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- Volume 56, 2005
Annual Review of Medicine - Volume 56, 2005
Volume 56, 2005
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Gene-Environment Interactions in Asthma and Other Respiratory Diseases*
Vol. 56 (2005), pp. 383–400More LessIt is generally agreed that many lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) have polygenic inheritance, and that the association of a specific genotype or genotypes with the disease is likely to vary between populations. Furthermore, it is recognized that the etiology of many lung diseases involves a complex interplay between genetic background and exposure to multiple environmental stimuli, and understanding the mechanisms through which genes and environment interact represents a major challenge for pulmonary researchers. We discuss experimental approaches and challenges that must be overcome to identify disease genes for asthma, COPD and chronic bronchitis, and occupational lung diseases. In particular, common polymorphisms in CD14, glutathione S-transferase, and tumor necrosis factor alpha have been found to be important in gene-environment interaction and asthma pathogenesis. An understanding of gene-environment interactions in complex lung diseases is essential to the development of new strategies for lung disease prevention and treatment.
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The Silent Revolution: RNA Interference as Basic Biology, Research Tool, and Therapeutic
Vol. 56 (2005), pp. 401–423More LessRNA interference (RNAi) is an evolutionarily conserved mechanism for silencing gene expression. In primitive organisms, RNAi protects the genome from viruses and other insertable genetic elements and regulates gene expression during development. The antisense (guide) strand of short double-stranded RNAs is incorporated into an RNA-induced silencing complex that can either suppress protein expression or direct degradation of messenger RNAs that contain homologous sequence(s). The discovery that RNAi works in mammalian cells has sparked intense investigation into its role in normal mammalian cell function, its use as a tool to understand or screen for genes functioning in cellular pathways in healthy and diseased cells and animals, and its potential for therapeutic gene silencing. RNAi may provide an important new therapeutic modality for treating infection, cancer, neurodegenerative disease, and other illnesses, although in vivo delivery of small interfering RNAs into cells remains a significant obstacle.
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Management of Adult Idiopathic Thrombocytopenic Purpura
Vol. 56 (2005), pp. 425–442More LessIdiopathic thrombocytopenic purpura (ITP) is a common hematologic disorder manifested by immune-mediated thrombocytopenia. The diagnosis remains one of exclusion, after other thrombocytopenic disorders are ruled out based on history, physical examination, and laboratory evaluation. The goal of treatment is to raise the platelet count into a hemostatically safe range. The disorder is usually chronic, although there is considerable variation in the clinical course and most patients eventually attain safe platelet counts off treatment. However, a subset of patients has severe disease refractory to all treatment modalities, which is associated with considerable morbidity and mortality. This article focuses on the management of primary ITP in adults. We discuss criteria for treatment, the roles of splenectomy and other treatment options along with their side effects, and the management of ITP during pregnancy.
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Monogenic Obesity in Humans
Vol. 56 (2005), pp. 443–458More LessUntil relatively recently, the small number of identifiable inherited human diseases associated with marked obesity were complex, pleiotropic developmental disorders, the molecular basis for which were entirely obscure. The molecular basis for many of these complex syndromes, such as Bardet Beidl syndrome, has been revealed, providing novel insights into processes essential for human hypothalamic function and energy balance. In addition to these discoveries, which were the fruits of positional cloning, the molecular constituents of the signaling pathways responsible for the control of mammalian energy homeostasis have been identified, largely through the study of natural or artificial mutations in mice. We discuss the increasing number of human disorders that result from genetic disruption of the leptin-melanocortin pathways that have been identified. Practical implications of these findings for genetic counseling, prognostication, and even therapy have already emerged.
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Application of Microbial Genomic Science to Advanced Therapeutics
Vol. 56 (2005), pp. 459–474More LessSince the publication of the first complete microbial genome sequence of Haemophilus influenzae in 1995, more than 200 additional microbial genome sequences have become available in the public domain. Approximately 40% of these represent important human pathogens. Comparative in silico methods, along with large-scale approaches such as transcriptomics and proteomics, are beginning to reveal insights into new virulence genes, pathogen-host interactions, and the molecular basis of host specificity. Sequence data are also starting to accumulate from multiple isolates or strains of a single pathogen, and this type of data has proven to be quite valuable in providing new insights into the genetic variability that is present in a particular species as well as in facilitating correlations between genotype and phenotype. Ultimately, a major goal of genome-enabled infectious disease research is the development of novel diagnostics, therapeutics, and vaccines.
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Atrial Fibrillation: Modern Concepts and Management
Vol. 56 (2005), pp. 475–494More LessAtrial fibrillation (AF) is a common cardiac arrhythmia responsible for significant morbidity and mortality. In recent years, progress has been made in determining the genetic abnormalities that may lead to AF. New trials have shown that rate control and anticoagulation are acceptable as a primary treatment strategy in many patients who have a high risk of recurrence. Newer and safer antiarrhythmics are now available. Pacemaker and implantable cardiac defibrillator technology is rapidly evolving and may play a significant role in future treatment and prevention of AF. Direct thrombin inhibitors are likely to add a user-friendly option to the current standard therapy for stroke prevention.
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DNA Repair Defects in Stem Cell Function and Aging*
Vol. 56 (2005), pp. 495–508More LessCellular DNA is under constant challenge by exogenous and endogenous genotoxic stress, which results in both transient and accumulated DNA damage and genomic instability. All cells are equipped with DNA damage response pathways that trigger DNA repair, cell cycle arrest, and, if need be, apoptosis, to eliminate DNA damage or damaged cells. The consequences of these processes for stem cells can be profound: diminution in stem cell pools, or, because of altered gene expression, an increased chance for stem cell differentiation or malignant transformation. Furthermore, a number of DNA repair abnormalities are linked to premature aging syndromes, and these are associated with defects in the stem cell population. The specific DNA repair systems for which there are data regarding the impact of repair defects on stem cell function include O6-alkylguanine DNA alkyltransferase, nucleotide excision repair, base excision repair, mismatch repair, non-homologous DNA end-joining Fanconi's anemia protein complex, and homologous recombination. It has recently become clear that deficiencies of these processes are associated not only with cancer and/or aging but also with stem cell defects. This discovery raises the possibility of a link between aging and stem cell dysfunction. In this review, we provide evidence for a link between DNA repair systems and the maintenance and longevity of stem cells.
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Hematopoietic Stem and Progenitor Cells: Clinical and Preclinical Regeneration of the Hematolymphoid System
Vol. 56 (2005), pp. 509–538More LessA vast literature exists on the biology of blood formation and regeneration under experimental and clinical conditions. The field of hematopoiesis was recently advanced by the capacity to purify to homogeneity primitive hematopoietic stem and progenitor cells. Isolation of cells at defined maturational stages has enhanced the understanding of the fundamental nature of stem cells, including how cell fate decisions are made, and this understanding is relevant to the development of other normal as well as malignant tissues. This review updates the basic biology of hematopoietic stem cells (HSC) and progenitors, the evolving use of purified HSC as grafts for clinical hematopoietic cell transplantation (HCT) including immune tolerance induction, and the application of HSC biology to other stem cell fields.
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Inherited Susceptibility to Colorectal Cancer
Vol. 56 (2005), pp. 539–554More LessThe principal Mendelian disorders predisposing to colorectal cancer are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). FAP is due to mutations in the APC gene. HNPCC is due to a mutation in one of at least five mismatch repair genes. Identification of individuals with these conditions is important because colon cancer will occur in ∼80% and onset is early. For FAP, protein truncation testing will identify the vast majority of mutations. For HNPCC, 80%–95% can be identified by microsatellite instability testing. A current U.S. study reports that 12% of consecutive colorectal cancers have high microsatellite instability and that, of this 12%, 25% have detectable mutations of MLH1, MSH2, or MSH6. Potential benefits of identification include improved compliance with recommended surveillance, early detection of polyps, reduction in cancer mortality, offering of testing to relatives, and reassurance for relatives found to be negative with attendant savings in the time and expense of surveillance.
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Aptamers: An Emerging Class of Therapeutics
Vol. 56 (2005), pp. 555–583More LessNumerous nucleic acid ligands, also termed decoys or aptamers, have been developed during the past 15 years that can inhibit the activity of many pathogenic proteins. Two of them, Macugen and E2F decoy, are in phase III clinical trials. Several properties of aptamers make them an attractive class of therapeutic compounds. Their affinity and specificity for a given protein make it possible to isolate a ligand to virtually any target, and adjusting their bioavailability expands their clinical utility. The ability to develop aptamers that retain activity in multiple organisms facilitates preclinical development. Antidote control of aptamer activity enables safe, tightly controlled therapeutics. Aptamers may prove useful in the treatment of a wide variety of human maladies, including infectious diseases, cancer, and cardiovascular disease. We review the observations that facilitated the development of this emerging class of therapeutics, summarize progress to date, and speculate on the eventual utility of such agents in the clinic.
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Gene Therapy for Severe Combined Immunodeficiency
Vol. 56 (2005), pp. 585–602More LessStudies of severe combined immunodeficiency (SCID), a group of rare monogenic disorders, have provided key findings about the physiology of immune system development. The common characteristic of these diseases is the occurrence of a block in T cell differentiation, always associated with a direct or indirect impairment of B cell immunity. The resulting combined immunodeficiency is responsible for the clinical severity of SCID, which, without treatment, leads to death within the first year of life. Eleven distinct SCID phenotypes have been identified to date. Mutations of ten genes have been found to cause SCID. Identifying the pathophysiological basis of most SCID conditions has led to the possibility of molecular therapy as an alternative to allogeneic hematopoietic stem cell transplantation. This review discusses recent developments in SCID identification and treatment.
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Previous Volumes
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Volume 76 (2025)
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Volume 75 (2024)
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Volume 74 (2023)
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Volume 73 (2022)
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Volume 72 (2021)
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Volume 71 (2020)
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Volume 70 (2019)
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Volume 69 (2018)
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Volume 68 (2017)
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Volume 67 (2016)
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Volume 66 (2015)
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Volume 65 (2014)
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Volume 64 (2013)
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Volume 63 (2012)
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Volume 62 (2011)
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Volume 61 (2010)
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Volume 60 (2009)
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Volume 59 (2008)
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Volume 58 (2007)
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Volume 57 (2006)
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Volume 56 (2005)
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Volume 55 (2004)
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Volume 54 (2003)
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Volume 53 (2002)
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Volume 52 (2001)
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Volume 51 (2000)
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Volume 50 (1999)
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Volume 49 (1998)
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Volume 48 (1997)
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Volume 47 (1996)
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Volume 46 (1995)
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Volume 45 (1994)
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Volume 44 (1993)
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Volume 43 (1992)
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Volume 42 (1991)
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Volume 41 (1990)
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Volume 40 (1989)
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Volume 39 (1988)
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Volume 38 (1987)
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Volume 37 (1986)
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Volume 36 (1985)
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Volume 35 (1984)
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Volume 34 (1983)
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Volume 33 (1982)
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Volume 32 (1981)
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Volume 31 (1980)
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Volume 30 (1979)
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Volume 29 (1978)
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Volume 28 (1977)
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Volume 27 (1976)
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Volume 26 (1975)
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Volume 25 (1974)
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Volume 24 (1973)
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Volume 23 (1972)
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Volume 22 (1971)
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Volume 21 (1970)
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Volume 20 (1969)
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Volume 19 (1968)
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Volume 18 (1967)
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Volume 17 (1966)
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Volume 16 (1965)
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Volume 15 (1964)
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Volume 14 (1963)
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Volume 13 (1962)
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Volume 12 (1961)
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Volume 11 (1960)
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Volume 10 (1959)
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Volume 9 (1958)
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Volume 8 (1957)
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Volume 7 (1956)
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Volume 6 (1955)
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Volume 5 (1954)
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Volume 4 (1953)
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Volume 3 (1952)
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Volume 2 (1951)
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Volume 1 (1950)
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Volume 0 (1932)