bluuebunny/crossref_metadata_2025 huggingface dataset:
Cosmic Questions
Authors: PRIMACK JOEL R. , ABRAMS NANCY ELLEN
Published: July 2010

Abstract: This introductory talk at the Cosmic Questions conference sponsored by the AAAS summarizes some earlier pictures of the universe and some pictures based on modern physics and cosmology. The uroboros (snake swallowing its tail) is an example of a traditional picture. The Biblical flat‐earth picture was very different from the Greek spherical earth‐centered picture, which was the standard view until the end of the Middle Ages. Many people incorrectly assume that the Newtonian picture of stars scattered through otherwise empty space is still the prevailing view. Seeing Earth from space shows the power of a new picture. The Hubble Space Telescope can see all the bright galaxies, all the way to the cosmic Dark Ages. We are at the center of cosmic spheres of time: looking outward is looking backward in time. All the matter and energy in the universe can be represented as a cosmic density pyramid. The laws of physics only allow the material objects in the universe to occupy a wedge‐shaped region on a diagram of mass versus size. All sizes — from the smallest size scale, the Planck scale, to the entire visible universe — can be represented on the Cosmic Uroboros. There are interesting connections across this diagram, and the human scale lies in the middle.
Extraterrestrial Intelligence? Not Likely
Authors: DeVORE IRVEN
Published: July 2010

Abstract: The possibility that there exist extraterrestrial creatures with advanced intelligence is considered by examining major events in mammalian, primate, and human evolution on earth. The overwhelming evidence is that the evolution of intelligence in creatures elsewhere who have the capability to communicate with us is vanishingly small. The history of the evolution of advanced forms of life on this planet is so beset by adventitious, unpredictable events and multiple contingencies that the evolution of human‐level intelligence is highly unlikely on any planet, including earth.
The West Nile Virus Encephalitis Outbreak in the United States (1999‐2000)
Authors: ASNIS DEBORAH S. , CONETTA RICK , WALDMAN GLENN , TEIXEIRA ALEX A.
Published: July 2010

Abstract: Viruses cause most forms of encephalitis. The two main types responsible for epidemic encephalitis are enteroviruses and arboviruses. The City of New York reports about 10 cases of encephalitis yearly. Establishing a diagnosis is often difficult. In August 1999, a cluster of five patients with fever, confusion, and weakness were admitted to a community hospital in Flushing, New York. Flaccid paralysis developed in four of the five patients, and they required ventilatory support. Three, less severe, cases presented later in the same month. An investigation was conducted by the New York City (NYC) and New York State (NYS) health departments and the national Centers for Disease Control and Prevention (CDC). The West Nile virus (WNV) was identified as the etiologic agent. WNV is an arthropod‐borne flavivirus, with a geographic distribution in Africa, the Middle East, and southwestern Asia. It has also been isolated in Australia and sporadically in Europe but never in the Americas. The majority of people infected have no symptoms. Fever, severe myalgias, headache, conjunctivitis, lymphadenopathy, and a roseolar rash can occur. Rarely, encephalitis or meningitis is seen. The NYC outbreak resulted in the first cases of WNV infection in the Western Hemisphere and the first arboviral infection in NYC since yellow fever in the nineteenth century. The WNV is now a public health concern in the United States.
Demographers and the Study of Mortality
Authors: CALDWELL JOHN C.
Published: July 2010

Abstract:Demographers have for a long time adopted an empirical approach to the study of the levels and trends of mortality, fertility, and population size. They depend for their analyses on data, usually collected until recent times by government and often for other purposes. Modern demography had its origins in Britain in the second half of the seventeenth century. The major focus of demographers has usually been on mortality, although fertility studies predominated in the 1960s and 1970s. Mortality decline in the West only became certain in the late nineteenth century. Until the 1960s the fastest mortality declines were for the young, but an unheralded mortality decline among the old thereafter became important. The world, especially in economically advanced countries, is faced with an increasingly high proportion of old people, explained largely, not by mortality decline, but by fertility decline. Explanations for the mortality transition place different emphases on the role of modern medicine, better nutrition, and behavioral and social change, particularly rising levels of education. Even among the old, at least until 85 years of age, there are wide differentials in mortality by educational level. Analysts have divided the mortality transition into stages: (1) high, pretransitional mortality, (2) early transitional mortality with the decline explained by the conquest of infectious disease, and (3) late transitional mortality largely attributable to degenerative disease. Some have now added stage (4), the reduction or delay in death from degenerative causes. Attempts have been made to effect the convergence of demographic and epidemiological approaches to the analysis of mortality, and they have been more successful in the case of medical demographic than in social demographic approaches.
Telomere Length Dynamics in Normal Individuals and in Patients with Hematopoietic Stem Cell‐Associated Disorders
Authors: BRÜMMENDORF TIM H. , RUFER NATHALIE , HOLYOAKE TESSA L. , MACIEJEWSKI JAREK , BARNETT MICHAEL J. , EAVES CONNIE J. , EAVES ALLEN C. , YOUNG NEAL , LANSDORP PETER M.
Published: July 2010

Abstract: The telomere length in nucleated peripheral blood (PB) cells indirectly reflects the mitotic history of their precursors: the hematopoietic stem cells (HSCs). The average length of telomeres in PB leukocytes can be measured using fluorescence in situ hybridization and flow cytometry (flow FISH). We previously used flow FISH to characterize the age‐related turnover of HSCs in healthy individuals. In this review, we describe results of recent flow FISH studies in patients with selected hematopoietic stem cell‐associated disorders: chronic myelogeneous leukemia (CML) and several bone marrow failure syndromes.

CML is characterized by a marked expansion of myeloid Philadelphia chromosome positive (Ph+) cells. Nevertheless, nonmalignant (Ph−) HSCs typically coexist in the bone marrow of CML patients. We analyzed the telomere length in >150 peripheral blood leukocytes (PBLs) and bone marrow samples of patients with CML as well as samples of Ph‐ T‐lymphocytes. Compared to normal controls, the overall telomere fluorescence in PBLs of patients with CML was significantly reduced. However, no telomere shortening was observed in Ph‐ T‐lymphocytes. Patients in late chronic phase (CP) had significantly shorter telomeres than those assessed earlier in CP. Our data suggest that progressive telomere shortening is correlated with disease progression in CML.

Within the group of patients with bone marrow failure syndromes, we only found significantly shortened telomeres (compared to age‐adjusted controls) in granulocytes from patients with aplastic anemia (AA). Strikingly, the telomere length in granulocytes from AA patients who had recovered after immunosuppressive therapy (recAA) did not differ significantly from controls, whereas untreated patients and nonresponders with persistent severe pancytopenia (sAANR) showed marked and significant telomere shortening compared to healthy donors and patients with recAA. Furthermore, an inverse correlation between age‐adjusted telomere length and peripheral blood counts was found in support of a model in which the degree of cytopenia and the amount of telomere shortening are correlated. These results support the concept of extensive proliferation of HSCs in subgroups of AA patients and suggest a potential use of telomere‐length measurements as a prognostic tool in this group of disorders as well.
Cardiac Vagal Chemosensory Afferents
Authors: SCHULTZ HAROLD D.
Published: July 2010

Abstract: Stimulation of cardiac vagal afferent endings evokes reflex hypotension and bradycardia, also known as a Bezold‐Jarisch effect. The physiological importance of this reflex pathway remains uncertain today, but it is increasingly apparent that cardiac vagal afferents can play an important role in modulating cardiovascular control in pathophysiological states, particularly myocardial ischemia. The afferent endings that compose this vagal input are functionally diverse. Ventricular endings exist that are stimulated by wall motion. However, cardiac chemosensitive endings, stimulated by a variety of metabolically active substances known to be produced by the stressed myocardium (e.g., bradykinin, prostaglandins, reactive oxygen species), play a major role in mediating reflex adjustments during myocardial ischemia. Data are presented highlighting the importance of arachidonic acid metabolites and oxygen radicals in activating cardiac vagal endings during myocardial ischemia and reperfusion, and their role in modulating cardiac afferent sensitivity in the disease states of heart failure and insulin‐dependent diabetes.
Adenovirus‐mediated Gene Transfer into the NTS in Conscious Rats
Authors: HIROOKA YOSHITAKA , SAKAI KOJI , KISHI TAKUYA , TAKESHITA AKIRA
Published: July 2010

Abstract: The nucleus tractus solitarii (NTS) is an important site for the regulation of sympathetic nerve activity. It receives the signals through afferent fibers from arterial baroreceptors, chemoreceptors, cardiopulmonary receptors, and other visceral receptors. Many studies have examined the role of nitric oxide (NO) in the NTS in cardiovascular regulation. However, most of these studies were conducted in an acute state with anesthesia. We have developed a novel technique of endothelial nitric oxide synthase (eNOS) gene transfer into the NTS in vivo. Adenovirus vectors encoding either the β‐galactosidase gene (Adβgal) or the endothelial nitric oxide synthase gene (AdeNOS) gene were transfected into the NTS. In the Adβgal‐treated rats, the local expression of β‐galactosidase was confirmed by X‐Gal staining, and β‐galactosidase activity was quantified using a colorimetric assay. In the AdeNOS‐treated rats, the local expression of eNOS protein was confirmed by immunohistochemistry, and eNOS production was measured by in vivo microdialysis. Blood pressure and heart rate were monitored by a radio‐telemetry system in a conscious state. The expression of each gene was observed from day 5 to day 10 after the gene transfer. In the AdeNOS‐treated rats, blood pressure and heart rate significantly decreased from day 5 to day 10, and then thereafter gradually recovered over time. Our method may be useful in examining the local effect of a particular substance produced by a specific gene in the brain on cardiovascular function.
Neurohumoral Regulation in Ischemia‐Induced Heart Failure
Authors: FELDER ROBERT B. , FRANCIS JOSEPH , WEISS ROBERT M. , ZHANG ZHI‐HUA , WEI SHUN‐GUANG , JOHNSON ALAN KIM
Published: July 2010

Abstract: Congestive heart failure (CHF) is characterized by neurohumoral excitation. Increased sympathetic drive and activation of the renin‐angiotensin‐aldosterone system (RAAS), with vasoconstriction and volume retention, are hallmarks of the CHF syndrome. Treatment strategies have targeted the peripheral influences of these two systems, but have not addressed the central mechanisms that drive them. We monitored the development of CHF following coronary ligation in adult Sprague‐Dawley rats. Left ventricular dysfunction characteristic of CHF was confirmed by echocardiography, and the CHF syndrome was validated by measurements of circulating hormones, sodium appetite, thirst, renal sodium and water retention, and renal sympathetic nerve activity (RSNA). In CHF rats, neuronal activity in the hypothalamic paraventricular nucleus (PVN), which mediates downstream effects of forebrain circumventricular organs, was increased and was inhibited by blocking components of the RAAS at the forebrain level. Forebrain (AV3V) lesions and intracarotid (forebrain directed) injections of agents (captopril, losartan, spironolactone) that block RAAS substantially attenuated the behavioral and physiological manifestations of CHF. Intravenous losartan and captopril, in doses that lower arterial pressure, increased RSNA. These findings demonstrate an important role for RAAS‐activated forebrain mechanisms in CHF and suggest that the central neural mechanisms driving sympathetic nerve activity and volume retention may persist and promote the progression of CHF despite treatments directed toward the peripheral influences of RAAS.
Laparoscopic Management of Adnexal Masses
Authors: PEJOVIC TANJA , NEZHAT FARR
Published: July 2010

Suspected ovarian neoplasm is a common clinical problem affecting women of all ages. Although the majority of adnexal masses are benign, the primary goal of diagnostic evaluation is the exclusion of malignancy. It has been estimated that approximately 5–10% of women in the United States will undergo a surgical procedure for a suspected ovarian neoplasm during their lifetime. Despite the magnitude of the problem, there is still considerable disagreement regarding the optimal surgical management of these lesions. Traditional management has relied on laparotomy to avoid undertreatment of a potentially malignant process. Advances in detection, diagnosis, and minimally invasive surgical techniques make it necessary now to review this practice in an effort to avoid unnecessary morbidity among patients. Here, we review the literature on the laparosopic approach to the treatment of the adnexal mass without sacrificing the principles of oncologic surgery. We highlight potentials of minimally invasive surgery and address the risks associated with the laparoscopic approach.
Neointimal Formation by Circulating Bone Marrow Cells
Authors: CAMPBELL JULIE H. , HAN CHIH‐LU , CAMPBELL GORDON R.
Published: July 2010

Abstract: The origin of smooth muscle cells involved in vascular healing was examined. Eighteen C57BL/6 (Ly 5.2) female mice underwent whole body irradiation followed by transfusion with 106 bone nucleated marrow cells from congenic (Ly 5.1) male donors. Successful repopulation by donor marrow was demonstrated after 4 weeks by flow cytometry with FITC‐conjugated A20.1/Ly 5.1 monoclonal antibody. The iliac artery of six of the chimeric mice was scratch‐injured by five passes of a probe, causing severe medial damage. After 4 weeks the arterial lumen was obliterated by a cell‐rich neointima, with α‐smooth muscle actin‐containing cells present around the residual lumen. Approximately half of these cells were of male donor origin, as evidenced by in situ hybridization with a Y chromosome‐specific probe. An organized arterial thrombus was formed in the remaining 12 chimeric mice by inserting an 8‐0 silk suture into the left common carotid artery. Donor cells staining with α‐smooth muscle actin were found in those arteries sustaining serious damage but not in arteries with minimal damage. Our results suggest that bone marrow‐derived cells are recruited in vascular healing as a complementary source of smooth muscle‐like cells when the media is severely damaged and few resident smooth muscle cells are available to effect repair.
Scavenger Receptors, Oxidized LDL, and Atherosclerosis
Authors: BOULLIER AGNES , BIRD DAVID A. , CHANG MI‐KYUNG , DENNIS EDWARD A. , FRIEDMAN PETER , GILLOTTE‐TAYLOR KRISTIN , HÖRKKÖ SOHVI , PALINSKI WULF , QUEHENBERGER OSWALD , SHAW PETER , STEINBERG DANIEL , TERPSTRA VALESKA , WITZTUM JOSEPH L.
Published: July 2010

Abstract: Oxidized LDL (OxLDL) competes with oxidatively damaged and apoptotic cells for binding to mouse peritoneal macrophages, implying the presence of one or more common domains. However, the nature of the ligands involved has not been determined. Studies in this laboratory over the last several years provide evidence that oxidized phospholipids, present in OxLDL and also in the membrane of apoptotic cells, represent one such ligand. These oxidized phospholipids, either in the lipid phase of OxLDL or becoming attached covalently to apoprotein B during LDL oxidation, have been shown to play a major role in the binding of OxLDL to CD36 and to SR‐B1 expressed in transfected cells. The lipid and protein moieties compete with each other to some extent, indicating that they are binding to at least one common site. A monoclonal antibody selected because of its reactivity with OxLDL proved to be an antibody against oxidized phospholipids (but not native phospholipids). This antibody (EO6) blocked the uptake of OxLDL by CD36 and by SR‐B1 in transfected cells by as much as 80%; it also inhibited macrophage phagocytosis of apoptotic cells by about 40%. Thus, the persistence of receptors for OxLDL during evolution is probably accounted for by their role in recognition of ligands on the surfaces of oxidatively damaged or apoptotic cells. This has important implications in biology generally and specifically in atherogenesis, because apoptosis is a prominent feature of late lesions.
Genomics and Atherosclerosis
Authors: SAKAKI YOSHIYUKI
Published: July 2010

Abstract: Recent progress in the human genome project allows us to study the genetic basis of complex traits such as atherosclerosis and diabetes. Among various approaches, a genetic approach such as affected sib‐paired analysis and case‐control study has successfully identified genes for susceptibility to Alzheimer's disease and diabetes. Several points to be considered are discussed for their successful application to athroscelorosis. In addition, functional genomic approaches based on powerful technology such as cDNA microarray and knockout mice allow us to identify genes and proteins involved in the complex biological (disease) process. As a successful example, a transgenic mice study of circadian rythm in transgenic mice is described.
Atherosclerosis and Cancer
Authors: ROSS JEFFREY S. , STAGLIANO NANCY E. , DONOVAN MICHAEL J. , BREITBART ROGER E. , GINSBURG GEOFFREY S.
Published: July 2010

Abstract: Recently, a series of shared molecular pathways have emerged that have in common a significant role in the pathogenesis and progression of both atherosclerosis and cancer. Oxidative stress and the cellular damage that results from it have been implicated in a wide variety of disease processes including atherogenesis and neoplasia. Toxic metabolites produced by cigarette smoking and increased dietary fat intake are implicated in the pathogenesis of both diseases. It has been hypothesized that atherosclerosis may begin when an injury or infection mutates or transforms a single arterial smooth muscle cell in the progenitor of a proliferative clone similar to the most widely held theory of carcinogenesis. Cell proliferation regulatory pathways including genes involved in the G1S checkpoint (p53, pRb, p15, p16, and cyclins A, D, E, and cdk 2,4) have been associated with plaque progression, stenosis and restenosis after angioplasty as well as in cancer progression. Alterations in cell adhesion molecules (integrins, cadherin‐catenins) have been linked to plaque formation and thrombosis as well as to tumor invasion and metastasis. Altered expression of proteases associated with thrombolysis has been implicated in atherosclerotic plaque expansion and hemorrhage and in the invasion and metastasis of malignancy. Ligand‐growth factor receptor interactions (tyrosine kinases) have been associated with early atherosclerotic lesions as well as cancer development and spread. Nuclear transcription factors such as NFκB have been associated with progression of both diseases. Angiogenesis modulators have recently been linked to plaque expansion and restenosis of atherosclerotic lesions as well as local and metastatic tumor expansion. Common disease treatments, such as the use of growth factor inhibitors and radiation treatment, established anticancer treatments, were recently introduced into atherosclerosis therapeutic strategies to prevent restenosis after angioplasty and endarterectomy. In conclusion, a series of molecular pathways of disease development and progression common to atherosclerosis and cancer support that the world's two most common diseases are far more closely aligned than previously believed and that emerging anti‐inflammatory and antiproliferative therapeutic strategies may ultimately be efficacious in both conditions.
Study on PDGF Receptor β Pathway in Glomerular Formation in Neonate Mice
Authors: SANO HIDETO , YOKODE MASAYUKI , TAKAKURA NOBUYUKI , TAKEMURA GENZOU , DOI TOSHIO , KATAOKA HIROSHI , SUDO TETSUO , NISHIKAWA SATOMI , FUJIWARA HISAYOSHI , NISHIKAWA SHIN‐ICHI , KITA TORU
Published: July 2010

Abstract: The assembly of vascular endothelial cells (ECs) and smooth muscle cells is a critical event in the development of the cardiovascular system. Although the role of ECs in this event has been studied intensively, the cross‐talk between the two cell components remains poorly understood. In this study, we blocked platelet‐derived growth factor receptor (PDGFR) pathways in mice by antagonistic rat monoclonal antibody APB5 against murine PDGFR‐β and examined glomerular capillary formation.
Elevated Expression of Type VIII Collagen Gene in the Atherosclerotic Plaque of the ApoE‐Deficient Mouse
Authors: YASUDA OSAMU , FUKUO KEISUKE , MAEDA NOBUYO , OGIHARA TOSHIO
Published: July 2010

Abstract: The proliferation of smooth muscle cells (SMCs) is a key event in the development of atherosclerosis. To compare the nature of SMCs from advanced atherosclerotic lesions and normal aortic segments, we established SMC lines from plaque‐containing portions (P) and non‐plaque portions (NP) of aortas of apolipoprotein‐E‐deficient mice. Differential display showed several transcripts that were differentially expressed in P and NP lines. One of the transcripts whose expression was elevated in P lines compared to their NP counterparts was for type VIII collagen. Type VIII collagen transcripts were also readily detectable by RT‐PCR in RNA isolated from plaques freshly dissected from apolipoprotein‐E‐deficient mice, but not in RNA isolated from the normal part of the aorta or from adventitia. In situ hybridization showed localization of Col8α1 transcripts near the luminal surface of the plaque. Thus, differential production of type VIII collagen in SMCs from atherosclerotic plaques continues when the cells are maintained in culture.
Bcr in Vascular Smooth Muscle Cells
Authors: ABE JUN‐ICHI , CHE WENYI , YOSHIZUMI MASANORI , HUANG QUNHUA , GLASSMAN MICHAEL , OHTA SHINSUKE , WU YUN , ARLINGHAUS RALPH , BERK BRADFORD C.
Published: July 2010

Abstract: Bcr gene was originally identified by its presence in the chimeric Bcr/Abl oncogene. In vascular smooth muscle cells, platelet‐derived growth factor‐BB (PDGF) stimulated Bcr kinase activity. The mutant PDGF receptor for PI3‐K, but not for PLC‐γ binding sites, showed significantly reduced Bcr kinase activity. Bcr wild‐type enhanced, whereas Bcr kinase negative form inhibited PDGF‐stimulated ERK1/2 activity. A dominant negative Ras did not inhibit Bcr kinase activation, and overexpression of Bcr increased Ras/Raf‐1 activity and DNA synthesis. These results demonstrated the importance of Bcr in PDGF‐mediated events such as activation of Ras, Raf‐1, and ERK1/2 and stimulation of DNA synthesis.
Enhanced Atherosclerosis in Lp(a) WHHL Transgenic Rabbits
Authors: FAN JIANGLIN , SUN HUIJUN , UNOKI HIROYUKI , SHIOMI MASAYUKI , WATANABE TERUO
Published: July 2010

Abstract: High lipoprotein(a) [Lp(a)] levels form a major risk factor for the development of atherosclerosis. The risk of elevated Lp(a) concentrations is significantly increased in patients who also have high levels of LDL cholesterol. Although the relation between Lp(a) and atherosclerosis has been reported in numerous studies, little is known about whether Lp(a) would exacerbate the complicated lesion formation in vivo. To test the hypothesis that increased plasma levels of Lp(a) may enhance the development of atherosclerosis in the setting of hypercholesterolemia, we generated WHHL transgenic rabbits expressing human apolipoprotein (a) and compared the atherosclerotic lesions with those of nontransgenic WHHL rabbits.
Peroxisome Proliferator‐Activated Receptor α Ligands Increase Lectin‐Like Oxidized Low Density Lipoprotein Receptor‐1 Expression in Vascular Endothelial Cells
Authors: HAYASHIDA KAZUTAKA , KUME NORIAKI , MINAMI MANABU , KATAOKA HIROHARU , MORIMOTO MASAFUMI , KITA TORU
Published: July 2010

Abstract: Lectin‐like oxidized low density lipoprotein receptor‐1 (LOX‐1) is a receptor for atherogenic oxidized LDL expressed in vascular endothelial cells, smooth muscle cells, and macrophages. Peroxiosme proliferator‐activated receptors (PPARs) include subfamilies PPARα and PPARγ, which are expressed in endothelial cells and involved in transcriptional regulation of a large number of genes that affect lipoprotein and fatty acid metabolism as well as inflammation. We therefore explored the effects of PPARα and PPARγ ligands on expression of LOX‐1. Treatment of cultured bovine aortic endothelial cells (BAECs) with PPARα ligands (fenofibrate and WY14643) remarkably upregulated LOX‐1 expression, which was detected by western and northern blot analyses. LOX‐1 promoter‐reporter gene assay showed that PPARα ligands activate transcription of the LOX‐1 gene. PPARγ ligands, in contrast, did not significantly affect LOX‐1 expression in BAECs. PPARα appears to be a key regulator in promoting LOX‐1 expression in BAECs. Upregulated expression of LOX‐1 may modulate the catabolism of oxidized LDL and atherosclerotic progression.
Chromatin Image Analysis Provides New Evidence of the Relation of Lymphocytes to Cytokines and sCAM in the Inflammatory Nature of Atherosclerosis
Authors: TEPLYAKOV A. I. , PRYSHCHEPAVA A. V. , CHEGEROVA T. I.
Published: July 2010

Abstract:Comparative analysis of cytokines and sCAM secretion within the lymphocyte chromatin state are possible evidence of inflammatory reactions in atherosclerosis. Two types of response were studied: coagulation and fibrinolysis (incubation of blood clot within 6 hours at 37°C) and standardized viscosimetric flow using a rotational viscometer (shear rate 100 l/s, 60 seconds at 37°C, and incubation within 6 hours at 37°C). Cytokines IL‐1α, IL‐1β, IL‐6, IL‐8, IL‐10 (Immunotech, France), endothelin‐1, and soluble cell adhesion molecules (sCAM) sP‐ and sE‐selectin, sICAM‐1, and sVCAM‐1 (R&D, UK) have been determined using ELISA kits (photometer, Biomek‐1000, Beckman, USA). The chromatin of lymphocyte nuclei was studied using the computer TV morphodensitometry system DiaMorph (Russia) and smears dyed specifically for DNA. Correlational changes in morphodensitometric (MDM) parameters and cytokine and sCAM levels in two tests were compared to initial levels. After rheologic testing, lymphocyte nuclei as a whole had not changed, but chromatin activity had decreased. Reorganization of nuclei after the coagulation test was observed. Endothelin‐1 and sP‐ and sE‐selectin levels were not related to function of lymphocytes (by MDM data) as seen in both tests; it is probable that another cell‐cell communication mechanism had been switched on. We established a strong correlation between chromatin activity of lymphocytes and the serum concentration of IL‐1β, IL‐6, and IL‐10, which are the active participants in the pro‐ and anti‐inflammatory program in atherogenesis. Results are evidence of the role of lymphocytes in pro‐ and anti‐inflammatory cytokine reactions and cytokine‐like sCAM activity in atherosclerosis.
Molecular Dissection of α‐ and Dense‐Core Granule Secretion of Platelets
Authors: YOSHIOKA AKIRA , HORIUCHI HISANORI , SHIRAKAWA RYUTARO , NISHIOKA HIROAKI , TABUCHI ARATA , HIGASHI TOMOHITO , YAMAMOTO AKITSUGU , KITA TORU
Published: July 2010

Abstract: Upon activation, platelets release many active substances stored in α‐ and dense‐core granules. However, the molecular mechanisms governing the regulated exocytosis are not yet fully understood. We have established an assay system using streptolysin‐O‐permeabilized platelets to analyze the Ca2+‐induced secretions of von Willebrand factor stored in α‐granules and [3H]5‐hydroxytryptamine (5‐HT) in dense‐core granules. Using the assay, we found that small GTPase Rab4 regulates α‐, but not dense‐core, granule secretion in platelets. Furthermore, we purified a cytosolic essential protein and currently are analyzing its function.
Stability of Atheromatous Plaque Affected by Lesional Composition
Authors: SHIOMI MASASHI , ITO TAKASHI , HIROUCHI YASUHIKO , ENOMOTO MAKOTO
Published: July 2010

Abstract: We examined how lesional composition is related to the stability of coronary plaques. WHHL rabbits (12 months old) were given pravastatin and fluvastatin orally for 52 weeks. Both statins decreased plasma cholesterol levels by about 25%, but the suppressive effects on the degree of coronary plaques were mild. Macrophage (Mφ) contents in fibromuscular cap regions were decreased by pravastatin, and smooth muscle cell (SMC) contents in those were decreased by fluvastatin. The plaque vulnerability index was low in Mφ‐poor plaques, but high in SMC‐poor plaques. Our results suggest that reduction in Mφs in the fibromuscular cap is related to plaque stabilization and that reduction in SMCs in the fibromuscular cap is related to plaque destabilization.
Contrasting Phenotypes in Reproductive Tissues of Female Estrogen Receptor Null Mice
Authors: COUSE JOHN F. , KORACH KENNETH S.
Published: July 2010

Abstract: The estrogen receptor (ER) exists in two known forms, ERα and ERβ, and acts as a ligand‐inducible transcription factor to fulfill critical roles in reproductive physiology. Although in vitro studies suggest the ERs may play redundant roles, a dissimilar tissue distribution indicates otherwise. Therefore, to gain insight into the role of each ER form, individual lines of mice lacking each respective receptor, as well as mice lacking both ER forms, were generated. αERKO and βERKO female mice possess a normally developed reproductive tract and maintain expression of the opposite ER. The αERKO female is infertile and exhibits a hypoplastic uterus that is refractory to estrogens. The ovaries of the αERKO female are consistently polycystic and lack indications of spontaneous ovulation. In contrast, the βERKO female exhibits a hormonally responsive uterus and grossly normal ovaries, but is subfertile in terms of the frequency and size of litters. Immature females of both ERKO lines successfully ovulate viable ova when superovulated with exogenous gonadotropins, yet the average yield of ooctyes is reduced. Mice lacking both known ER forms (αβERKO) are infertile, possess the expected reproductive tract structures, but exhibit a remarkably distinct ovarian phenotype characterized by postnatal loss of oocytes and redifferentiation of the remaining somatic cells to Sertoli‐like cells. This “sex‐reversal” in the αβERKO ovary is accompanied by the ectopic expression of testis‐specific genes, for example, Sox9 and sulfated‐glycoprotein‐2.
Are the Mediterranean Top Predators Exposed to Toxicological Risk Due to Endocrine Disrupters?
Authors: FOSSI M. C. , CASINI S. , MARSILI L. , AUSILI A. , NOTARBARTOLO DI SCIARA G.
Published: July 2010

Abstract: Man‐made endocrine disrupting chemicals (EDCs) range across all continents and oceans; some geographic areas are potentially more threatened than others: one of these is the Mediterranean Sea. This basin has limited exchange of water with the Atlantic Ocean and is surrounded by some of the most heavily populated and industrialized countries in the world. Accordingly, levels of some xenobiotics are much higher here than in other seas and oceans. In this research the unexplored hypothesis that Mediterranean top predator species (such as large pelagic fish and marine mammals) are potentially at risk due to EDCs is investigated. Here we illustrate the development of sensitive biomarkers (Vitellogenin, Zona Radiata proteins) for evaluation of toxicological risk in top marine predators (Xiphias gladius, Thunnus thynnus thynnus), and nonlethal techniques, such as nondestructive biomarkers (BPMO activities in skin biopsy), for the hazard assessment of threatened species exposed to EDCs, such as marine mammals (Stenella coeruleoalba, Tursiops truncatus, Delphinus delphis, and Balaenoptera physalus).
Peptide Hormones Versus Steroid Hormones: Case Studies from Snail and Turtle Populations
Authors: OBERDÖRSTER EVA
Published: July 2010

Abstract: The proposed mechanisms of masculinization in gastropod mollusks (imposex) and feminization in oviparous vertebrates has focused primarily on the interaction of xenobiotics with the steroid hormone system. The evidence does not support the proposed mechanism of imposex induction, inhibition of CYP 19 (aromatase), since the changes in steroid titers occur only in the later stages of imposex. In addition, the role of vertebrate sex steroid hormones is limited in gastropods. Recent evidence suggests that peptide hormones play a key role in masculinization in snails and may be a more plausible mechanism of imposex induction. Steroid hormones play a role in feminization of oviparous vertebrates. Vitellogenin (Vtg, egg yolk) induction has been used extensively as a biomarker of feminization. However, in some species of turtles there is evidence that high levels of estradiol are necessary to initially induce Vtg. Once this imprinting occurs, lower levels of estradiol can then induce high levels of Vtg. It was found that environmental levels of estradiol do not always induce Vtg in male and juvenile turtles. However, these same levels of estradiol significantly elevate female Vtg levels. Elevated female Vtg may lead to larger, but fewer, eggs, and therefore fewer offspring. However, these offspring may have better survivorship. Alternatively, elevated Vtg may lead to a larger number of smaller eggs, which have been shown to produce smaller hatchlings with reduced survival. The effects of elevate female Vtg on fitness are difficult to assess in such long‐lived species.
Uterine Leiomyoma
Authors: MOOREHEAD MYRON E. , CONARD CRAIG J.
Published: July 2010

Abstract: Many risk factors have been identified as having either a protective or a negative effect on the development of fibroids, but due to methodological issues and a lack of long‐term studies, the exact effect of these factors is ambiguous. In similar dispute is the proper treatment of fibroids. Recent technological advances have introduced newer, less invasive techniques that can remove part or most of the fibroids, but do not eliminate fibroid redevelopment or adhesion formation. In addition, the long‐term effects of these procedures have not been studied fully. More prospective research is required to better understand the epidemiology and treatment of this highly morbid condition.
Nuclear Receptors, Coregulators, Ligands, and Selective Receptor Modulators
Authors: McKENNA NEIL J. , O'MALLEY BERT W.
Published: July 2010

Abstract: Nuclear receptors are ligand‐inducible transcription factors that specifically regulate the expression of target genes involved in metabolism, development, and reproduction. Their primary function is to mediate the transcriptional response in target cells to hormones such as the sex steroids (progestins, estrogens, and androgens), adrenal steroids (glucocorticoids and mineralocorticoids), vitamin D3, and thyroid and retinoid (9‐cis and all‐trans) hormones, in addition to a variety of other metabolic ligands. More than 100 nuclear receptors are known to exist and, together, these proteins comprise the single largest family of metazoan transcription factors, the nuclear receptor superfamily. Their natural ligands, as well as synthetic ligands (selective receptor modulators, or SRMs), are known to influence the interaction of these receptors with accessory molecules called coregulators.
Capitalizing on the Complexities of Estrogen Receptor Pharmacology in the Quest for the Perfect SERM
Authors: McDONNELL DONALD P. , CHANG CHING‐YI , NORRIS JOHN D.
Published: July 2010

Abstract: The term Selective Estrogen Receptor Modulators (SERMs) has been used of late to describe a group of pharmaceuticals that manifest estrogen receptor (ER) agonist activity in some tissues, but that oppose estrogen action in others. Whereas the name describing this class of drugs is new, the concept is not. Indeed, compounds exhibiting tissue‐selective ER agonist/antagonist properties have been around for nearly 40 years. What is new is the idea that it may be possible to capitalize on the paradoxical activities of these drugs and develop them as treatments for estrogenopathies where it is desirable to direct therapy to a specific estrogen‐responsive target organ. This realization has provided the impetus for research in this area and has pushed the development and clinical use of this class of drugs. The objective of this review is to describe how the medical need for SERMs arose and how recent studies of the mechanism of action of the currently available drugs are paving the way for the development of novel drugs with improved selectivity.
Use of SERMs for the Adjuvant Therapy of Early‐Stage Breast Cancer
Authors: WOLFF ANTONIO C. , DAVIDSON NANCY E.
Published: July 2010

Abstract: Tamoxifen was the first in a class of drugs now commonly referred to as selective estrogen receptor modulators or SERMs. SERMs exhibit tissue‐specific estrogenic agonist/antagonist activity through their ability to bind to the estrogen receptor α (ER) protein and interact with coregulatory proteins, thereby modulating transcription of estrogen target genes. Since its first approval by the United States Food and Drug Administration (FDA) in 1977, tamoxifen has been found to (a) lower the risk of recurrence and death for women with early‐stage hormone receptor‐positive breast cancer, irrespective of menopausal and node status or use of adjuvant chemotherapy; (b) reduce the risk of invasive breast cancer following breast conservation in women with ductal carcinoma in situ (DCIS); and (c) reduce the risk of breast cancer in high‐risk women. Toremifene is the only other SERM approved by the FDA for breast cancer treatment. However, it offers no clear clinical advantage over tamoxifen in the adjuvant or metastatic settings. Several other SERMs are in various phases of clinical development. In addition, strategies to combine SERMs with other endocrine therapy like ovarian suppression or aromatase inhibitors are active areas of investigations. At present, SERMs are recognized as the first targeted and relatively nontoxic medical therapy for women with high‐risk or steroid hormone receptor‐positive breast cancer.
The Role of Tamoxifen in Breast Cancer Prevention
Authors: WOLMARK NORMAN , DUNN BARBARA K.
Published: July 2010

Abstract: The Breast Cancer Prevention Trial (P‐1: BCPT) of the National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized 13,388 women, ≥35 years of age, at increased risk for breast cancer [≥1.66% by Gail model criteria or with a history of lobular carcinoma in situ (LCIS)] to 5 years of tamoxifen or placebo. A 49% reduction (P < 0.00001) in invasive breast cancers occurred, 175 with placebo versus 89 with tamoxifen, mainly among estrogen receptor (ER)‐positive tumors (130 with placebo vs. 41 with tamoxifen). The major toxicities of tamoxifen were endometrial cancer (15 with placebo vs. 36 with tamoxifen) and thromboembolic disease, both predominantly in women who were ≥50 years old. Ramifications emerging from the P‐1 results regarding the efficacy and toxicities of preventive tamoxifen include the following: (1) Does tamoxifen induce more virulent breast cancers? (2) Does tamoxifen induce more virulent endometrial cancers? (3) Tamoxifen is especially efficacious in reducing breast cancer risk in LCIS (18 invasive breast cancers with placebo vs. 8 with tamoxifen group) and atypical ductal hyperplasia (AH) (23 invasive breast cancers with placebo vs. 3 with tamoxifen). (4) Does tamoxifen reduce breast cancer risk in women at increased risk due to genetic mutations? (5) How can we prevent tamoxifen‐resistant breast cancers? (6) What do the BCPT results tell us about who should take preventive tamoxifen? In its ongoing effort to lower the incidence of breast cancer, the NSABP is now implementing its second breast cancer prevention trial, the Study of Tamoxifen and Raloxifene (STAR), which is comparing the two agents with regard to efficacy and toxicity.
The Effects of Estrogen and Selective Estrogen Receptor Modulators on Cardiovascular Risk Factors
Authors: WALSH BRIAN W.
Published: July 2010

Abstract: Raloxifene, a selective estrogen receptor modulator, favorably alters several markers of cardiovascular risk in healthy postmenopausal women. While many of its effects are similar to those of conventional hormone replacement therapy (HRT), there are also important differences. Raloxifene lowered low‐density lipoprotein cholesterol levels similarly to estrogen. However, raloxifene lacked the potentially beneficial effects of HRT on high‐density lipoprotein cholesterol levels and plasminogen activation inhibitor‐1, as well as the potentially adverse effects of HRT on triglycerides and C‐reactive protein. Raloxifene also had a potentially beneficial fibrinogen‐lowering effect not seen with conventional HRT. The net effect of these differences is unclear. Proof that raloxifene or HRT reduces the risk of heart disease must await the results of ongoing clinical trials with cardiovascular event end points.
The Effect of SERMs on the Endometrium
Authors: GOLDSTEIN STEVEN R.
Published: July 2010

Abstract:Tamoxifen, the first clinically available SERM, was developed in 1966 and approved by the FDA (United States Food and Drug Administration) in 1978. It is the most prescribed antineoplastic drug in the world, with approximately 10 million women‐use‐years of experience. Tamoxifen has proved efficacious in all settings of breast cancer. However, in the mid‐to‐late 1980s, a series of letters to the editor and case reports announced an association between tamoxifen therapy in women with breast cancer and the development of endometrial carcinoma. Subsequently, in 1998, the observation of a significant 49% reduction in invasive breast cancer relative to placebo in a cohort of women at increased risk for the disease resulted in the early stopping of the National Surgical Adjuvant Breast and Bowel Project's (NSABP) P‐1: Breast Cancer Prevention Trial (BCPT). Importantly, this was the first time that information became available about the effects of tamoxifen in healthy women, that is, women who did not already have breast cancer. In this healthy population, the relative risk of developing endometrial carcinoma in the tamoxifen arm was 2.54, although when stratified by age, in women over 50, the risk grew to 4.01. Thus, the risk appears to be confined to women over 50 because, in contrast, in women under 50 there was no statistically significant increase in the risk of endometrial carcinoma.
SERMs, Ethnicity, and Clinical Trials
Authors: TAYLOR ANNE L.
Published: July 2010

Abstract:Selective estrogen receptor modulators (SERMs) are an exciting new class of pharmacotherapeutics that may have application in a wide variety of disease states. The science, both basic and clinical, that would guide the usage of these agents is in some respects at a relatively early developmental stage. Thus, the research community has an opportunity, before their use becomes widespread, to structure clinical trials such that the most complete profiles of benefits and risks are described. Tamoxifen is the SERM that has been most extensively studied and for which there are indications for both treatment and prevention of breast cancer based on trials involving more than 50,000 women. Despite this seemingly adequate sample size, an extremely important question remains unanswered—namely, whether there are ethnic differences in benefit and adverse effects of SERMs. It has generally been the case that new pharmacologic agents are tested in relatively small numbers of subjects, often only male, in North America and western Europe. While the populations are multiethnic, clinical trial subjects are most often not representative of the ethnic variability of these areas. Guidelines for usage of new drugs based on data from small, ethnically limited population groups are then generalized to other population groups, without consideration that differences in drug metabolism and/or responsiveness might exist.
Tamoxifen for the Reduction in the Incidence of Breast Cancer in Women at High Risk for Breast Cancera
Authors: HONIG SUSAN FLAMM
Published: July 2010

Abstract: Recent legislation, including the Prescription Drug User Fee Act (1992) and the FDA Modernization Act (FDAMA) (1997), has provided an environment in which new drug applications (NDA) can be efficiently reviewed, resulting in rapid access to new drugs or to new uses for approved drugs by the public. The recent submission of a supplemental NDA for tamoxifen for the reduction in the incidence of breast cancer in women at high risk for breast cancer is an excellent example of the application of this legislation. First, the application received expedited but thorough multidisciplinary and interdivisional review by the FDA. Second, it required collaboration between the manufacturer (AstraZeneca Pharmaceuticals), the National Surgical Adjuvant Breast and Bowel Project (NSABP), the National Cancer Institute (NCI), and the FDA. This process worked well and demonstrated that cooperative group data can be used effectively to support an application. Third, a single large adequate and well‐controlled trial was sufficient to support the effectiveness of tamoxifen for this indication. The quantity of evidence required to support approval has been discussed in FDA guidances (“Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products”) and is part of FDAMA.
The Transition to Nonlinearity and New Constraints on Biasing
Authors: Juszkiewicza Roman , Gaztañagab Enrique
Published: July 2010

Abstract: We present two new dynamical tests of the biasing hypothesis. The first is based on the amplitude and the shape of the galaxy‐galaxy correlation function, ξg(r), where r is the separation of the galaxy pair. The second test uses the mean relative peculiar velocity for galaxy pairs, ν12(r). This quantity is a measure of the rate of growth of clustering and it is related to the two‐point correlation function for the matter density fluctuations, ξ(r). Under the assumption that galaxies trace the mass (ξg=ξ), the expected relative velocity can be calculated directly from the observed galaxy clustering. The above assumption can be tested by confronting the expected ν12 with direct measurements from velocity‐distance surveys. Both our methods are checked against N‐body experiments and then compared with the ξg(r) and ν12 estimated from the APM galaxy survey and the Mark III catalogue, respectively. Our results suggest that cosmological density parameter is low, Ωm∼ 0.3, and that the APM galaxies trace the mass at separations r≥ 5 h−1, where h is the Hubble constant in units of 100 km s−1 Mpc. The present results agree with earlier studies, based on comparing higher‐order correlations in the APM with weakly nonlinear perturbation theory. Both approaches constrain the linear bias factor to be within 20% of unity. If the existence of the feature we identified in the APM ξg(r) — the inflection point near ξg= 1 — is confirmed by more accurate surveys, we may have discovered gravity's smoking gun: the long awaited “shoulder” in ξ, generated by gravitational dynamics and predicted by Gott and Rees 25 years ago.