bluuebunny/crossref_metadata_2025 huggingface dataset:
Programmed Cell Death (PCD): Apoptosis, Autophagic PCD, or Others?
Authors: BURSCH W. , ELLINGER A. , GERNER CH. , FRÖHWEIN U. , SCHULTE‐HERMANN R.
Published: July 2010

Abstract: The occurrence of cell death as a physiological event in multicellular organisms has been known for more than 150 years; in 1972 the term apoptosis was introduced on morphological grounds. However, accumulating evidence suggests that programmed cell death (PCD) is not confined to apoptosis, but that cells use different pathways for active self‐destruction as reflected by different morphology: condensation prominent, type I or apoptosis; autophagy prominent, type II; etc. Autophagic PCD appears to be a phylogenetically old phenomenon; it may occur in physiological and disease states. We have studied the relation between morphological and biochemical events during autophagic and apoptotic PCD in human mammary, lymphoblast, and colon cancer cells using electron microscopy and proteom analysis. We find that autophagic cell death (type II) PCD includes degradation of Golgi apparatus, polyribosomes, and endoplasmic reticulum, which precedes nuclear destruction. Intermediate and microfilaments are largely preserved; presumably the cytoskeleton is required for autophagocytosis. Apoptosis (type I) PCD is characterized by condensation of cytoplasm and preservation of organelles; cytoskeletal elements disintegrate in early stages. Either type of PCD involves synthesis of distinct proteins. Finally, both types of PCD share features some of a cell's stress response (e.g., translocation of hsp90). In conclusion our findings support the concept that autophagic cell death is a separate pathway of PCD distinctly different from “classical” apoptosis. However, autophagic and apoptotic PCD should not be considered as mutually exclusive phenomena. Rather, they appear to reflect a high degree of flexibility in a cell's response to changes of environmental conditions, both physiological or pathological.
Apoptosis as a Scaffold for Building up the B Cell Repertoire
Authors: BRÁS ALEXANDRA , RUIZ‐VELA ANTONIO , GARCÍA‐DOMINGO DAVID , MARTÍNEZ‐A CARLOS
Published: July 2010

Abstract: Control of cell number is determined by a balance between cell proliferation and cell death, both of which are highly regulated processes, with numerous checks and balances. cells control their own death through activation of an internally coded suicide program that, when activated, initiates a characteristic form of cell death called apoptosis. this type of regulation allows elimination of cells that have been produced in excess, that have developed improperly, or that have sustained genetic damage. apoptosis is, therefore, the most common physiological form of cell death and occurs during embryonic development, tissue remodeling, immune regulation, cell activation and tumor regression.
Quantitation of CD95 and CD95L mRNA Expression in Chronic and Acute HIV‐1 Infection by Competitive RT‐PCR
Authors: PINTI MARCELLO , NASI MILENA , MORETTI LAURA , MUSSINI CRISTINA , PETRUSCA DANIELA , ESPOSITO ROBERTO , COSSARIZZA ANDREA
Published: July 2010

Abstract: Human immunodeficiency virus‐type 1 (HIV‐1) infection is characterized by increased immune cell apoptosis. Apoptosis can be triggered by signals that arise from within the cell, or by signals that are elicited by binding of extracellular “death ligands” to their “death receptors,” most of which belong to the tumor necrosis factor (TNF)‐receptor family, such as CD95 (Fas/Apo‐1). In immune cells the oligomerization of CD95, induced by its ligand CD95L, and the recruitment of different intracytoplasmic molecules that in turn activate FLICE/caspase 8 are crucial. To study the role of CD95/CD95L interactions during HIV‐1 infection, we developed an original method based upon quantitative‐competitive (QC) RT‐PCR that allowed us to quantify the amounts of mRNA coding for the total (tCD95) and membrane (mCD95) forms of CD95. We first studied the expression of different forms of CD95 mRNA in a classical model of chronic HIV infection using two infected cell lines of different origin‐lymphocytic (ACH‐2) or monocytic (U1). We have shown that infected cells of monocytic origin preferentially produce the “protective” (soluble) form of CD95, and no detectable CD95L mRNA, while lymphoid cells produce more mRNA for the membrane form of CD95 (which triggers apoptosis) along with low but detectable amounts of CD95L mRNA. One can hypothesize that a complex balance exists between pro‐apoptotic events, perhaps triggered by the host to limit viral production, and anti‐apoptotic events likely triggered by the virus to increase its production and survival. In cells of monocytic origin, which act as a reservoir for the virus, the anti‐apoptotic molecules are favored; in cells of lymphocytic origin, molecules with an apoptotic meaning are prevalent.
The Role of the Pro‐Apoptotic Bcl‐2 Family Member Bim in Physiological Cell Death
Authors: BOUILLET PHILIPPE , HUANG DAVID C.S. , O'REILLY LORRAINE A. , PUTHALAKATH HAMSA , O'CONNOR LIAM , CORY SUZANNE , ADAMS JERRY M. , STRASSER ANDREAS
Published: July 2010

Abstract: Apoptosis, an evolutionarily conserved process for killing unwanted cells in multicellular organisms, is essential for normal development, tissue homeostasis and as a defense against pathogens. The control of apoptosis is of considerable importance for clinical medicine, as its deregulation can lead to cancer, autoimmunity or degenerative diseases. We have disrupted the Bim gene in the mouse and demonstrated that it plays a major and non‐redundant role in embryogenesis, in the control of hematopoietic cell death, and as a barrier against autoimmunity.
Primary Human Fibroblasts from a Maple Syrup Urine Disease Patient Undergo Apoptosis following Exposure to Physiological Concentrations of Branched Chain Amino Acids
Authors: JOUVET PHILIPPE , KOZMA MARY , MEHMET HUSEYIN
Published: July 2010

Abstract: Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by a deficiency in branched chain α‐ketoacid dehydrogenase. We have recently found that msud neurodegeneration may result, at least in part, from apoptosis triggered by branched chain amino acids and their α‐ketoacid derivatives. In the present study, we investigated the sensitivity of MSUD fibroblasts to defined mixtures of MSUD metabolites. Defined combinations of MSUD metabolites, at levels comparable to those in MSUD patients, triggered cell death in skin fibroblasts from a MSUD patient, while control fibroblasts were resistant. the mechanism of cell death wasconfirmed as apoptosis by in situ end labeling.
Heat Shock Protein 70 Is Required for the Survival of Cancer Cells
Authors: NYLANDSTED JESPER , BRAND KARSTEN , JÄÄTTELÄ MARJA
Published: July 2010

Abstract: The major stress‐inducible heat shock protein, Hsp70, is a chaperone protein abundantly and preferentially expressed in human tumors and tumor cell lines. Owing to the ability of Hsp70 to protect cells from a wide range of apoptotic and necrotic stimuli, it has been assumed that Hsp70 may confer survival advantage to tumor cells. To investigate this hypothesis in human tumor cell lines, we generated an adenovirus expressing antisense Hsp70 (Ad.asHsp70). The effective and specific depletion of Hsp70 by Ad.asHsp70 resulted in massive cell death of all tumorigenic cell lines tested (carcinomas of breast, colon, prostate and liver as well as glioblastoma). Inspite of an effective depletion of Hsp70, Ad.asHsp70 had no effect on the survival or growth of fetal fibroblasts or non‐tumorigenic epithelial cells of breast or prostate. Anti‐apoptotic proteins Bcl‐2, Bcl‐XLand CrmA as well as peptide‐inhibitors of caspases, DEVD‐CHO and zVAD‐FMK, failed to rescue tumor cells from Ad.asHsp70‐induced cell death. These results indicate that the high expression of Hsp70 is a prerequisite for the survival of human cancer cells of various origins and reveal Hsp70 as the only protein described so far whose expression is specifically needed for the survival of tumorigenic cells.
A Single Cell Analysis of Apoptosis: Ordering the Apoptotic Phenotype
Authors: GOLDSTEIN JOSHUA C. , KLUCK RUTH M. , GREEN DOUGLAS R.
Published: July 2010

Abstract: Microcinematography was applied to the analysis of the kinetics of apoptotic cell death. Apoptosis was found to be a process that proceeds in different cells at different times after an initial stress, and therefore kinetic studies of apoptotic events in bulk cultures can be problematic. Using single cell analysis we found that stronger apoptotic stimuli induce an earlier onset of apoptosis, but that there is no relationship between time of onset and duration of the apoptotic process. That is, cells that initiate apoptosis shortly after induction do not proceed more rapidly through the process. This suggests an all‐or‐none mechanism that is supported by some models of the biochemical pathways of apoptosis.
Turbulent Convection in the Classical Variable Stars
Authors: BUCHLER J. ROBERT , KOLLÁTH ZOLTÁN
Published: July 2010

Abstract: We give a status report of convective Cepheid and RR Lyrae model pulsations. Some striking successes can be reported, despite the use of a rather simple treatment of turbulent convection with a 1D time‐dependent diffusion equation for the turbulent energy. It is now possible to obtain stable double‐mode (beat) pulsations in both Cepheid and RR Lyrae models with astrophysical parameters, i.e. periods and amplitude ratios, that are in agreement with observations. The turbulent convective models, however, have difficulties giving global agreement with the observations. In particular, the Magellanic Cloud Cepheids which have been observed in connection with the microlensing projects have imposed novel observational constraints because of the low metallicity of the MCs.
Coherent Transport of Angular Momentum: The Ranque‐Hilsch Tube as a Paradigm
Authors: COLGATE STIRLING A. , BUCHLER J. ROBERT
Published: July 2010

Abstract: The mechanism for efficient and coherent angular momentum transport remains one of the unsolved puzzles in astrophysics despite the enormous efforts that have been made. We suggest that important new insight could be gained in this problem through an experimental and theoretical study of a laboratory device (Ranque‐Hilsch tube) that displays a similar enhanced angular momentum transfer which cannot be explained by a simple turbulent model. There is already good experimental evidence to suggest that the cause of this enhancement is the formation of aligned vortices that swirl around the symmetry axes very much like virtual paddle blades.
Fifty Years of Radical Ideas
Authors: GILBERT DANIEL L.
Published: July 2010

Abstract: My role in the free radical theory of oxygen toxicity is discussed. Rebeca Gerschman and I published several papers on this subject. This sparked my interest in geochemistry and I developed the idea that oxygen was the best qualified biological potential energy source for the following reasons: great abundance, easily accessible, possession of a high thermodynamic potential, and its slow reaction rate. Ionization radiation can be viewed as a catalyst for reactive oxygen species since a killing dose imparts an infinitesimal small amount of energy. Next, Carol A. Colton and I showed that in the mammalian brain that stimulated microglia produce the superoxide radical anion and its implications in Alzheimer's disease is discussed. More recently, I have become interested in the role of sulfhydryl groups in transcription factors.
Ionizing Radiation Potentiates the Induction of Nitric Oxide Synthase by Interferon‐γ and/or Lipopolysaccharide in Murine Macrophage Cell Lines: Role of Tumor Necrosis Factor‐α
Authors: MCKINNEY LESLIE C. , AQUILLA ELIZABETH M. , COFFIN DEBORAH , WINK DAVID A. , VODOVOTZ YORAM
Published: July 2010

Abstract: Macrophages respond to infection or injury by changing from a “resting” cellular phenotype to an “activated” state defined by the expression of various cytotoxic effector functions. Regulation of the transition from a resting to an activated state is effected by cytokine and/or pathogenic signals. Some signals do not directly induce activation, but instead “prime” the macrophage to respond more vigorously to a second signal. One example of this priming phenomenon involves induction of nitric oxide (NO) synthesis by the enzyme nitric oxide synthase (NOS2). Our experiments indicate that low doses (1–5 Gy) of ionizing radiation can enhance the induction of enzymatically active NOS2 by IFN‐γ or LPS in J774.1 and RAW264.7 murine macrophage cell lines. Radiation alone did not produce this induction, rather, it was effective as a priming signal; cells exposed to radiation produced more NO when a second signal, either IFN‐γ or LPS, was applied 24 h later.
Genetic Responses to Free Radicals: Homeostasis and Gene Control
Authors: GONZÁLEZ‐FLECHA BEATRIZ , DEMPLE BRUCE
Published: July 2010

Abstract: Gene regulation mechanisms have evolved allowing cells to fine‐tune the level of “endogenous” oxidative stress and to cope with increased free radicals from external sources. Levels of H2O2 are tightly controlled in E. coli by OxyR, which is activated by H2O2 to increase scavenging activities and limit H2O2 generation by the respiratory chain. Sub‐micromolar levels of H2O2 are maintained in mammalian tissues, though the regulatory systems that govern this control are unknown. Excess superoxide triggers the soxRS system in E. coli, which is controlled by the oxidant‐sensitive iron‐sulfur centers of the SoxR protein. Nitric oxide activates SoxR by a different modification of the iron‐sulfur centers. The soxRS regulon mobilizes diverse functions to scavenge free radicals and repair oxidative damage in macromolecules, and other mechanisms that exclude many environmental agents from the cell. Mammalian cells also sense and respond to sub‐toxic levels of nitric oxide, activating expression of heme oxygenase 1 through stabilization of its mRNA. These inductions give rise to adaptive resistance to nitric oxide in neuronal and other cell types.
Regulation of Mitochondrial Respiration by Oxygen and Nitric Oxide
Authors: BOVERIS ALBERTO , COSTA LIDIA E. , PODEROSO JUAN J. , CARRERAS MARIA C. , CADENAS ENRIQUE
Published: July 2010

Abstract: Although the regulation of mitochondrial respiration and energy production in mammalian tissues has been exhaustively studied and extensively reviewed, a clear understanding of the regulation of cellular respiration has not yet been achieved. In particular, the role of tissue pO2 as a factor regulating cellular respiration remains controversial. The concept of a complex and multisite regulation of cellular respiration and energy production signaled by cellular and intercellular messengers has evolved in the last few years and is still being researched. A recent concept that regulation of cellular respiration is regulated by ADP, O2 and NO preserves the notion that energy demands drive respiration but places the kinetic control of both respiration and energy supply in the availability of ADP to F1‐ATPase and of O2 and NO to cytochrome oxidase. In addition, recent research indicates that NO participates in redox reactions in the mitochondrial matrix that regulate the intramitochondrial steady state concentration of NO itself and other reactive species such as superoxide radical (O2−) and peroxynitrite (ONOO−). In this way, NO acquires an essential role as a mitochondrial regulatory metabolite. NO exhibits a rich biochemistry and a high reactivity and plays an important role as intercellular messenger in diverse physiological processes, such as regulation of blood flow, neurotransmission, platelet aggregation and immune cytotoxic response.
Nitrone Inhibition of Age‐Associated Oxidative Damage
Authors: FLOYD ROBERT A. , HENSLEY KENNETH
Published: July 2010

Abstract:The mechanistic basis of the neuroprotective activity of the nitrone‐based free radical trap PBN (α‐phenyl‐N‐tert‐butyl nitrone) has been investigated extensively. Key observations exclude its simple mass action spin trapping of free radicals activity as the key mechanism of action. These include: A) the fact that it protects in experimental stroke even if administered several hours after the event and B) the fact that its chronic low‐level administration to old experimental animals reverses their age‐enhanced susceptibility to stroke even several days after the last dosage. PBN was found to inhibit gene induction in several models including stroke and an LPS‐mediated septic shock model. Stoke causes inducible nitric oxide synthase (iNOS) to be expressed. High levels of nitric oxide and peroxynitrite (formed from nitric oxide), produced by iNOS, is particularly neurotoxic. PBN inhibits iNOS induction. Therefore, it seems that prevention of the formation of neurotoxic products is a rational mechanism of action of PBN in the stroke model. There is strong rationale to consider that there is an enhanced propensity for a “smoldering” neuro‐inflammatory state in the old brain. Reversal of this state by PBN may explain its action in preventing age‐enhanced stroke susceptibility in old experimental animals. Significant new findings underscore the importance of neuro‐inflammatory processes in neuronal death or dysfunction in Alzheimer's disease. Neuro‐inflammatory processes implicate enhanced signal transduction processes. Strong evidence for this is the enhanced p38 kinase activation in neurons near plaques and tangles of the Alzheimer's brain in contrast to normal aged‐matched control brain which did not show p38 activation. In rat primary astrocytes p38 activation by the pro‐inflammatory cytokine IL‐1β, as well as by H2O2, was significantly suppressed by PBN. Mechanistically it was shown that PBN suppresses the amount of reactive oxygen species (ROS) produced in mitochondrial respiration. Much evidence indicates that ROS are signaling molecules and that they also are involved in maintaining brain phosphatases in an inactive state. We argue that finding a specific high affinity site mechanism for the neuroprotective action of PBN is unlikely based on the complexity of the system reflecting ROS generation and signal transduction processes that have apparently evolved to maintain adaptive responses. The promising pharmacological activity of molecules like PBN is not diminished by this however, for only excessive amounts of ROS is considered detrimental. The action of PBN in suppressing signal transduction processes, most likely by suppressing ROS production in mitochondrial respiration, effectively controls excessive oxidative damage and prevents induction of genes that form neurotoxic products.
Effects of Atypical Antioxidative Agents,S‐nitrosoglutathione and Manganese, on Brain Lipid Peroxidation Induced by Iron Leaking from Tissue Disruption
Authors: RAUHALA PEKKA , CHIUEH CHUANG C.
Published: July 2010

Abstract:A fluorescent assay of brain lipid peroxidation was used for screening new antioxidants for the prevention of neurodegeneration caused by free radicals. Incubation of rat brain homogenates led to a temperature‐dependent increase in production of fluorescent adducts of peroxidized poly‐unsaturated fatty acids; it was inhibited completely by lowering the incubation temperature to 4°C. This tissue disruption‐induced brain lipid peroxidation at 37°C was blocked by deferoxamine (IC50= 0.3 μM) and EDTA; it was augmented by adding submicromolar iron and hemoglobin. Ferrous ion's pro‐oxidative activities were five times more potent than ferric ion. Micromolar manganese completely inhibited lipid peroxidation, confirming earlier unexpectedin vivoreports. Trolox and vitamin C suppressed brain lipid peroxidation with IC50values of 20 and 500 μM, respectively. U‐78517F was approximately 20 times more potent than Trolox. 17β‐Estradiol, hydralazine,S‐nitrosoglutathione and 3‐hydroxybenzylhydrazine were as potent as Trolox. Melatonin, glutathione, α‐lipoic acid andl‐deprenyl were about 20 times less potent than Trolox. Surprisingly,N‐tert‐butyl‐α‐phenylnitrone was a weak antioxidant. Furthermore, this procedure can also detect pro‐oxidative side effects of vitamin C, oxidized glutathione, penicillamine and Angeli's salt. The present results obtained from this selective fluorescent assay are consistent with earlier reports that iron complexes promote while manganese inhibits brain lipid peroxidation caused by cell disruption.S‐Nitrosoglutathione, melatonin, 17β‐estradiol, and manganese have been successfully tested in cell/animal models for their potential neuroprotective effects. In conclusion, monitoring fluorescent adducts of peroxidizing polyunsaturated fatty acids in brain homogenates is a simple, quantitative method for studying iron‐dependent brain lipid peroxidation and for screening of potential neuroprotective antioxidants in bothin vitroandin vivopreparations.
Effect of MAO‐B Inhibitors on MPP+Toxicityin Vivo
Authors: WU RUEY‐MEEI , CHEN RONG‐CHI , CHIUEH CHUANG C.
Published: July 2010

Abstract:l‐Deprenyl (Selegiline), a selective and irreversible type B monoamine oxidase inhibitor, has been used as an adjunct to levodopa therapy in Parkinson's disease. Recently, it is proposed as a putative neuroprotective agent in delaying the progression of cell death based on its capability of reducing the oxidative stress derived from the MAO‐B dependent metabolism of dopamine, and blocking the development of MPTP‐parkinsonism. However, a variety of experimental models suggest thatl‐deprenyl provides neuroprotection through multiple modes of mechanism other than the inhibition of MAO‐B. We have previously shown thatl‐deprenyl protects midbrain dopamine neurons from MPP+ toxicity by a novel antioxidant effect. In the present study we examined whether the protection against MPP+ toxicity is also shared by other reversible or irreversible MAO‐B inhibitors including (+)‐deprenyl, Ro16‐6491 and pargyline. Our data show that non of these MAO‐B inhibitors changes the dopamine loss in the striatum induced by intranigral injection of MPP+. Our result suggests thatl‐deprenyl may possess a unique neuroprotective action on nigral neuron against MPP+ toxicity independent of the MAO‐B inhibition.
Neuroprotective Antioxidants from Marijuanaa
Authors: HAMPSON A. J. , GRIMALDI M. , LOLIC M. , WINK D. , ROSENTHAL R. , AXELROD J.
Published: July 2010

Abstract:Cannabidiol and other cannabinoids were examined as neuroprotectants in rat cortical neuron cultures exposed to toxic levels of the neurotransmitter, glutamate. The psychotropic cannabinoid receptor agonist Δ9‐tetrahydrocannabinol (THC) and cannabidiol, (a non‐psychoactive constituent of marijuana), both reduced NMDA, AMPA and kainate receptor mediated neurotoxicities. Neuroprotection was not affected by cannabinoid receptor antagonist, indicating a (cannabinoid) receptor‐independent mechanism of action. Glutamate toxicity can be reduced by antioxidants. Using cyclic voltametry and a fenton reaction based system, it was demonstrated that Cannabidiol, THC and other cannabinoids are potent antioxidants. As evidence that cannabinoids can act as an antioxidants in neuronal cultures, cannabidiol was demonstrated to reduce hydroperoxide toxicity in neurons. In a head to head trial of the abilities of various antioxidants to prevent glutamate toxicity, cannabidiol was superior to both a‐tocopherol and ascorbate in protective capacity. Recent preliminary studies in a rat model of focal cerebral ischemia suggest that cannabidiol may be at least as effectivein vivoas seen in thesein vitrostudies.
Antioxidants in Nutrition
Authors: JOVANOVIC SLOBODAN V. , SIMIC MICHAEL G.
Published: July 2010

Abstract:The harmful effects of oxidative processes in living organisms, in addition to chemical and biochemical media, can be reduced by antioxidants. The efficacy of an antioxidant depends on its reduction potential and kinetics of elimination of diverse free radicals. Redox potentials and reaction rate constants of selected gallocatechins and flavonoids were measured by pulse radiolysis and laser photolysis. The reduction potentials of the flavonoids studied were in the range of 0.33 V (quercetin) and 0.75 V (kaempferol). The rate constants of the superoxide radical with 15 flavonoids ranged from 105‐107M−1s−1. Singlet oxygen quenching by flavonoids was also very rapid (from 105to 108M−1s−1). These studies may be crucial in optimizing health and increasing longevity by reducing oxidative stress and biological damage.
The Hypothalamic‐Pituitary‐Thyroid Axis and the Female Reproductive System
Authors: DOUFAS ANTHONY G. , MASTORAKOS GEORGE
Published: July 2010

Abstract: Increasing evidence derived from experimental and clinical studies suggests that the hypothalamic‐pituitary‐thyroid axis (HPT) and the hypothalamic‐pitutitary‐ovarian axis (HPO) are physiologically related and act together as a unified system in a number of pathological conditions. The suggestion that specific thyroid hormone receptors at the ovarian level might regulate reproductive function, as well as the suggested influence of estrogens at the higher levels of the HPT axis, seems to integrate the reciprocal relationship of these two major endocrine axes. Both hyper‐ and hypothyroidism may result in menstrual disturbances. In hyperthyroidism the most common manifestation is simple oligomenorrhea. Anovulatory cycles are very common. Increased bleeding may also occur, but it is rare. Hypothyroidism in girls can cause alterations in the pubertal process; this is usually a delay, but occasionally it can result in pseudoprecocious puberty. In mature women hypothyroidism usually is associated with abnormal menstrual cycles characterized mainly by polymenorrhea, especially anovulatory cycles, and an increase in fetal wastage.
Thyroidopathies
Authors: KOUTRAS DEMETRIOS A.
Published: July 2010

Abstract: Pregnancy affects thyroid physiology in many ways: (a) The renal iodide clearance rate is increased, hence iodine requirements increase. (b) The fetal requirements for thyroid hormones and iodide are an additional problem. (c) Serum thyroxine‐binding globulin increases, thus producing an increase in the levels of total T4 and T3. (d) Chorionic gonadotropin has a thyroid‐stimulating activity. This may be compensated for by a decrease in TSH, but in some cases gestational thyrotoxicosis occurs. (e) Thyroid autoimmunity usually subsides during pregnancy, but may rebound a few months after parturition, and postpartum thyroiditis may occur. Because maternal antithyroid autoantibodies cross the placenta readily, fetal and neonatal hyperthyroidism (or hypothyroidism) may develop. Pre‐existing thyroid diseases are influenced. Nontoxic goiter increases in size. Iodine and/or thyroxine may be required. Graves' disease may remit. If present, antithyroid drugs should be given in small doses, and quite often they may be stopped altogether. Hypothyroid patients may require a larger T4 dose.
The Potential Role of Intraovarian Factors on Ovarian Androgen Production
Authors: CHRYSSIKOPOULOS ATHANASSIOS
Published: July 2010

Abstract: The circuit of gonadotropins (FSH, LH) and ovaries (theca and granulosa cells) in ovarian estrogen and androgen production is well established. Recent research has revealed an intraovarian network that may ultimately prove relevant to the understanding of ovarian hyperandrogenism. Most of these substances, such as growth factors and cytokines, do not have independent effects on basal androgen production, but exhibit their regulatory potential by modulating hCG‐ or LH‐stimulated steroid production. Precise understanding of the regulatory role of intraovarian factors in ovarian androgen production would shed new light on the pathophysiology and therapy of hyperandrogenemic excess in women.
Dysmenorrhea
Authors: DELIGEOROGLOU E.
Published: July 2010

Abstract: Dysmenorrhea presents as painful periods that start two to three years after menarche. The pain usually begins when the bleeding starts and lasts for 48–32 hours. The cause of menstrual cramps and associated symptoms in primary dysmenorrhea is related to prostaglandin production. In secondary dysmenorrhea, there is documented pelvic pathology that causes the painful menstrual cramps, and treatment is cause related. Available treatments for primary dysmenorrhea‐NSAIDS, oral combined contraceptives, β‐blockers, psychotherapeutic methods, and crevical dilatation—are discussed.
Combined Oral Contraceptive Treatment of Adolescent Girls with Polycystic Ovary Syndrome: Lipid Profile
Authors: CREATSAS GEORGE , KOLIOPOULOS CAROLINA , MASTORAKOS GEORGE
Published: July 2010

Abstract: The clinical signs and neuroendocrine features of adolescents with polycystic ovary syndrome (PCOS) resemble those found in adult women with PCOS. These adolescent patients are candidates for long‐term treatment by one of the different therapeutic approaches that have been proposed. It is therefore essential that the treatment does not induce unfavorable metabolic effects. We investigated and compared the effects of cyproterone acetate (CA) and desogestrel (D), as part of combined oral contraceptives (COC), on lipid metabolism and hirsutism in adolescents with PCOS. Twenty‐four girls with clinical signs of PCOS were recruited. They were all hyperandrogenemic and euthyroid and had normal prolactin plasma levels. Nonclassic congenital adrenal hyperplasia was ruled out by the ACTH stimulation test. Blood samples were obtained for sex hormone binding globulin (SHBG), total cholesterol (TC), LDL cholesterol, HDL cholesterol, triglycerides (TGs), apolipoproteins A‐I, A‐II, B, and lipoprotein (a) (Lp(a)) measurements. After the initial exam‐ination, therapy was initiated in a randomly selected order (12 and 12 patients were treated daily by 2 mg CA and 0.150 mg D, respectively, plus 0.035 and 0.030 mg ethinylestradiol, respectively). The degree of hirsutism and the lipid profile were reevaluated every 3 months after initiation of therapy for 1 year. Our data show that after 12 months of treatment with the D or CA COC, the Ferriman‐Gallway hirsutism score decreased and TC and LDL‐C increased. TGs and HDL‐C were raised significantly in the CA COC group, whereas apolipoprotein A1 increased during D COC treatment. The atheromatic indices did not change. These data suggest that treatment of adolescent girls with PCOS is comparably effective with the two contraceptive formulations and that the desogestrel COC could be considered in the treatment of adolescent PCOS patients because it does not have side effects on lipid metabolism.
Adhesions: Laparoscopic Surgery versus Laparotomy
Authors: MILINGOS S. , KALLIPOLITIS G. , LOUTRADIS D. , LIAPI A. , MAVROMMATIS K. , DRAKAKIS P. , TOURIKIS J. , CREATSAS G. , MICHALAS S.
Published: July 2010

Abstract: This study was undertaken to assess the effectiveness in pregnancy rates of microsurgery and operative laparoscopy in adhesiolysis. Adhesions were found to be the sole infertility factor in 15% of our patients. One hundred and ninety infertile patients with periadnexal adhesions as the only cause of their infertility were treated by microsurgery (86) or operative laparoscopy (104) and were followed up for 24 months. Our results indicate that advanced laparoscopic surgery in general is as effective as microsurgery in healthy infertile patients with adhesions but offers some advantages in comparison to laparotomy. Factors that adversely affect the postoperative success rates are the age of the women, the duration of infertility, and the severity of the adhesions.
Autoimmune Antiovarian Antibodies and Their Impact on the Success of an IVF/ET Program
Authors: HOŘEJŠÍ JAN , MARTÍNEK JINDRICH , NOVÁKOVÁ DANA , MADAR JINDRICH , BRANDEJSKA MILADA
Published: July 2010

Abstract: In previous papers, we referred to studies of the influence of anti‐ovarian autoantibodies on menstrual cycle disorders in adolescent girls. We examined autoantibodies against ooplasma, zona pellucida, membrana granu‐losa, theca folliculi interna, and lutein cells. In infertile women in the IVF/ET program, we studied the positivity of antiovarian antibodies and cytokines, namely, TNF‐α and IL‐1β, in follicular fluid correlated with the following sub‐groups, characterized by the outcome of in vitro fertilization, as follows: G, pregnant; F, fertilized; N, nonfertilized; and O, no oocyte gained. The presence of autoantibodies corresponds to the success or failure of the IVF/ET program. Our results support the hypothesis that antiovarian autoantibodies play an important role in both the endocrine and the reproductive function of the human ovary and that it can influence them negatively.
Complexity IX. Closure over the Organization of a Scientific Truth
Authors: CHANDLER JERRY L.R.
Published: July 2010

Abstract:The specificity of human knowledge allow one to construct specific truths about human behavior. A structural notation and language for describing a complex hierarchically organized biological system was developed for the explicit purpose of analyzing the origins of health and disease. A specific application of these concepts to a specific patient (such as an individual suffering from the heritable disease, sickle cell anemia) requires a systematic formulation of a scientific truth. No universal law is applicable. The value of a clinical truth for the patient, as well as for the physician and society, is substantial. This value has moral, ethical, and legal weight. Both physics and chemistry use a universalexternalinvariant reference system. Human beings and other living organisms function by aninternalreference system that is neither invariant nor universal. In order to address the complexity of scientific truths within living systems, a mathematical graph is constructed from observations, descriptions, and symbolizations of the relevant human scientific activities and is placed in mutual coreference with three philosophical theories of truth. Consistency within the referencing relations of the graphic object creates an image of complex truths. When mapped over degrees of internal organization, the structural consistencies can form hierarchically transitive relations (many‐to‐one) creating redundancies that confirm one‐another. Both structural and dynamic information can be composed within the graphic framework. The redundancies intrinsic to the degrees of organization notation, semantics, and syntax augment one another in the search for scientific truth. The degree of certitude emerging from structural implications increases in relation to the number of hierarchical degrees of organization invoked to represent the various behaviors of complex systems (as illustrated by the sickle cell anemia example). The successful synthesis of the complex image (or complex simple) of a scientific truth approaches the Heideggerian notion of identity in the sense thatA=AandA is A.
Fundamental and Modal Processes in the Evolution of Natural Systems
Authors: FARRE GEORGE L.
Published: July 2010

Abstract:This paper offers a brief sketch of the evolution ofnatural systemswithin the context of cosmic evolution. The argument, conducted from an energy stance but without recourse to the mathematical apparatus of quantum physics, distinguishes the processes by which energy is transformed from the processes in which it is distributed in a local context. The main focus is on the energetic stratification of natural systems, its causes, and its consequences. A brief coda points to some implications of this treatment.
The Nature of the Organism: Life Has a Life of Its Own
Authors: BROOKS DANIEL R.
Published: July 2010

Abstract:The question of closure in biological systems is central to understanding the origins of the biological variation and complexity upon which various forms of selection act. Much of evolutionary theory, especially in the second half of the twentieth century, is concerned with the consequences of environmental selection acting on biodiversity, but neglects questions of the origin of that diversity. This has permitted us to act as if an explanation ofconsequences was the ultimate explanation in biology. However, Darwin understood that evolution was both information driven and information constrained. The link between evolutionary constraints and closure can be profitably explored by starting with Darwin's notion of the primacy of “the nature of the organism” over “the nature of the conditions” articulated in the sixth edition ofOrigin of Species. Contemporary ideas of self‐organization, emergence, complexity, and inherent (developmental and phylogenetic) constraints can be seen as an elaboration and refinement of Darwin's views if we adopt the following perspective: (1) information is cheap, not costly, to produce, but may have costly consequences; and (2) information is produced by systems that are informationally closed but remain thermodynamically open.
The Organism and the Open System: Ervin Bauer and Ludwig von Bertalanffy
Authors: BRAUCKMANN SABINE
Published: July 2010

Abstract:In this historical treatise two biological‐system theories, formulated in the 1920s and 1930s, are roughly sketched. The first part discusses the concept of a thermodynamically open system, as coined by the Russian pathologist Ervin Bauer (1890–1942). Like Bertalanffy, Bauer wanted to prove the specificity of the biological sciences against physics. To achieve this, he postulated the necessity to formulate specific laws of motion which are valid for living matter alone. In the second part of the paper, the organismic‐system theory of the Austrian‐Canadian philosopher and biologist Ludwig von Bertalanffy (1901–1972) is outlined. The focus of this theory relied on the process dynamics that is inherent inside an organismic system. Both theories exemplify closure models for a living organism from a methodical point of view that distinguishes these earlier models from semantic closure, developed by Howard Pattee as an epistemic clue in solving the enigma of living phenomena. The objective here is to disclose the essential differences between these closure conceptions. To encourage further research on closure, the essay concludes with a few questions concerning clarification of the term.
The Formal Nature of Emergent Biological Organization and Its Implications for Understandings of Closure
Authors: SHEETS‐JOHNSTONE MAXINE
Published: July 2010

Abstract:This paper shows how recognition of biological form, of which the dynamics of closure is an integral part, is mandated by research on autopoietic systems, self‐organization, evolutionary theory, and on topics in a variety of other areas, including infant and child development. It shows how a “matter pure and simple” (a mechanical concept of nature) is inimical to veridical understandings and explanations of emergent organization from the level of cells to the level of intact organisms‐animate forms. By means of an analysis and discussion of writings by prominent researchers in diverse fields, a brief inquiry into neuron firing, and a consideration of intrinsic dynamics and primal animation, this paper shows that a principle of motion or animation informs biological nature. In other words, the fundamentally dynamic character of biological form at all levels exemplifies the kinetic character of living matter. The final section of this paper pinpoints implications for closure, emphasizing the need for an acknowledgement of the dynamics of closure and the need for theoretical and biological reformulations of living systems that incorporate that dynamics. It exemplifies the implication in each instance with reference to authors represented in this volume.
Tailored Therapy to Fit Individual Profiles: Genetics and Coronary Artery Disease
Authors: JUKEMA J. WOUTER , KASTELEIN JOHN J.P.
Published: July 2010

Abstract: In the twentieth century, coronary artery disease (CAD) was the major cause of morbidity and mortality in western societies. Genetics and environmental influences clearly contribute to CAD. Our genetic makeup contributes to not only coronary risk factors, but also determines an individual's response to environmental challenges such as diet, drugs, and tobacco. Genetic testing is likely to be more predictive of our predisposition to CAD than current conventional testing of known risk factors. Therapy aimed at altering the regulation of genes or their transcribed proteins may prove appropriate in individual patients, depending on their genetic background. The understanding of our genetic predisposition to CAD may enable targeted environmental modification strategies aimed at individuals at greatest risk. Both in terms of the huge costs of drugs to society and in terms of needless medicalization, genotyping in order to tailor therapy might become a routine part of risk management earlier than we think.
Scavenger Receptor Classes A and B: Their Roles in Atherogenesis and the Metabolism of Modified LDL and HDL
Authors: VAN BERKEL THEO J.C. , VAN ECK MIRANDA , HERIJGERS NICOLE , FLUITER KEES , NION S.
Published: July 2010

Abstract: Scavenger‐receptor class A has been held responsible for the clearance of modified LDL from the blood circulation. However, in mice deficient in scavenger‐receptor class A, the decay in vivo of acetylated LDL (t1/2 < 2 min), as well as tissue distribution and liver uptake (at 5 min 77.4 ±6 4.6% of the injected dose) are not significantly different from control mice. The degradation capacity of acetylated LDL with liver endothelial cells, Kupffer cells, and peritoneal macrophages from knock‐out mice was 58%, 63%, and 17% of the control, respectively, indicating that scavenger‐receptor class A is relatively more important for the degradation of acetylated LDL and foam cell formation in peritoneal macrophages as compared to the liver cell types. This might explain the 60% reduction in atherosclerotic lesion area in scavenger‐receptor‐deficient apoE knock‐out mice as compared to control apoE knock‐out mice. Scavenger‐receptor BI can facilitate selective uptake of cholesterol esters from HDL. A high cholesterol diet for two weeks induced an 80% downregulation of scavenger‐receptor BI in the liver parenchymal cells while expression in liver macrophages is increased fourfold. The in vivo kinetics for the selective uptake of (oxidized) cholesterol esters from HDL correlate with the changes in scavenger‐receptor BI expression. It is suggested that scavenger‐receptor BI is subject to different regulatory mechanisms in parenchymal liver cells and macrophages related to a difference in function in these cell types.
Roles of the AGE‐RAGE System in Vascular Injury in Diabetesa
Authors: YAMAMOTO YASUHIKO , YAMAGISHI SHO‐ICHI , YONEKURA HIDETO , DOI TOSHIO , TSUJI HIROKO , KATO ICHIRO , TAKASAWA SHIN , OKAMOTO HIROSHI , ABEDIN JOYNAL , TANAKA NOBUSHIGE , SAKURAI SHIGERU , MIGITA HIDEYUKI , UNOKI HIROYUKI , WANG HUA , ZENDA TAKAHIRO , WU PING‐SHENG , SEGAWA YASUNORI , HIGASHIDE TOMOMI , KAWASAKI KAZUO , YAMAMOTO HIROSHI
Published: July 2010

Abstract: This study concerns whether advanced glycation endproducts (AGE) are related to microvascular derangement in diabetes, exemplified by pericyte loss and angiogenesis in retinopathy and by mesangial expansion in nephropathy. AGE caused a decrease in viable pericytes cultivated from bovine retina. On the other hand, AGE stimulated the growth and tube formation of human microvascular endothelial cells (EC), this being mediated by autocrine vascular endothelial growth factor. In AGE‐exposed rat mesangial cells, type IV collagen synthesis was induced. Those AGE actions were dependent on a cell surface receptor for AGE (RAGE), because they were abolished by RAGE antisense or ribozyme. The AGE‐RAGE system may thus participate in the development of diabetic microangiopathy. This proposition was supported by experiments with animal models; several indices characteristic of retinopathy were correlated with circulating AGE levels in OLETF rats. The predisposition to nephropathy was augmented in RAGE transgenic mice when they became diabetic.
Properties of Two VEGF Receptors, Flt‐1 and KDR, in Signal Transductiona
Authors: SATO YASUFUMI , KANNO SHINICHI , ODA NOBUYUKI , ABE MAYUMI , ITO MIKITO , SHITARA KENYA , SHIBUYA MASABUMI
Published: July 2010

Abstract: The properties of two VEGF receptors, Flt‐1 and KDR, in the signal transduction of VEGF in human umbilical vein endothelial cells (HUVECs) were investigated by using two newly developed blocking monoclonal antibodies (mAbs) against Flt‐1 and KDR. VEGF stimulated the expression of transcription factor Ets‐1 as well as matrix metalloproteinase‐1 (MMP‐1) and Flt‐1 in HUVECs. The KDR/Flt‐1 heterodimer and the KDR homodimer mediate the expression of Ets‐1, MMP‐1, and Flt‐1. VEGF also stimulated DNA synthesis and migration of HUVECs. DNA synthesis is mediated by the same signaling system as the expression of Ets‐1. In contrast, cell migration is regulated by two distinct signaling systems. The Flt‐1 homodimer is required for actin reorganization. The KDR/Flt‐1 heterodimer and the KDR homodimer are required for the assembly of vinculin in focal adhesion plaque by regulating the phosphorylation of focal adhesion kinase (FAK) and paxillin.
Role of the Vascular NADH/NADPH Oxidase System in Atherosclerosis
Authors: YOKOYAMA MITSUHIRO , INOUE NOBUTAKA , KAWASHIMA SEINOSUKE
Published: July 2010

Abstract:It is apparent that vascular tissues can produce reactive oxygen species, including the superoxide anion, and that their increased production can contribute to altered control of vasomotor tone and atherosclerosis. The NADH/NADPH oxidase system, which includes a 22 kD subunit (p22 phox), is the major source of superoxide production in vascular tissues. The superoxide radical oxidizes LDL and oxidized LDL is shown to be a key component in atherogenesis. Superoxide anion inactivates the NO radical, an anti‐atherogenic molecule. Lysophosphatidylcholine, which accumulates during oxidative modification of LDL, has multiple effects on vascular cells, including cell proliferation, migration, apoptosis, and gene expression. Lysophosphatidylcholine stimulates superoxide production in endothelial cells through the NADH/NADPH oxidase‐dependent mechanism. To investigate the expression of p22 phox in normal and atherosclerotic coronary arteries, samples were obtained from autopsy and examined using immunohistochemistry. In normal vessels, weak positive staining of p22 phox was detectable only in the adventitial layer. In contrast, strong immunoreactivity for p22 phox was present in atherosclerotic lesions around lipid core and shoulder regions. P22 phox was localized in the macrophages, fibroblasts, endothelial cells, and some smooth muscle cells which was identified by immunofluorescence double staining. The genetic analysis of the p22 phox gene by restriction fragment length polymorphism (RFLP) for control subject and patients with coronary artery disease revealed that the prevalence of the TC+TT genotype of the C242T polymorphism of the p22 phox gene in control subjects was significantly more frequent than in coronary artery disease patients, indicating that the mutation of the p22 phox gene might reduce the susceptibility for coronary artery disease, which is independent of other coronary risk factors. These observations suggest that oxidative stress, mainly via the NADH/NADPH oxidase system in the vasculature, may play an important role in the pathogenesis of atherosclerosis.
Annexin II and Regulation of Cell Surface Fibrinolysis
Authors: HAJJAR KATHERINE A. , ACHARYA SUCHITRA S.
Published: July 2010

Abstract: The regulated function of the fibrinolytic system is fundamental to the solubilization of fibrin‐containing thrombi and to a number of other biologic processes. In recent years, several receptors, which serve to localize proteolytic activity on the cell surface, have been identified on endothelial cells, blood cells, neuronal cells, and tumor cells. One such receptor is annexin II, a calcium‐ and phospholipid‐binding protein that serves as a profibrinolytic coreceptor for tissue plasminogen activator and plasminogen on endothelial cells. Accumulating evidence suggests that impaired cell surface fibrinolytic assembly could lead to progressive atherothrombotic disease. In addition, dysregulation of annexin II expression in acute promyelocytic leukemia is an important mechanism for the bleeding diathesis associated with this malignancy.