bluuebunny/crossref_metadata_2025 huggingface dataset:
COMPUTATIONAL HYPERSONIC RAREFIED FLOWS
Authors: Ivanov M. S. , Gimelshein S. F.
Published: July 2002

▪ Abstract  Recent considerable progress in the field of rarefied hypersonic computational fluid dynamics (CFD) gives reason to address its evolution to an independent CFD branch that covers many fundamental and closely related applied problems of high-altitude aerothermodynamics of space vehicles. The primary purpose of this review is to describe the main numerical methods and real gas models for investigation of problems of rarefied hypersonic flows, and to review results that we believe demonstrate most clearly the achievements and capabilities of the field of rarefied hypersonic CFD in the last years.
FLUID COATING ON A FIBER
Authors: Quéré David
Published: July 2002

▪ Abstract  We discuss the thickness of the liquid layer entrained by a solid drawn out of a bath, focusing on the case where the solid is a fiber or a wire. Slow withdrawals out of a pure or a complex fluid are described as well as quick coatings. We specify the general laws of entrainment and stress the cases where the fiber curvature plays a role. We finally give an overview on the further evolution of the coated film.
GENETIC ANALYSIS OF CHLOROPHYLL BIOSYNTHESIS
Authors: Suzuki Jon Y. , Bollivar David W. , Bauer Carl E.
Published: July 2002

▪ Abstract  During this decade, there have been major advancements in the understanding of genetic loci involved in synthesis of the family of Mg-tetrapyrroles known as chlorophylls and bacteriochlorophylls. Molecular genetic analysis of Mg-tetrapyrrole biosynthesis was initiated by the performance of detailed sequence and mutational analysis of the photosynthesis gene cluster from Rhodobacter capsulatus. These studies provided the first detailed understanding of genes involved in bacteriochlorophyll a biosynthesis. In the short time since these studies were initiated, most of the chlorophyll biosynthesis genes have been identified by virtue of their ability to complement bacteriochlorophyll a biosynthesis mutants as well as by sequence homology comparisons. This review is centered on a discussion of our current understanding of bacterial, algal, and plant genes that code for enzymes in the Mg-branch of the tetrapyrrole biosynthetic pathway that are responsible for synthesis of chlorophylls and bacteriochlorophylls.
Mitochondrial Genome Evolution and the Origin of Eukaryotes
Authors: Lang B. Franz , Gray Michael W. , Burger Gertraud
Published: July 2002

▪ Abstract  Recent results from ancestral (minimally derived) protists testify to the tremendous diversity of the mitochondrial genome in various eukaryotic lineages, but also reinforce the view that mitochondria, descendants of an endosymbiotic α-Proteobacterium, arose only once in evolution. The serial endosymbiosis theory, currently the most popular hypothesis to explain the origin of mitochondria, postulates the capture of an α-proteobacterial endosymbiont by a nucleus-containing eukaryotic host resembling extant amitochondriate protists. New sequence data have challenged this scenario, instead raising the possibility that the origin of the mitochondrion was coincident with, and contributed substantially to, the origin of the nuclear genome of the eukaryotic cell. Defining more precisely the α-proteobacterial ancestry of the mitochondrial genome, and the contribution of the endosymbiotic event to the nuclear genome, will be essential for a full understanding of the origin and evolution of the eukaryotic cell as a whole.
FUNCTIONS AND MECHANISMS OF RNA EDITING
Authors: Gott Jonatha M. , Emeson Ronald B.
Published: July 2002

▪ Abstract  RNA editing can be broadly defined as any site-specific alteration in an RNA sequence that could have been copied from the template, excluding changes due to processes such as RNA splicing and polyadenylation. Changes in gene expression attributed to editing have been described in organisms from unicellular protozoa to man, and can affect the mRNAs, tRNAs, and rRNAs present in all cellular compartments. These sequence revisions, which include both the insertion and deletion of nucleotides, and the conversion of one base to another, involve a wide range of largely unrelated mechanisms. Recent advances in the development of in vitro editing and transgenic systems for these varied modifications have provided a better understanding of similarities and differences between the biochemical strategies, regulatory sequences, and cellular factors responsible for such RNA processing events.
Conservation and Divergence in Molecular Mechanisms of Axis Formation
Authors: Lall Sabbi , Patel Nipam H.
Published: July 2002

▪ Abstract  Genetic screens in Drosophila melanogaster have helped elucidate the process of axis formation during early embryogenesis. Axis formation in the D. melanogaster embryo involves the use of two fundamentally different mechanisms for generating morphogenetic activity: patterning the anteroposterior axis by diffusion of a transcription factor within the syncytial embryo and specification of the dorsoventral axis through a signal transduction cascade. Identification of Drosophila genes involved in axis formation provides a launch-pad for comparative studies that examine the evolution of axis specification in different insects. Additionally, there is similarity between axial patterning mechanisms elucidated genetically in Drosophila and those demonstrated for chordates such as Xenopus. In this review we examine the postfertilization mechanisms underlying axis specification in Drosophila. Comparative data are then used to ask whether aspects of axis formation might be derived or ancestral.
Trinucleotide Repeats: Mechanisms and Pathophysiology
Authors: Cummings C. J. , Zoghbi H. Y.
Published: July 2002

Within the closing decade of the twentieth century, 14 neurological disorders were shown to result from the expansion of unstable trinucleotide repeats, establishing this once unique mutational mechanism as the basis of an expanding class of diseases. Trinucleotide repeat diseases can be categorized into two subclasses based on the location of the trinucleotide repeats: diseases involving noncoding repeats (untranslated sequences) and diseases involving repeats within coding sequences (exonic). The large body of knowledge accumulating in this fast moving field has provided exciting clues and inspired many unresolved questions about the pathogenesis of diseases caused by expanded trinucleotide repeats. This review summarizes the current understanding of the molecular pathology of each of these diseases, starting with a clinical picture followed by a focused description of the disease genes, the proteins involved, and the studies that have lent insight into their pathophysiology.
Gene Family Evolution and Homology: Genomics Meets Phylogenetics
Authors: Thornton Joseph W. , DeSalle Rob
Published: July 2002

▪ Abstract  With the advent of high-throughput DNA sequencing and whole-genome analysis, it has become clear that the coding portions of the genome are organized hierarchically in gene families and superfamilies. Because the hierarchy of genes, like that of living organisms, reflects an ancient and continuing process of gene duplication and divergence, many of the conceptual and analytical tools used in phylogenetic systematics can and should be used in comparative genomics. Phylogenetic principles and techniques for assessing homology, inferring relationships among genes, and reconstructing evolutionary events provide a powerful way to interpret the ever increasing body of sequence data. In this review, we outline the application of phylogenetic approaches to comparative genomics, beginning with the inference of phylogeny and the assessment of gene orthology and paralogy. We also show how the phylogenetic approach makes possible novel kinds of comparative analysis, including detection of domain shuffling and lateral gene transfer, reconstruction of the evolutionary diversification of gene families, tracing of evolutionary change in protein function at the amino acid level, and prediction of structure-function relationships. A marriage of the principles of phylogenetic systematics with the copious data generated by genomics promises unprecedented insights into the nature of biological organization and the historical processes that created it.
The Interleukin-2 Receptor γ Chain: Its Role in the Multiple Cytokine Receptor Complexes and T Cell Development in XSCID
Authors: Sugamura Kazuo , Asao Hironobu , Kondo Motonari , Tanaka Nobuyuki , Ishii Naoto , Ohbo Kazuyuki , Nakamura Masataka , Takeshita Toshikazu
Published: July 2002

Interleukin 2 (IL-2), a T cell–derived cytokine, targets a variety of cells to induce their growth, differentiation, and functional activation. IL-2 inserts signals into the cells through IL-2 receptors expressed on cell surfaces to induce such actions. In humans, the functional IL-2 receptor consists of the subunit complexes of the α, β, and γ chains, or the β and γ chains. The third component, the γ chain, of IL-2 receptor plays a pivotal role in formation of the full-fledged IL-2 receptor; together with the β chain, the γ chain participates in increasing the IL-2 binding affinity and intracellular signal transduction. Moreover, the cytokine receptors for at least IL-2, IL-4, IL-7, IL-9, and IL-15 utilize the same γ chain as an essential subunit. Interestingly, mutations of the γ chain gene cause human X-linked severe combined immunodeficiency (XSCID) characterized by a complete or profound T cell defect. Among the cytokines sharing the γ chain, at least IL-7 is essentially involved in early T cell development in the mouse organ culture system. The molecular identification of the γ chain brought a grasp of the structures and functions of the cytokine receptor and an in-depth understanding of the cause of human XSCID. To investigate the mechanism of XSCID and development of gene therapy for XSCID, knockout mice for the γ chain gene were produced that showed similar but not exactly the same phenotypes as human XSCID.
REGULATION OF MHC CLASS II GENES: Lessons from a Disease
Authors: Mach Bernard , Steimle Viktor , Martinez-Soria Eduardo , Reith Walter
Published: July 2002

▪ Abstract  Precise regulation of major histocompatibility complex class II (MHC-II) gene expression plays a crucial role in the control of the immune response. A major breakthrough in the elucidation of the molecular mechanisms involved in MHC-II regulation has recently come from the study of patients that suffer from a primary immunodeficiency resulting from regulatory defects in MHC-II expression. A genetic complementation cloning approach has led to the isolation of CIITA and RFX5, two essential MHC-II gene transactivators. CIITA and RFX5 are mutated in these patients, and the wild-type genes are capable of correcting their defect in MHC-II expression. The identification of these regulatory factors has furthered our understanding of the molecular mechanisms that regulate MHC-II genes. CIITA was found to be a non-DNA binding transactivator that functions as a molecular switch controlling both constitutive and inducible MHC-II expression. The finding that RFX5 is a subunit of the nuclear RFX-complex has confirmed that a deficiency in the binding of this complex is indeed the molecular basis for MHC-II deficiency in the majority of patients. Furthermore, the study of RFX has demonstrated that MHC-II promoter activity is dependent on the binding of higher-order complexes that are formed by highly specific cooperative binding interactions between certain MHC-II promoter-binding proteins. Two of these proteins belong to families of which the other members, although capable of binding to the same DNA motifs, are probably not directly involved in the control of MHC-II expression. Finally, the facts that CIITA and RFX5 are both essential and highly specific for MHC-II genes make possible novel strategies designed to achieve immunomodulation via transcriptional intervention.
DIFFERENTIAL SIGNALING BY LYMPHOCYTE ANTIGEN RECEPTORS
Authors: Alberola-Ila Jose , Takaki Satoshi , Kerner James D. , Perlmutter Roger M.
Published: July 2002

▪ Abstract  Studies performed during the past several years make plain that ligand occupancy of antigen receptors need not necessarily provoke identical responses in all instances. For example, ligation of antigen receptors may stimulate a proliferative response, induce a state of unresponsiveness to subsequent stimulation (anergy), or induce apoptosis. How does a single type of transmembrane receptor induce these very heterogeneous cellular responses? In the following pages, we outline evidence supporting the view that the nature of the ligand/receptor interaction directs the physical recruitment of signaling pathways differentially inside the lymphocyte and hence defines the nature of the subsequent immune response. We begin by providing a functional categorization of antigen receptor components, considering the ways in which these components interact with the known set of signal transduction pathways, and then review the evidence suggesting that differential signaling through the TCR is achieved by qualitative differences in the effector pathways recruited by TCR, perhaps reflecting the time required to bring complicated signal transduction elements into proximity within the cell. The time-constant of the interaction between antigen and receptor in this way determines, at least in part, the nature of the resulting response. Finally, although our review focuses substantially on T cell receptor signaling, we have included a less detailed description of B cell receptor signaling as well, simply to emphasize the parallels that exist in these two closely related systems.
STRUCTURE AND FUNCTION OF THE PRE-T CELL RECEPTOR
Authors: von Boehmer Harald , Fehling Hans Jörg
Published: July 2002

▪ Abstract  The pre-T cell receptor (pre-TCR) that minimally consists of the TCRβ chain and the disulfide-linked pre-T cell receptor alpha (pTα) chain in association with signal-transducing CD3 molecules rescues from programmed cell death cells with productive TCRβ rearrangements. The pre-TCR induces expansion and differentiation of these cells such that they become TCRαβ bearing CD4+8+thymocytes, which express only a single TCRβ chain and then either die of neglect or—upon TCR-ligand interaction—undergo either positive or negative selection. The newly discovered pTα gene encodes a transmembrane protein that belongs to the Ig superfamily and contains a cytoplasmic tail that, however, has no essential function in signal transduction, which is mediated by CD3 molecules and most likely p56lck. Experiments in pTα gene–deficient mice show that the pre-TCR has a crucial role in maturation as well as allelic exclusion of αβ T cells but is not required for the development of γδ-expressing cells. The function of the pre-TCR cannot be fully assumed by an αβ TCR that is expressed abnormally early in T cell development.
POSITIVE VERSUS NEGATIVE SIGNALING BY LYMPHOCYTE ANTIGEN RECEPTORS
Authors: Healy James I. , Goodnow Christopher C.
Published: July 2002

▪ Abstract  Antigen receptors on lymphocytes play a central role in immune regulation by transmitting signals that positively or negatively regulate lymphocyte survival, migration, growth, and differentiation. This review focuses on how opposing positive or negative cellular responses are brought about by antigen receptor signaling. Four types of extracellular inputs shape the response to antigen: (a) the concentration of antigen; (b) the avidity with which antigen is bound; (c) the timing and duration of antigen encounter; and (d) the association of antigen with costimuli from pathogens, the innate immune system, or other lymphocytes. Intracellular signaling by antigen receptors is not an all-or-none event, and these external variables alter both the quantity and quality of signaling. Recent findings in B lymphocytes have clearly illustrated that these external inputs affect the magnitude and duration of the intracellular calcium response, which in turn contributes to differential triggering of the transcriptional regulators NFκB, JNK, NFAT, and ERK. The regulation of calcium responses involves a network of tyrosine kinases (e.g. lyn, syk), tyrosine or lipid phosphatases (CD45, SHP-1, SHIP), and accessory molecules (CD21/CD19, CD22, FcRγ2b). Understanding the biochemistry and logic behind these integrative processes will allow development of more selective and efficient pharmaceuticals that suppress, modify, or augment immune responses in autoimmunity, transplantation, allergy, vaccines, and cancer.
DEGRADATION OF CELL PROTEINS AND THE GENERATION OF MHC CLASS I-PRESENTED PEPTIDES
Authors: Rock Kenneth L. , Goldberg Alfred L.
Published: July 2002

▪ Abstract  Major histocompatibility complex (MHC) class I molecules display on the cell surface 8- to 10-residue peptides derived from the spectrum of proteins expressed in the cells. By screening for non-self MHC-bound peptides, the immune system identifies and then can eliminate cells that are producing viral or mutant proteins. These antigenic peptides are generated as side products in the continual turnover of intracellular proteins, which occurs primarily by the ubiquitin-proteasome pathway. Most of the oligopeptides generated by the proteasome are further degraded by distinct endopeptidases and aminopeptidases into amino acids, which are used for new protein synthesis or energy production. However, a fraction of these peptides escape complete destruction and after transport into the endoplasmic reticulum are bound by MHC class I molecules and delivered to the cell surface. Herein we review recent discoveries about the proteolytic systems that degrade cell proteins, how the ubiquitin-proteasome pathway generates the peptides presented on MHC-class I molecules, and how this process is stimulated by immune modifiers to enhance antigen presentation.
Negative Regulation of Cytokine Signaling Pathways
Authors: Yasukawa Hideo , Sasaki Atsuo , Yoshimura Akihiko
Published: July 2002

The Janus family of protein tyrosine kinases (JAKs) and STAT transcription factors regulate cellular processes involved in cell growth, differentiation, and transformation through their association with cytokine receptors. The CIS family of proteins (also referred to as the SOCS or SSI family) has been implicated in the regulation of signal transduction by a variety of cytokines. Most of them appear to be induced after stimulation with several different cytokines, and at least three of them (CIS1, CIS3/SOCS3, and JAB/SOCS1) negatively regulate cytokine signal transduction by various means: CIS1 inhibits STAT5 activation by binding to cytokine receptors that recruit STAT5, whereas JAB/SOCS-1 and CIS3/SOCS-3 directly bind to the kinase domain of JAKs, thereby inhibiting tyrosine-kinase activity. Therefore, these CIS family members seem to function in a classical negative feedback loop of cytokine signaling. Biochemical characterization as well as gene disruption studies indicate that JAB/SOCS1/SSI-1 is an important negative regulator of interferon γ signaling. The mechanisms by which these inhibitors of cytokine signal transduction exert their effects have been extensively studied and will provide useful information for regulating tyrosine-kinase activity.
Immunology at the Maternal-Fetal Interface: Lessons for T Cell Tolerance and Suppression
Authors: Mellor A. L. , Munn D. H.
Published: July 2002

Mammalian reproduction poses an immunological paradox because fetal alloantigens encoded by genes inherited from the father should provoke responses by maternal T cells leading to fetal loss. Current understanding of T cell immunobiology and the critical role of inflammatory processes during pregnancy is reviewed and discussed. Lessons derived from studies on the regulation of T cell responsiveness during mammalian gestation are considered in the wider context of T cell tolerance toward some microbial infections and tumors, avoidance of autoimmunity, and tissue allograft rejection.
DNA Vaccines: Immunology, Application, and Optimization
Authors: Gurunathan Sanjay , Klinman Dennis M. , Seder Robert A.
Published: July 2002

The development and widespread use of vaccines against infectious agents have been a great triumph of medical science. One reason for the success of currently available vaccines is that they are capable of inducing long-lived antibody responses, which are the principal agents of immune protection against most viruses and bacteria. Despite these successes, vaccination against intracellular organisms that require cell-mediated immunity, such as the agents of tuberculosis, malaria, leishmaniasis, and human immunodeficiency virus infection, are either not available or not uniformly effective. Owing to the substantial morbidity and mortality associated with these diseases worldwide, an understanding of the mechanisms involved in generating long-lived cellular immune responses has tremendous practical importance. For these reasons, a new form of vaccination, using DNA that contains the gene for the antigen of interest, is under intensive investigation, because it can engender both humoral and cellular immune responses. This review focuses on the mechanisms by which DNA vaccines elicit immune responses. In addition, a list of potential applications in a variety of preclinical models is provided.
Tolerance to Islet Autoantigens in Type 1 Diabetes
Authors: Bach Jean-François , Chatenoud Lucienne
Published: July 2002

Tolerance to β cell autoantigens represents a fragile equilibrium. Autoreactive T cells specific to these autoantigens are present in most normal individuals but are kept under control by a number of peripheral tolerance mechanisms, among which CD4+CD25+CD62L+T cell–mediated regulation probably plays a central role. The equilibrium may be disrupted by inappropriate activation of autoantigen-specific T cells, notably following to local inflammation that enhances the expression of the various molecules contributing to antigen recognition by T cells. Even when T cell activation finally overrides regulation, stimulation of regulatory cells by CD3 antibodies may reset the control of autoimmunity. Other procedures may also lead to disease prevention. These procedures are essentially focused on Th2 cytokines, whether used systemically or produced by Th2 cells after specific stimulation by autoantigens. Protection can also be obtained by NK T cell stimulation. Administration of β cell antigens or CD3 antibodies is now being tested in clinical trials in prediabetics and/or recently diagnosed diabetes.
The Immunological Synapse
Authors: Bromley Shannon K. , Burack W. Richard , Johnson Kenneth G. , Somersalo Kristina , Sims Tasha N. , Sumen Cenk , Davis Mark M. , Shaw Andrey S. , Allen Paul M. , Dustin Michael L.
Published: July 2002

The adaptive immune response is initiated by the interaction of T cell antigen receptors with major histocompatibility complex molecule-peptide complexes in the nanometer scale gap between a T cell and an antigen-presenting cell, referred to as an immunological synapse. In this review we focus on the concept of immunological synapse formation as it relates to membrane structure, T cell polarity, signaling pathways, and the antigen-presenting cell. Membrane domains provide an organizational principle for compartmentalization within the immunological synapse. T cell polarization by chemokines increases T cell sensitivity to antigen. The current model is that signaling and formation of the immunological synapse are tightly interwoven in mature T cells. We also extend this model to natural killer cell activation, where the inhibitory NK synapse provides a striking example in which inhibition of signaling leaves the synapse in its nascent, inverted state. The APC may also play an active role in immunological synapse formation, particularly for activation of naïve T cells.
T Cell Memory
Authors: Sprent Jonathan , Surh Charles D.
Published: July 2002

Typical immune responses lead to prominent clonal expansion of antigen-specific T and B cells followed by differentiation into effector cells. Most effector cells die at the end of the immune response but some of these cells survive and form long-lived memory cells. The factors controlling the formation and survival of memory T cells are reviewed.
Mechanisms for Enhanced Formation of the C54 Phase of Titanium Silicide Ultra-Large-Scale Integration Contacts
Authors: Harper J. M. E. , Cabral C. , Lavoie C.
Published: July 2002

▪ Abstract  Three methods have recently been developed to enhance the formation of the low-resistivity C54 phase of TiSi2, the most widely used silicide contact in ultra-large-scale integration devices. These methods are (a) ion implantation of a transition metal into the Si before Ti deposition; (b) deposition of a thin transition metal interlayer between the Si and Ti; and (c) codeposition of Ti alloyed with a transition metal. Each of these methods decreases the C49-to-C54 transformation temperature by >100°C and improves the probability of phase formation in narrow lines by increasing the nucleation site density. In this paper, we identify the aspects of phase formation that are shared by these three methods, review the methodology by which they were developed, and summarize the applications to silicon devices. Mechanisms that are responsible for the enhanced formation of C54 TiSi2 are reviewed, based on a combination of temperature-controlled in situ measurements of resistance, X-ray diffraction, and optical scattering, coupled with ex situ studies of phase formation and morphology. The main mechanisms are identified as enhanced nucleation of the C54 phase by a reduction of grain size in the C49 phase and the creation of crystallographic templates of the C40 disilicide phase and the metal-rich Ti5Si3 phase.
MARROW TRANSPLANTATION FROM UNRELATED VOLUNTEER DONORS
Authors: Anasetti, M.D Claudio , Etzioni, Ph.D Ruth , Petersdorf, M.D Effie W. , Martin, M.D Paul J. , Hansen, M.D John A.
Published: July 2002

▪ Abstract  Marrow transplants from human leukocyte antigen (HLA)-compatible unrelated volunteer donors have become feasible for more than 30% of patients without a family match and have allowed long-term, disease-free survival in 15–65% of patients with a variety of hematological disorders. However, unrelated donor transplants have a higher incidence of graft failure and graft versus host disease (GVHD) than do HLA-matched sibling transplants. This increase may be due to disparities between donor and recipient for undetected HLA determinants or for non-HLA histocompatibility genes. Because of the large number of HLA loci and their high degree of polymorphism, fully compatible donors will not be found for most patients. Fortunately, a limited degree of HLA mismatch does not necessarily impair long-term survival in patients with hematologic malignancy. Current studies are defining the risk associated with mismatching for each histocompatibility locus and are developing methods for marrow transplantation that can decrease morbidity and improve survival despite genetic disparity between donor and recipient.
GENETICS OF COLON CANCER: Impact of Inheritance on Colon Cancer Risk
Authors: Burt, M.D Randall W. , DiSario, M.D James A. , Cannon-Albright, Ph.D Lisa
Published: July 2002

▪ Abstract  The genes that are mutated in two of the rare syndromes of hereditary colon cancer were recently identified, and genetic diagnosis is already possible in some cases. Acquired mutations of these same genes also appear to be important in sporadic colon cancers. Familial clustering of sporadic cases is common and may likewise arise from inherited susceptibility. Screening strategies for both the rare syndromes and the common cases of colon cancer with familial risk have been suggested. Certain clinical features allow stratification of colon cancer risk among common cases. It is anticipated that continued genetic investigation will result in more precise screening and improved diagnostic and therapeutic options for colon cancer.
APOLIPOPROTEIN E ALLELES AS RISK FACTORS IN ALZHEIMER'S DISEASE
Authors: Roses, M.D Allen D.
Published: July 2002

▪ Abstract  Alzheimer's disease (AD) is unique in medicine in that millions of people suffer from what appears to be the same form of disease, and unlike most other late-onset diseases, the genetic etiologies have been well identified. Three early onset forms of AD inherited as autosomal dominant traits account for less than 2% of prevalent AD. A major susceptibility locus, apolipoprotein E (APOE, gene; apoE, protein) is associated with risk and age of onset distributions for the common familial and sporadic late-onset AD. The identification of additional genetic susceptibility genes in the etiology of AD and the metabolic mechanisms leading to differences in age of onset and disease pathogenesis are active areas of current research.
INFECTIVE ENDOCARDITIS CAUSED BY HACEK MICROORGANISMS
Authors: Das, MD M. , Badley, MD A.D. , Cockerill, MD F.R. , Steckelberg, MD J.M. , Wilson, MD W. R.
Published: July 2002

▪ Abstract  The HACEK group of fastidious gram-negative organisms is a recognized but unusual cause of infective endocarditis, responsible for approximately 3% of cases. We report our experience with 45 cases of endocarditis caused by HACEK organisms. In Olmsted County, Minnesota, the incidence of HACEK endocarditis was 0.14 per 100,000 person-years. In patients with native valves, 33 cases occurred, and in patients with prosthetic valves, 12 cases occurred. The most common presenting symptoms were fever, splenomegaly, new or changing murmur, and microvascular phenomena. Symptoms were present in the majority of patients anywhere from two weeks to six months prior to diagnosis. Blood cultures became positive in a mean of 3.375 days, and therapy with a beta-lactam alone or as part of a combination was given for anywhere between three and six weeks. Within the first month of diagnosis, surgery was performed for 13 regurgitant valves in 11 patients (24%). Echocardiography was an insensitive predictor of subsequent major arterial embolization (odds ratio, 1.33; 95% confidence interval, 0.31–5.67). The overall survival in our cohort of patients was 87%. These results confirm previous reports that HACEK endocarditis portends a favorable prognosis.
BEREAVEMENT AND LATE-LIFE DEPRESSION: Grief and Its Complications in the Elderly
Authors: Rosenzweig, MD, MPH Andrew , Prigerson, PhD Holly , Miller, MD Mark D. , Reynolds III, MD Charles F.
Published: July 2002

▪ Abstract  Spousal bereavement is a common event in later life and, not infrequently, an important cause of psychiatric and medical morbidity. Depression (along with suicide), anxiety, substance abuse, and symptoms of “complicated” grief are among the more important psychiatric sequelae of spousal bereavement. They may represent, in part, forms of abnormal reaction to the stress of loss and the challenges of adaption to becoming widowed. This paper summarizes current knowledge about the clinical phenomenology of the psychiatric sequelae to late-life attachment bereavment, some of the hypothesized antecedents of abnormal stress response to bereavement, psychobiologic correlates of bereavement-related depression, and the long-term course (including preliminary evidence on response to treatment with psychotherapy and antidepressant medication).
Hereditary Breast Cancer
Authors: Ellisen Leif W. , Haber Daniel A.
Published: July 2002

Genetic predisposition is responsible for 5–10% of all breast cancer, and a much larger percent of early-onset disease. Within the past few years, a number of genes associated with a high risk of breast cancer have been identified, including BRCA1, BRCA2, p53, and the Cowden disease gene PTEN/MMAC1. These genes appear to function as tumor suppressors, and although their mutation frequency in the general population is low, certain populations have a carrier frequency of up to 1% for particular BRCA1 and BRCA2 mutations. The isolation of these genes is likely to provide important insight into the pathogenesis of human cancer. The clinical application of these molecular discoveries raises controversial issues regarding presymptomatic testing for patients suspected of harboring cancer predisposing mutations.
Spectrum of Hantavirus Infection: Hemorrhagic Fever with Renal Syndrome and Hantavirus Pulmonary Syndrome
Authors: Peters, MD C. J. , Simpson, MD, PhD, MPH Gary L. , Levy, MD, PhD H.
Published: July 2002

Hantaviruses chronically infect rodents without apparent disease, but when they are spread by aerosolized excreta to humans, two major clinical syndromes result: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Both diseases appear to be immunopathologic, and inflammatory mediators are important in causing the clinical manifestations. In HPS, T cells act on heavily infected pulmonary endothelium, and it is suspected that gamma interferon and tumor necrosis factor are major agents of a reversible increase in vascular permeability that leads to severe, noncardiogenic pulmonary edema. HFRS has prominent systemic manifestations. The retroperitoneum is a major site of vascular leak and the kidneys suffer tubular necrosis. Both syndromes are accompanied by myocardial depression and hypotension or shock. HFRS is primarily a Eurasian disease, whereas HPS appears to be confined to the Americas; these geographic distinctions correlate with the phylogenies of the rodent hosts and the viruses that coevolved with them.
The Surgical Treatment of Parkinson’s Disease
Authors: Follett Kenneth A.
Published: July 2002

▪ Abstract  Surgical treatment of Parkinson’s disease (PD) can provide gratifying symptomatic improvements for many individuals who suffer from persistent disabling symptoms despite the best available medical management. Current surgical therapies include ablative techniques (thalamotomy and pallidotomy), augmentative techniques (nondestructive) (deep brain stimulation), and restorative techniques (tissue transplantation and gene therapy). Ablative procedures can provide substantial clinical benefit, but the current trend is toward deep brain stimulation, which can provide similar symptomatic improvement in a nondestructive manner. Restorative techniques, such as tissue transplantation and gene therapy, are exciting but have significant obstacles to overcome before their promise can be realized. Until the underlying pathological defect of PD can be identified and treated, surgical intervention is likely to remain important in the symptomatic treatment of this disabling disease.
Regulation of Leukotrienes in the Management of Asthma: Biology and Clinical Therapy
Authors: R. Leff Alan
Published: July 2002

▪ Abstract  Leukotrienes (LTs) are the ultimate synthetic product resulting from the intracellular hydrolysis of membrane phospholipid at the nuclear envelope in inflammatory cells. Activated cytosolic phospholipase (cPLA2) catalyzes the production of arachidonic acid, which is converted by cyclooxygenases into leukotriene A4(LTA4) and subsequently into the chemotaxin LTB4, which has no direct bronchoconstrictor activity. In certain inflammatory cells, LTA4is converted into the cysteinyl leukotriene (cysLT) LTC4, which is converted into LTD4and finally to LTE4after extracellular transport. All cysLTs occupy the same receptors and are extremely potent bronchoconstricting agents that are pathogenetic in both asthma and allergy. With the identification of the structure of the cysLT receptor, antileukotriene therapies have been developed that either (a) inhibit synthesis of leukotriene (through 5-lipoxygenase inhibition) or (b) block the cysLT receptor. Preliminary investigations indicate that corticosteroids also may partially block the synthesis of cysLT and that cysLTs may be chemotactic for other inflammatory cells, e.g. eosinophils, by a mechanism that has not yet been defined. Currently, anti-LT therapies are approved by the US Food and Drug Administration (FDA) only for patients with asthma. These drugs generally are moderately efficacious agents, although they are highly efficacious in aspirin-induced asthma (AIA). In other forms of asthma, inhaled corticosteroid (ICS) therapy has been more effective than anti-LT therapy in improving air flow obstruction. However, anti-LT agents are additive to beta-adrenoceptor and ICS in their effects. Accordingly, anti-LT therapies are used frequently as supplemental treatments in asthmatic patients whose asthma is not optimally controlled by a combination of other drugs, including long-acting beta-adrenoceptor drugs and ICS agents. The growth of leukotriene receptor antagonists (LTRAs) has been extraordinary in the United States. The exceptional safety of these agents and their ease of administration as tablets taken once or twice daily has spurred this growth. In the past year, the high-affinity cysLT receptor has been cloned. This holds forth the promise of a second generation of LTRA agents of even greater efficacy and possibly greater duration of action.
Cyclooxygenase-2: A Therapeutic Target
Authors: Turini Marco E. , DuBois Raymond N.
Published: July 2002

▪ Abstract  Cyclooxygenase (COX), also known as prostaglandin endoperoxide synthase, is the key enzyme required for the conversion of arachidonic acid to prostaglandins. Two COX isoforms have been identified, COX-1 and COX-2. In many situations, the COX-1 enzyme is produced constitutively (e.g., in gastric mucosa), whereas COX-2 is highly inducible (e.g., at sites of inflammation and cancer). Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both enzymes, and a new class of COX-2 selective inhibitors (COXIBs) preferentially inhibit the COX-2 enzyme. This review summarizes our current understanding of the role of COX-1 and COX-2 in normal physiology and disease.
MICROALGAL METABOLITES: A New Perspective
Authors: Shimizu Yuzuru
Published: July 2002

Occurrence of secondary metabolites in microalgae (protoctista) is discussed with respect to the phylogenic or taxonomic relationships of organisms. Biosynthetic mechanisms of certain metabolites such as paralytic shellfish poisoning toxins and polyether toxins are also discussed, and genetic aspects of the secondary metabolite production as well.
AGAINST ALL ODDS: The Survival Strategies of Deinococcus radiodurans
Authors: Battista J. R.
Published: July 2002

▪ Abstract  Bacteria of the genus Deinococcus exhibit an extraordinary ability to withstand the lethal and mutagenic effects of DNA damaging agents—particularly the effects of ionizing radiation. These bacteria are the most DNA damage–tolerant organisms ever identified. Relatively little is known about the biochemical basis for this phenomenon; however, available evidence indicates that efficient repair of DNA damage is, in large part, responsible for the deinococci's radioresistance. Obviously, an explanation of the deinococci's DNA damage tolerance cannot be developed solely on the basis of the DNA repair strategies of more radiosensitive organisms. The deinococci's capacity to survive DNA damage suggests that (a) they employ repair mechanisms that are fundamentally different from other prokaryotes, or that (b) they have the ability to potentiate the effectiveness of the conventional complement of DNA repair proteins. An argument is made for the latter alternative.
Transmissible Spongiform Encephalopathies in Humans
Authors: Belay Ermias D.
Published: July 2002

▪ Abstract  Creutzfeldt-Jakob disease (CJD), the first transmissible spongiform encephalopathy (TSE) to be described in humans, occurs in a sporadic, familial, or iatrogenic form. Other TSEs in humans, shown to be associated with specific prion protein gene mutations, have been reported in different parts of the world. These TSEs compose a heterogeneous group of familial diseases that traditionally have been classified as familial CJD, Gerstmann-Sträussler-Scheinker syndrome, or fatal familial insomnia. In 1996, a newly recognized variant form of CJD among young patients (median age, 28 years) with unusual clinical features and a unique neuropathologic profile was reported in the United Kingdom. In the absence of known CJD risk factors or prion protein gene abnormalities, the UK government concluded that the clustering of these cases may represent transmission to humans of the agent causing bovine spongiform encephalopathy. Additional epidemiologic and recent laboratory data strongly support the UK government's conclusion.
Roles of the Glutathione- and Thioredoxin-Dependent Reduction Systems in the Escherichia Coli and Saccharomyces Cerevisiae Responses to Oxidative Stress
Authors: Carmel-Harel Orna , Storz Gisela
Published: July 2002

▪ Abstract  The glutathione- and thioredoxin-dependent reduction systems are responsible for maintaining the reduced environment of the Escherichia coli and Saccharomyces cerevisiae cytosol. Here we examine the roles of these two cellular reduction systems in the bacterial and yeast defenses against oxidative stress. The transcription of a subset of the genes encoding glutathione biosynthetic enzymes, glutathione reductases, glutaredoxins, thioredoxins, and thioredoxin reductases, as well as glutathione- and thioredoxin-dependent peroxidases is clearly induced by oxidative stress in both organisms. However, only some strains carrying mutations in single genes are hypersensitive to oxidants. This is due, in part, to the redundant effects of the gene products and the overlap between the two reduction systems. The construction of strains carrying mutations in multiple genes is helping to elucidate the different roles of glutathione and thioredoxin, and studies with such strains have recently revealed that these two reduction systems modulate the activities of the E. coli OxyR and SoxR and the S. cerevisiae Yap1p transcriptional regulators of the adaptive responses to oxidative stress.
The Disease Spectrum ofHelicobacter Pylori: The Immunopathogenesis of Gastroduodenal Ulcer and Gastric Cancer
Authors: Ernst Peter B. , Gold Benjamin D.
Published: July 2002

▪ Abstract  Helicobacter pylori is a gram-negative bacterium that resides under microaerobic conditions in a neutral microenvironment between the mucus and the superficial epithelium of the stomach. From this site, it stimulates cytokine production by epithelial cells that recruit and activate immune and inflammatory cells in the underlying lamina propria, causing chronic, active gastritis. Although epidemiological evidence shows that infection generally occurs in children, the inflammatory changes progress throughout life. H. pylori has also been recognized as a pathogen that causes gastroduodenal ulcers and gastric cancer. These more severe manifestations of the infection usually occur later in life and in a minority of infected subjects. To intervene and protect those who might be at greatest risk of the more severe disease outcomes, it is of great interest to determine whether bacterial, host, or environmental factors can be used to predict these events. To date, several epidemiological studies have attempted to define the factors affecting the transmission of H. pylori and the expression of gastroduodenal disease caused by this infection. Many other laboratories have focused on identifying bacterial factors that explain the variable expression of clinical disease associated with this infection. An alternative hypothesis is that microorganisms that cause lifelong infections can ill afford to express virulence factors that directly cause disease, because the risk of losing the host is too great. Rather, we propose that gastroduodenal disease associated with H. pylori infection is predominantly a result of inappropriately regulated gastric immune responses to the infection. In this model, the interactions between the immune/inflammatory response, gastric physiology, and host repair mechanisms would dictate the disease outcome in response to infection.
Interaction of Bacterial Pathogens with Polarized Epithelium
Authors: Kazmierczak B. I. , Mostov K. , Engel J. N.
Published: July 2002

▪ Abstract  Many pathogens must surmount an epithelial cell barrier in order to establish an infection. While much has been learned about the interaction of bacterial pathogens with cultured epithelial cells, the influence of cell polarity on these events has only recently been appreciated. This review outlines bacterial-host epithelial cell interactions in the context of the distinct apical and basolateral surfaces of the polarized epithelium that lines the lumens of our organs.
NONLEPTONIC DECAYS AND LIFETIMES OF CHARM AND BEAUTY PARTICLES
Authors: Browder Thomas E. , Honscheid Klaus , Pedrini Daniele
Published: July 2002

▪ Abstract  We review recent experimental results on lifetimes and on hadronic decays of hadrons that contain c and b quarks. The theoretical implications of these results are also considered. An understanding of hadronic decays of heavy quarks is required to interpret the charge-parity–violating asymmetries in B decays that will be observed in experiments planned for the near future.
LARGE-Nc BARYONS
Authors: Jenkins Elizabeth
Published: July 2002

▪ Abstract  A spin-flavor symmetry emerges for baryons in the large-Nc limit. Large-Nc baryons form irreducible representations of the spin-flavor algebra, and their static properties can be computed in a systematic expansion in 1/Nc. Symmetry relations for static baryon matrix elements are obtained at various orders in the 1/Nc expansion by neglecting subleading 1/Nc corrections. Equivalent relations arise in the quark and Skyrme models, which satisfy the same large-Nc group theory as quantum chromodynamics (QCD). The 1/Nc expansion yields useful results for QCD baryons with Nc = 3.
DIETARY FACTORS IN HUMAN COLORECTAL CANCER
Authors: Lipkin Martin , Reddy Bandaru , Newmark Harold , Lamprecht Sergio A.
Published: July 2002

▪ Abstract  Colorectal cancer is a significant cause of mortality in Western societies. The progression of the disease from normal colonic epithelium to the acquisition of the malignant phenotype is accompanied by numerous genetic and epigenetic alterations. Compelling experimental and epidemiological evidence indicates that diet and nutrition are key factors in the modulation of colorectal cancer. A salient case in point is the recent observation that a dietary regimen based on a Western-style diet provokes in the rodent colon the appearance of preneoplastic lesions in the absence of any genotoxic insult. This review mainly describes dietary factors that inhibit the development and progression of colorectal cancer. Much is unknown about the precise mechanisms of action of chemically disparate nutrients and how they interfere with the development and progression of this disease. Current knowledge about this important issue is summarized. We believe that continuing scrutiny and precise assessment of the benefits (and potential risks) of nutrients in the treatment and prevention of colorectal cancer will prove significant to controlling this devastating disease.
Leptin—Much More Than a Satiety Signal
Authors: Harris Ruth B. S.
Published: July 2002

Much attention has focused on the effects of leptin as a central satiety agent. There is now a significant amount of evidence that leptin is active in the periphery. This review focuses on the ability of leptin to modify insulin sensitivity, tissue metabolism, stress responses, and reproductive function. Leptin's effect on several of these systems is mediated via the hypothalamic-pituitary axis. Therefore, although in vitro studies provide evidence for direct effects on specific tissues and metabolic pathways, it is essential to consider the interactions between leptin and other regulatory factors in vivo. Little is known about the regulation of peripheral receptor expression or the production of binding proteins. Both of these factors determine the bioactivity of circulating leptin and have the potential to induce a peripheral resistance to leptin, similar to the central “leptin resistance” observed in obese subjects. Future research will clarify which of the endocrine and metabolic actions of peripheral leptin are of physiological relevance and which should be considered a pharmacological manipulation.