebrate receptors. Insect GABA receptor molecules are important target sites for several chemically-distinct classes of insecticidally-active molecules. By characterizing these pharmacological properties in detail, it may prove possible to exploit differences between vertebrate and insect GABA receptors in the rational design of novel, more selective pest control agents. The recent application of the powerful techniques of molecular biology has revealed a diversity of vertebrate GABAA receptor subunits and their respective isoforms that can assemble in vivo to form a multiplicity of receptor subtypes. Molecular cloning of insect GABA receptor subunits will not only enhance our understanding of invertebrate neurotransmitter receptor diversity but will also permit the precise identification of the sites of action of pest control agents.

Language of Publication

English

Unique Identifier

93136645

MeSH Heading (Major)

Insects|*PH; Nervous System|*PH; Receptors, GABA-A|GE/ME/*PH

MeSH Heading

Amino Acid Sequence; Animal; Binding Sites; Comparative Study; Human; Ion Channels|PH; Membrane Proteins|PH; Molecular Sequence Data; Sequence Homology, Amino Acid; Vertebrates

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

Country of Publication

SWITZERLAND

CAS Registry/EC Number

0 (Chloride Channels); 0 (Ion Channels); 0 (Membrane Proteins); 0 (Receptors, GABA-A)

Record 89 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Non-P-glycoprotein multidrug resistance in cell lines which are defective in the cellular accumulation of drug.

Author

Center MS

Address

Division of Biology, Kansas State University, Manhattan 66506.

Source

Cytotechnology, 1993, 12:1-3, 109-25

Abstract

Non-Pgp mdr related to a defect in drug accumulation has now been documented in a number of different cell lines exposed to certain cytotoxic agents. In studies conducted thus far most isolates have been obtained after selection in either adriamycin or mitoxantrone. The work in this area is in its early stages and very little is known about the molecular events which contribute to this mode of drug resistance. At the present time no protein with drug binding properties comparable to Pgp has been identified in non-Pgp mdr isolates. Evidence based on the finding that all isolates do not respond in the same way to reversal agents such as verapamil suggests the possibility that more than one mechanism may exist for non-Pgp mdr. Future studies may thus reveal that cells contain a multiplicity of genes which upon transcriptional activation can function to alter drug transport processes and thus contribute to the development of mdr. Identifying and characterizing these genes will be important since they may function in transport systems of normal cells. The exact identify of proteins which contribute to non-Pgp mdr remains to be determined. One protein designated P190 has been found to be overexpressed in cell lines of human promyelocytic leukemia, lung and adenocarcinoma treated with adriamycin. The protein also is increased in some clinical samples from patients undergoing chemotherapy. P190 which has a minor sequence homology with Pgp can bind ATP and may thus contribute to the energy dependent drug efflux systems found in cells containing this protein. Transfection studies with a P190 cDNA should determine whether this protein actually contributes to drug resistance. Many other protein changes have been detected in non-Pgp mdr cells but the importance of these in resistance also remains to be determined. In some systems a particular protein change can be identified in multiple independent isolates suggesting a correlation between the development of resistance and the presence of this cellular alteration. Experiments conducted thus far on the mechanism of non-Pgp mdr are intriguing. Studies utilizing fluorescence microscopy to follow the fate of daunomycin suggests that the drug passes to the interior of the cell and eventually localizes in the Golgi apparatus. Drug located at this site may move directly into an efflux pathway for rapid extrusion from the cell. Evidence also indicates that as drug leaves the Golgi some may be sequestered into other organelles such as lysosomes or mitochondria.(ABSTRACT TRUNCATED AT 250 WORDS)

Language of Publication

English

Unique Identifier

94153635

MeSH Heading (Major)

Antineoplastic Agents|*TO; Carrier Proteins|GE/*ME; Drug Resistance|*PH; Membrane Glycoproteins|GE/*ME

MeSH Heading

Animal; Cell Line; Cell Survival|DE/PH; Human; Neoplasms|DT/ME; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Transfection; Tumor Cells, Cultured

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0920-9069

Country of Publication

NETHERLANDS

CAS Registry/EC Number

0 (Antineoplastic Agents); 0 (Carrier Proteins); 0 (Membrane Glycoproteins); 0 (P-Glycoprotein)

Record 90 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

The autonomic nervous system and adrenergic receptors in pediatric practice.

Author

Rubenstein JS

Address

Department of Pediatrics, University of Rochester School of Medicine & Dentistry, NY.

Source

Pediatr Rev, 1993 Dec, 14:12, 489-92

Abstract

The autonomic nervous system, with its normal balance between sympathetic and parasympathetic effects, is responsible for control of the body's involuntary functions. The importance of this balance is shown by the severe physiologic derangements seen after cervical spine injury, when the absolute loss of sympathetic function leads to unopposed action of the parasympathetic system that causes bradycardia, vasodilation, and hypotension that can be life-threatening. The sympathetic nervous system controls a multiplicity of functions and can be manipulated pharmacologically to the pediatric patient's advantage in some disease states. A basic understanding of the actions of the available sympathetic receptor agonists and antagonists can simplify and clarify many of these therapeutic options and improve the care of these children.

Language of Publication

English

Unique Identifier

94159493

MeSH Heading (Major)

Adrenergic alpha-Agonists|*PD/*TU; Adrenergic beta-Agonists|*PD/*TU; Autonomic Nervous System|AH/*DE/PP; Respiratory Tract Diseases|*DT/PP

MeSH Heading

Child; Human; Neurotransmitters|PH

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0191-9601

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Adrenergic alpha-Agonists); 0 (Adrenergic beta-Agonists); 0 (Neurotransmitters)

Record 91 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Arrhythmia control by prolonging repolarization: the concept and its potential therapeutic impact.

Author

Singh BN

Address

Department of Cardiology, Wadsworth VA Hospital, Los Angeles, California 90073.

Source

Eur Heart J, 1993 Nov, 14 Suppl H:, 14-23

Abstract

Over the last decade, there has been an increasing confluence of experimental and clinical data on the gravity of proarrhythmic effects of class I agents. Over the same period, beta blockers have been shown to reduce mortality in a variety of subsets of patients. The properties of amiodarone and sotalol have also drawn attention to their potential as antifibrillatory compounds, perhaps acting principally by prolonging myocardial repolarization with little or no effect on conduction. However, amiodarone and sotalol are complex molecules and, therefore, attention is also focused on compounds that act simply by selective prolongation of cardiac repolarization. These agents have been termed 'pure' class III agents. The properties of sotalol, the prototype of class III agents, are of particular interest, as it is a racemic mixture of the levo- and dextro-isomers. The levo-isomer has 50 times the beta-blocking potency of the dextro-isomer, actions. Studies of the antiarrhythmic properties of beta blockers, d- and d,l-sotalol, and amiodarone may provide insights into the nature of class III actions. There is clinical evidence indicating that class III drugs exert a varying spectrum of antifibrillatory and proarrhythmic (characterized by torsade de pointes) actions for a given degree of prolongation of repolarization. These differences currently are not accountable in terms of specificity of their actions on ionic channels. There are differences between the so-called pure class III agents, such as sematilide, dofetilide and E-4031, and more complex compounds, such as sotalol and amiodarone, that also exert antiadrenergic actions. In the development of newer drugs an appropriate balance needs to be struck between proarrhythmic actions and the antifibrillatory properties. At present, it is unclear whether such antifibrillatory compounds should be relatively simple molecules with clearly-defined electrophysiologic profiles in terms of actions on ion channels, currents, receptors and pumps, or whether they need to be those with complex electropharmacologic profiles with multiplicity of actions.

Language of Publication

English

Unique Identifier

94123686

MeSH Heading (Major)

Anti-Arrhythmia Agents|CH/CL/*PD; Arrhythmia|CI/*DT; Heart Conduction System|*DE/PH

MeSH Heading

Action Potentials|DE; Adrenergic beta-Antagonists|PD; Amiodarone|PD; Animal; Human; Sotalol|PD

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0195-668X

Country of Publication

ENGLAND

CAS Registry/EC Number

0 (Adrenergic beta-Antagonists); 0 (Anti-Arrhythmia Agents); 1951-25-3 (Amiodarone); 3930-20-9 (Sotalol)

Record 92 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Biochemical markers of aging.

Author

Stadtman ER

Address

Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892.

Source

Exp Gerontol, 1988, 23:4-5, 327-47

Abstract

It is the purpose of this report to identify possible metabolic deficiencies that might serve as biochemical markers of aging. It is proposed that the multiplicity of physical and physiological changes associated with aging could be most readily explained by alterations in the regulation and/or the activities of enzymes that occupy central positions in metabolism. Specifically, a search for metabolic markers of aging might include efforts to determine if there are age-related changes in the following enzymes or enzyme systems: (a) allosteric enzymes that catalyze reactions in highly branched metabolic pathways; (b) enzymes that catalyze opposing reactions between metabolites that are common intermediates in biosynthetic and biodegradative pathways (reactions which in the absence of final control would lead to futile substrate cycling); (c) enzymes that catalyze bimolecular reactions in which one member of a coenzyme pair is a cosubstrate (e.g., reactions involving NAD+ or NADH); (d) enzymes that are regulated by phosphorylation/dephosphorylation cycles; and (e) G-protein-dependent enzyme systems. It is also emphasized that changes in the concentrations and ratios of coenzyme substrate pairs (e.g., [NAD]/[NADH], [CoA]/[acyl CoA]) and the energy charge ratio [ATP] + 0.5 [ADP]/[ATP] + [ADP] + [AMP] may signal deviations from normal metabolism and therefore might be reliable markers of aging. In addition, because of their critical roles in metabolism, changes in the concentration of GTP, GDP and the second messengers, c-AMP, c-GMP should be monitored. Finally, it is noted that the accumulation of the altered forms of some enzymes which occurs during aging reflects imbalance between posttranslational modification of the enzymes and the degradation of the altered enzyme forms. The biological mechanisms involved and the genetic implications are discussed.

Language of Publication

English

Unique Identifier

89064942

MeSH Heading (Major)

Aging|*ME; Biological Markers|*AN

MeSH Heading

Animal; Coenzymes|ME; Energy Metabolism; Enzymes|ME; G-Proteins|ME; Human; Phenotype; Substrate Cycling

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0531-5565

Country of Publication

ENGLAND

CAS Registry/EC Number

0 (Biological Markers); 0 (Coenzymes); 0 (Enzymes); 0 (G-Proteins)

Record 93 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Modulation of arachidonic acid metabolites as potential therapy of asthma.

Author

Wasserman MA

Address

Department of Pharmacology, Smith Kline and French Laboratories, King of Prussia, Pennsylvania 19406-0939.

Source

Agents Actions Suppl, 1988, 23:, 95-111

Abstract

Bronchial asthma is a multifactorial disease characterized by reversible bronchoconstriction, airway hyperreactivity, oedema and excessive mucus production. Present therapy directed against specific mediators has not been overwhelmingly successful. Even though there exists a multiplicity of purported mediators, perhaps the key to better therapy is a vigorous understanding of the arachidonic acid cascade and investigations to modulate specific products of these pathways. Within the cyclooxygenase pathway an interesting scenario might be to effectively antagonize the potent bronchoconstrictive effects of prostaglandin (PG)D2 and its recently identified predominant metabolite, an 11-hydroxyl epimer, 9 alpha,11 beta-PGF2. PGD2 is the major cyclooxygenase product released from sensitized human lung and bronchoalveolar lavage (BAL) mast cells; it possesses a myriad of biological actions relevant to the pathogenesis of asthma. While no specific antagonists of PGD2 or 9 alpha,11 beta-PGF2 have been identified, some preliminary studies have suggested that, perhaps, PGD2 may be interacting, at least in part, with thromboxane receptors. In addition, peroxidation of arachidonic acid catalyzed by 5-lipoxygenase produces the leukotrienes, which are extremely potent bronchoconstrictors as well as oedema and mucus secretagogues. Leukotrienes are primary mast cell mediators which may be the vital link to both early (acute) and late (chronic) asthmatic attacks. Research seeking leukotriene antagonists has been intensive. Leading clinical candidates have emerged from Smith Kline and French, Lilly, Merck-Frosst, ICI-Stuart and other groups. However, we must await the outcome of ongoing clinical trials in asthmatics to determine just how important the leukotrienes really are in the pathogenesis of asthma, allergy and inflammation. Thus, modulation of the effects of products of arachidonic acid metabolism may provide a new and more specific treatment for bronchial asthma.

Language of Publication

English

Unique Identifier

89022500

MeSH Heading (Major)

Arachidonic Acids|*ME; Asthma|*DT/ME

MeSH Heading

Animal; Human; In Vitro; Leukotrienes|ME/PD; Prostaglandin D2|ME/PD; Respiratory System|DE/ME

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0379-0363

Country of Publication

SWITZERLAND

CAS Registry/EC Number

0 (Arachidonic Acids); 0 (Leukotrienes); 41598-07-6 (Prostaglandin D2); 506-32-1 (Arachidonic Acid)

Record 94 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Pharmacological mechanisms of opioid analgesics.

Author

Pasternak GW

Address

Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.

Source

Clin Neuropharmacol, 1993 Feb, 16:1, 1-18

Abstract

The description of multiple classes of opioid receptors has had a major impact on our understanding of the mechanisms of analgesia. Three major classes of opioid receptors have been defined: mu, kappa, and delta. The mu receptors have been further subclassified into two distinct subtypes (mu 1 and mu 2), as have the delta receptors (delta 1 and delta 2). Kappa receptors have been subdivided into kappa 1, kappa 2, or kappa 3 subtypes. All of these subtypes modulate pain perception, with the exception of the kappa 2 receptor, which has not been adequately examined. Supraspinal systems have been described for mu 1, kappa 3, and delta 2 receptors while mu 2, kappa 1, and delta 1 receptors modulate pain at the spinal level. In addition to their ability to act independently, the various systems also interact synergistically with each other. Thus, the relief of pain involves the complex interaction of at least six receptor systems. This review discusses the implications of opiate receptor multiplicity on the control of pain.

Language of Publication

English

Unique Identifier

93137234

MeSH Heading (Major)

Analgesics, Opioid|*PD/TU; Receptors, Opioid|CL/*DE

MeSH Heading

Amino Acid Sequence; Animal; Drug Synergism; Drug Tolerance; Human; Molecular Sequence Data; Pain|DT

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0362-5664

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Analgesics, Opioid); 0 (Receptors, Opioid)

Record 95 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

The molecular control of hemopoiesis and leukemia.

Author

Sachs L

Address

Department of Molecular Genetics and Virology, Weizmann Institute of Science, Rehovot, Israel.

Source

C R Acad Sci III, 1993 Sep, 316:9, 871-91

Abstract

The establishment of a cell culture system for the clonal development of hemopoietic cells made it possible to discover the proteins that regulate cell viability, growth and differentiation of different hemopoietic cell lineages and the molecular basis of normal and abnormal development in blood-forming tissues. These regulators include cytokines now called colony stimulating factors (CSFs) and interleukins (ILs). Different cytokines can induce cell viability, multiplication and differentiation, and hemopoiesis is controlled by a network of cytokine interactions. This multigene network includes positive regulators such as CSFs and ILs and negative regulators such as transforming growth factor beta and tumor necrosis factor. The cytokine network which has arisen during evolution allows considerable flexibility depending on which part of the network is activated and the ready amplification of response to a particular stimulus. The CSFs and ILs induce cell viability by inhibiting programmed cell death (apoptosis). Programmed cell death is also regulated by the genes wild-type and mutant p53, c-myc and bcl-2, and suppression or induction of this program can result in tumor promotion or tumor suppression. Cytokines that regulate normal hemopoiesis can control the abnormal growth of certain types of leukemic cells and suppress malignancy by inducing differentiation. Genetic abnormalities that give rise to malignancy in these leukemic cells can be by-passed and their effects nullified by inducing differentiation and programmed cell death. The hemopoietic cytokines discovered in culture are active in vivo and are being used clinically to correct defects in hemopoiesis.

Language of Publication

ENG LA=FRE

Unique Identifier

94356710

MeSH Heading (Major)

Hematopoiesis|GE/*PH; Leukemia|GE/*PP

MeSH Heading

Animal; Apoptosis|GE/PH; Cell Differentiation; Cell Division; Cell Line; Colony-Stimulating Factors|PH/TU; Human; Interleukins|PH/TU; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0764-4469

Country of Publication

FRANCE

CAS Registry/EC Number

0 (Colony-Stimulating Factors); 0 (Interleukins)

Record 96 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

DNA lesions, inducible DNA repair, and cell division: three key factors in mutagenesis and carcinogenesis.

Author

Ames BN; Shigenaga MK; Gold LS

Address

Division of Biochemistry and Molecular Biology, University of California, Berkeley 94720.

Source

Environ Health Perspect, 1993 Dec, 101 Suppl 5:, 35-44

Abstract

DNA lesions that escape repair have a certain probability of giving rise to mutations when the cell divides. Endogenous DNA damage is high: 10(6) oxidative lesions are present per rat cell. An exogenous mutagen produces an increment in lesions over the background rate of endogenous lesions. The effectiveness of a particular lesion depends on whether it is excised by a DNA repair system and the probability that it gives rise to a mutation when the cell divides. When the cell divides, an unrepaired DNA lesion has a certain probability of giving rise to a mutation. Thus, an important factor in the mutagenic effect of an exogenous agent whether it is genotoxic or non-genotoxic, is the increment it causes over the background cell division rate (mitogenesis) in cells that appear to matter most in cancer, the stem cells, which are not on their way to being discarded. Increasing their cell division rate increases mutation and therefore cancer. There is little cancer from nondividing cells. Endogenous cell division rates can be influenced by hormone levels, decreased by calorie restriction, or increased by high doses of chemicals. If both the rate of DNA lesions and cell division are increased, then there will be a multiplicative effect on mutagenesis (and carcinogenesis), for example, by high doses of a mutagen that also increases mitogenesis through cell killing. The defense system against reactive electrophilic mutagens, such as the glutathione transferases, are also almost all inducible and buffer cells against increments in active forms of chemicals that can cause DNA lesions. A variety of DNA repair defense systems, almost all inducible, buffer the cell against any increment in DNA lesions. Therefore, the effect of a particular chemical insult depends on the level of each defense, which in turn depends on the past history of exposure. Exogenous agents can influence the induction and effectiveness of these defenses. Defenses can be partially disabled by lack of particular micronutrients in the diet (e.g., antioxidants).

Language of Publication

English

Unique Identifier

94283344

MeSH Heading (Major)

Cell Division|*; DNA Damage|*; DNA Repair|*

MeSH Heading

Animal; Clone Cells; Diet; Female; Human; Male; Mutagenesis; Mutation; Neoplasms|ET/GE/PA; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0091-6765

Country of Publication

UNITED STATES

Record 97 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Development of breast cancer chemopreventive drugs.

Author

Kelloff GJ; Boone CW; Steele VE; Crowell JA; Lubet R; Doody LA; Greenwald P

Address

Chemoprevention Investigational Studies Branch (CISB), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD 20892.

Source

J Cell Biochem Suppl, 1993, 17G:, 2-13

Abstract

Breast cancer is the second highest cause of cancer mortality (19%) estimated for U.S. women in 1993 and accounts for the highest proportion of new cancer cases (32%) in this population. The rate of documented cases increased during the early 1970s and again in 1980-87, probably due to early mammographic detection. Increased knowledge of personal risk may also have been a consideration; however, 60% of women diagnosed with breast cancer have no known risk factor(s), such as family history, early age at menarche, late age at menopause, nulliparity, late age at first live birth, socioeconomic status, contraceptive use, postmenopausal estrogen replacement, or high fat intake. To prevent cancer, one strategy undertaken by the NCI is cancer chemoprevention, or intervention with chemical agents at the precancer stage to halt or slow the carcinogenic process. An objective of the NCI, DCPC is to develop promising cancer chemopreventive chemical agents as drugs for human use. Briefly, the process begins with identification of potential agents (e.g., pharmaceuticals, natural products, minor dietary constituents) from surveillance and analysis of the literature and from in vitro prescreen assays. Data on both efficacy (i.e., biological activities that either directly or indirectly indicate inhibition of carcinogenesis) and toxicity are gathered these sources. Various criteria are used to select and prioritize agents for entry into the NCI, DCPC preclinical testing program. The program begins with battery of in vitro efficacy screens using both animal and human cells to select agents for further testing; agents positive in these assays are considered for further testing. In the assay used for breast cancer chemoprevention, 7,12-dimethylbenz(a)anthracene (DMBA)-induced mouse mammary organ culture, 64 chemicals have inhibited formation of hyperplastic alveolar-like nodules. A panel of organ-specific animal screening assays are then used to assess efficacy in vivo. Two assays relevant for breast cancer chemoprevention are inhibition of N-methyl-N-nitrosourea- and DMBA-induced rat mammary gland carcinogenesis. Of 89 agents tested, 29 have inhibited cancer incidence, multiplicity, or both in at least one of the mammary assays; 21 agents are currently on test. Highly promising agents are then placed in traditional preclinical toxicity tests performed in two species. Finally, the most promising and least toxic agents enter clinical trials. Phase I clinical trials are designed to investigate human dose-related safety and pharmacokinetics of the drug. Phase II trials are small scale, placebo-controlled studies designed to determine chemopreventive efficacy and optimal dosing regimens.(ABSTRACT TRUNCATED AT 400 WORDS)

Language of Publication

English

Unique Identifier

94276614

MeSH Heading (Major)

Antineoplastic Agents|*TU; Breast Neoplasms|*PC

MeSH Heading

Adult; Aged; Animal; Clinical Trials, Phase II; Clinical Trials, Phase III; Cohort Studies; Drug Design; Female; Human; Middle Age; National Institutes of Health (U.S.); Tumor Markers, Biological; United States

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0733-1959

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Antineoplastic Agents); 0 (Tumor Markers, Biological)

Record 98 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

The multiplicity of actions of benzodiazepine receptor ligands.

Author

Haefely WE; Martin JR; Richards JG; Schoch P

Address

Pharma Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.

Source

Can J Psychiatry, 1993 Nov, 38 Suppl 4:, S102-8

Abstract

The benzodiazepine receptor is an allosteric modulatory site present on most, if not all, gamma-aminobutyric acid A (GABAA) receptor channels (GABAA-R). The benzodiazepine receptor recognizes a large spectrum of compounds from different chemical classes that are grouped together as benzodiazepine receptor ligands--of benzodiazepine and non benzodiazepine structure. The GABAA-R is thought to be a heteropentameric protein complex composed of at least three different classes of subunits, with each subunit comprised of up to six structural variants. Binding of GABA to the extracellular domain of the receptor causes a conformational change that opens the channel pore to anions. A classical benzodiazepine achieves a positive allosteric modulation of the GABA channel gating function by increasing the affinity of the receptor for GABA and, possibly, by facilitating the conformational transition from the closed to the open form (benzodiazepine receptor agonists). Inverse agonists of benzodiazepine receptors cause negative allosteric modulation (a decrease in the GABA activity). Benzodiazepine receptor antagonists bind to the benzodiazepine receptor with little effect on GABAA-R functioning. The intrinsic efficacy of benzodiazepine receptor ligands determines the direction and magnitude of allosteric modulation. Benzodiazepine receptor agonists affect neuronal activity in all major neuronal networks. The classical pharmacological profile of benzodiazepine receptor agonists consists of anxiolytic, anticonvulsant, sedative, and myorelaxant activities. Partial agonists of benzodiazepine receptors conserve anxiolytic and anticonvulsant activity, with greatly reduced sedation and muscle relaxation. They promise to present therapeutic advantages, in particular for long term use. In initial studies. they have produced fewer side-effects and showed reduced tolerance development and physical dependence liability.(ABSTRACT TRUNCATED AT 250 WORDS)

Language of Publication

English

Unique Identifier

94138831

MeSH Heading (Major)

Brain|*DE/PH; Neural Inhibition|*DE/PH; Receptors, GABA-A|*DE/PH

MeSH Heading

Animal; Arousal|DE/PH; Chloride Channels|DE/PH; Human; Membrane Potentials|DE/PH; Structure-Activity Relationship

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0706-7437

Country of Publication

CANADA

CAS Registry/EC Number

0 (Chloride Channels); 0 (Receptors, GABA-A)

Record 99 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

Inhibitors of enkephalin-degrading enzymes as potential therapeutic agents.

Author

Patel A; Smith HJ; Sewell RD

Address

Welsh School of Pharmacy, University of Wales, Cardiff, U.K.

Source

Prog Med Chem, 1993, 30:, 327-78

Abstract

A limited number of enzymes such as membrane metalloendopeptidase (enkephalinase) and angiotensin converting enzyme appear to be involved in deactivation and modulation of circulatory regulatory peptides. Peptides such as the enkephalins are also involved in a large number of physiological processes. This multiplicity of physiological roles has made it difficult to establish the therapeutic role of enkephalin-degrading enzyme inhibitors. Other factors such as difficulty in quantification and thus measurement of processes involved in pain and mental illness have also hindered the process of establishing any therapeutic role of enkephalin-degrading enzyme inhibitors in these conditions. However, they have proved to be useful pharmacological 'tools'. The most likely therapeutic role at present appears to be in the treatment of cardiovascular disorders. As a 'profile' of pharmacological actions of enkephalin-degrading enzymes emerges, it is becoming apparent that bioavailability rather than a high degree of specificity or inhibitory potency may be the most important factor. This may be used to an advantage in future developments by the use of less specific or combined inhibitors in the form of prodrugs, designed to be active at specific sites such as the central nervous system.

Language of Publication

English

Unique Identifier

94134939

MeSH Heading (Major)

Aminopeptidases|*AI; Analgesics|*; Anti-Inflammatory Agents|*; Antidepressive Agents|*; Cardiovascular Agents|*; Enkephalins|*ME

MeSH Heading

Human

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0079-6468

Country of Publication

NETHERLANDS

CAS Registry/EC Number

EC 3.4.11. (Aminopeptidases); EC 3.4.11.- (enkephalin degrading enzyme); 0 (Analgesics); 0 (Anti-Inflammatory Agents); 0 (Antidepressive Agents); 0 (Cardiovascular Agents); 0 (Enkephalins)

Record 100 from database: MEDLINE
Return To The Top
Return To Menu Item 60
Return To Menu Item 80

Title

A hypothesis on the primate neocortex evolution: column-multiplication hypothesis.

Author

Sawaguchi T; Kubota K

Address

 

Source

Int J Neurosci, 1986 Aug, 30:1-2, 57-64

Abstract

A hypothesis is proposed, that the primate neocortex has evolved by the multiplication of cortical columns. As the column size is similar across primate species, it is considered that the columns have multiplied to expand the neocortex during primate evolution. This hypothesis would explain the expansion of neocortical sensory-motor-associational areas and multiple sensory and motor areas which had occurred during evolution. Further, the hypothesis predicts the existence of columns neutral for the fitness, genetic control upon the columns, and intraspecies variations of the columns.

Language of Publication

English

Unique Identifier

86303315

MeSH Heading (Major)

Cerebral Cortex|AH/*PH; Evolution|*; Models, Neurological|*

MeSH Heading

Afferent Pathways|AH/PH; Animal; Cell Aggregation; Cell Count; Haplorhini; Human; Recombination, Genetic; Visual Fields

Publication Type

JOURNAL ARTICLE; REVIEW

ISSN

0020-7454

Country of Publication

ENGLAND

SUBSCRIBE:  The Wednesday Letter is a free electronic monthly newsletter written and published by Karl Loren.  You can view more than 50 back issues of this publication by clicking here.  The Wednesday Letter subscription list is maintained on a secure server, no name is ever given or sold to anyone, and it is never used except for this Newsletter.  It is automatically published on the Tuesday night just before the first Wednesday of every month.  You can subscribe to this free monthly electronic letter by entering your eMail address and name below.  You will then automatically receive a request for confirmation, sent to whatever address you have entered.  If you do NOT receive this confirmation request, then you will not be subscribed.  There may have been an error with your address and you should resubmit.  The letter is never sent twice to the same address -- so you do not have to worry about a duplicate subscription.  When you receive this confirmation request you must reply to it, or your subscription will not become active.  No one can subscribe your name, and address, without you being notified, and if you get an unwanted notice of subscription you only need to DO NOTHING and the subscription will NOT be active.

REMOVAL:  You can remove yourself from the subscription list in several different ways.  Click here to read about this entire newsletter system.  Every edition of The Wednesday Letter is delivered to your address with YOUR name and address in view on the letter, with a link that allows you to remove THAT name from the subscription list.  If you try to send this removal message from an address different from the one you used to send in your original confirmation, then you will get a warning notice first, sent to the subscription address, asking you to confirm that you want to be removed from the list -- by replying to THAT request for confirmation, you will then be automatically removed.  Thus, no one else can unsubscribe you, from some other computer, without your knowledge.  But, if you send in the unsubscribe notice from the same machine used to receive the Letter, then the removal from the subscription list is automatic.

Personal Message:  When you send a personal message to Karl Loren, you will receive a personal reply as per his instructions.  Karl pledges that every personal message will get a personal answer. When you provide your mail address, we will send you free information including our free catalog and a cassette tape lecture by Karl Loren about heart disease, no charge, by mail, even if outside the US.  You can select particular information you would like to receive, along with the free cassette tape and catalog.

You can reach Vibrant Life in many ways, including by mail to Vibrant Life, 2808 N. Naomi St., Burbank, CA 91504.  Within the US and Canada, use the toll free number:  (800) 523-4521, the local number:  (818) 558-1799, the FAX:  (818) 558-7299, eMail to kimberly@oralchelation.com or any one of the hundreds of message forms throughout the 50 web sites.  Vibrant Life normally ships the same day we get an order.  There are message forms on each of the 100,000+ pages on this and other sites where you can communicate with Vibrant Life.  Check out our companion site, at:  http://www.oralchelation.net where Karl's 2000 page book is published.  Karl Loren is the author and webmaster for this BOOK, as well as for another web site about ORAL CHELATION.  His personal philosophical articles are at PHILOSOPHY. 

Copyright © May 20, 2008 6:24 AM by Karl Loren on behalf of Vibrant Life, ALL RIGHTS RESERVED.  Permission is granted for non-commercial downloading, copying, distribution or redistribution on two conditions:  One, that some form of copyright notice is included in every copy distributed or copied, showing the copyright belonging to Vibrant Life, Burbank, CA, at www.oralchelation.com . The second condition is that the material is not to be used for any purpose contrary to the purposes and objectives of this site.  This permission does not extend to materials on this site which are copyrighted by others.