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- Volume 59, 2008
Annual Review of Medicine - Volume 59, 2008
Volume 59, 2008
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Complement Regulatory Genes and Hemolytic Uremic Syndromes
Vol. 59 (2008), pp. 293–309More LessHemolytic uremic syndrome is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. It is one of a group of conditions termed the thrombotic microangiopathies, which are characterized by prominent endothelial cell injury. It may be diarrheal-associated or atypical (aHUS). Evidence for a pathogenic role of the alternative pathway of complement was first suggested in 1974. Mutations in the complement regulatory proteins factor H, membrane cofactor protein (CD46), and factor I predispose to aHUS development. Mutations of the activating components factor B and complement C3 have also been reported. Penetrance is ∼50%, suggesting other genetic and environmental modifiers are needed for disease expression. Identification of mutations is important owing to differences in mortality, renal survival, and outcome of renal transplantation. Current treatment is plasma infusion/exchange, but complement inhibitor therapy provides hope for the future.
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Mesenchymal Stem Cells in Acute Kidney Injury
Vol. 59 (2008), pp. 311–325More LessThe potential role of mesenchymal stem cells (MSCs, also called mesenchymal stromal cells) in endogenous repair and cell-based therapies for acute kidney injury (AKI) is under intensive investigation. Preclinical studies indicate that administered MSCs both ameliorate renal injury and accelerate repair. These versatile cells home to sites of injury, where they modulate the repair process. The mechanisms responsible for their protective and regenerative effects are incompletely understood. Some have reported that MSCs are capable of direct engraftment into injured nephrons under certain circumstances. This is highly controversial, however, and even those who argue there is engraftment acknowledge that the primary means of repair by these cells most likely involves paracrine and endocrine effects, including mitogenic, antiapoptotic, anti-inflammatory, and angiogenic influences. There is a good deal of interest in MSC-based approaches for the treatment of human kidney injury, thanks to positive preclinical results, the strong clinical need for novel therapies to treat AKI, the ease of isolation and expansion of MSCs, and encouraging preliminary clinical trial results in other fields. This review summarizes current knowledge and identifies gaps in our understanding of MSC biology that will need to be filled in order to translate recent discoveries into therapies for AKI in humans.
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Asthma Genetics: From Linear to Multifactorial Approaches
Vol. 59 (2008), pp. 327–341More LessAsthma risk has a clear hereditary component but, unexpectedly, the majority of reported associations between genetic variants and asthma have not been consistently replicated across studies. Methodological flaws have been indicated as a possible explanation for these inconsistencies. However, an alternative explanation is that the effects of genetic variants depend on other factors whose frequency and distribution vary, both across individuals and across populations. Within this framework, we review recent advances in asthma genetics and conclude that a paradigm shift is needed, because a static model in which the DNA sequence is associated with disease risk in a linear fashion fails to consider the interdependence of the diverse components of asthma risk. We propose an integrated approach, linking sequence variation to specific phenotypic manifestations of the disease by taking into account concurrent influences from biological systems and environmental factors that interact within specific developmental windows of opportunity.
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The Effect of Toll-Like Receptors and Toll-Like Receptor Genetics in Human Disease*
Vol. 59 (2008), pp. 343–359More LessToll-like receptors (TLRs) enable innate immune recognition of endogenous and exogenous prototypic ligands. They also orchestrate innate and adaptive immune response to infection, inflammation, and tissue injury. Given their significance in the immune response, it is not surprising that genetic variations of TLRs can affect their function and by extension affect the response of the organism to environmental stimuli. The genetics of TLRs provides important insights in gene-environment interactions in health and disease, and it may enable scientists to assess patients’ susceptibility to diseases or predict their response to treatments.
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Advances in Antifungal Therapy
Vol. 59 (2008), pp. 361–379More LessThe prevalence of invasive fungal infections (IFIs) has increased over the past three decades owing to the increasing numbers of immunocompromised hosts. These infections are associated with significant morbidity and mortality. Recent significant advances in antifungal therapy include the broad-spectrum triazoles (voriconazole and posaconazole) and a new class of antifungals, the echinocandins (caspofungin, micafungin, and anidulafungin). New treatment strategies, such as combination therapy and pre-emptive therapy, are being investigated. There have also been significant improvements in diagnostics; the galactomannan enzyme immunoassay and the β-glucan test are now part of the EORTC/MSG criteria for diagnosis of IFI. Despite these advances, there remain a number of unanswered questions regarding optimal management of serious fungal infections, and research continues to discover and develop new therapies and evaluate new management strategies.
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Herpes Simplex: Insights on Pathogenesis and Possible Vaccines
Vol. 59 (2008), pp. 381–395More LessAbstractHerpes simplex viruses are evolutionarily ancient and ubiquitous. In the past 20 years, there has been increasing recognition of a worldwide pandemic of HSV-2 infection. Moreover, HSV-2 prevalence has increased despite fairly widespread use of antiviral drugs for HSV. The success of HSV-1 and HSV-2 stems from latency within long-lived neurons and frequent mucocutaneous shedding. The generally mild medical consequences of HSV infection reflect a functional equilibrium between host and microbe in most immunocompetent persons. However, significant gaps in our knowledge of the correlates of disease severity and HSV immune evasion are limiting rational advances in these areas. Human genetic studies are gradually outlining important innate responses, while recent imaging and biopsy studies have begun to show that the temporal and spatial anatomic interplay between virus reactivation and host immune response may be important in reactivations and disease expression.
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Medical Management of Influenza Infection
Vol. 59 (2008), pp. 397–413More LessAntiviral drugs are important in the management of seasonal influenza and critical to pandemic planning. Although several other classes of anti-influenza compounds exist, the neuraminidase (NA) inhibitors are currently the only option in most clinical settings. These drugs, zanamivir and oseltamivir, prevent the release of newly replicated influenza virions from infected cells. They are highly effective when used for treatment of seasonal influenza early in the course of infection, or for prevention when given soon after exposure. Treatment strategies for avian influenza infections in humans are still provisional owing to inadequate clinical data. As predicted by molecular studies, resistance to the NA inhibitors is now emerging, although at a level less significant than adamantane resistance. NA inhibitor resistance is a cause for concern if indeed some mutant strains of avian influenza are transmissible and pathogenic. In the near term, appropriate use of the available NA inhibitors will be of major benefit in lessening morbidity and mortality due to influenza infection. Priorities include developing appropriate formulations and guidelines for use of these drugs in children and people infected with avian influenza, study of the mechanisms and clinical significance of drug resistance, and identification of new antiviral therapies that target different points in the viral life cycle in order to limit the effect of emerging drug resistance.
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Bacterial and Fungal Biofilm Infections
Vol. 59 (2008), pp. 415–428More LessBiofilms are communal structures of microorganisms encased in an exopolymeric coat that form on both natural and abiotic surfaces and have been associated with a variety of persistent infections that respond poorly to conventional antibiotic chemotherapy. Biofilm infections of certain indwelling medical devices by common pathogens such as staphylococci are not only associated with increased morbidity and mortality but are also significant contributors to the emergence and dissemination of antibiotic resistance traits in the nosocomial setting. Current treatment paradigms for biofilm-associated infections of semipermanent indwelling devices typically involve surgical replacement of the device combined with long-term antibiotic therapy and incur high health care costs. This review summarizes the existing data relating to the nature, prevalence, and treatment of biofilm-associated infections and highlights experimental approaches and therapies that are being pursued toward more effective treatments.
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EGFR Tyrosine Kinase Inhibitors in Lung Cancer: An Evolving Story
Vol. 59 (2008), pp. 429–442More LessDrugs that target the epidermal growth factor receptor (EGFR) have had a major impact on the treatment of non–small cell lung cancer (NSCLC). The use of these drugs has also motivated pivotal advances in the understanding of the molecular biology of NSCLC, including the discovery that mutations in EGFR are associated with dramatic and sustained responses to anti-EGFR treatments. This review summarizes the clinical development of EGFR tyrosine kinase inhibitors, the discovery of molecular predictors of response, and the future directions for research in the field.
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Adaptive Treatment Strategies in Chronic Disease
Vol. 59 (2008), pp. 443–453More LessAn adaptive treatment strategy (ATS) is a rule for adapting a treatment plan to a patient's history of previous treatments and the response to those treatments. The ongoing management of chronic disease defines an ATS, which may be implicit and hidden or explicit and well-specified. The ATS is characterized by the use of intermediate, early markers of response to dynamically alter treatment decisions, in order to achieve a favorable ultimate outcome. We illustrate the ATS concept and describe how the effect of initial treatment decisions depends on the performance of subsequent decisions at later stages. We show how to compare two or more ATSs, or to determine an optimal ATS, using a sequential multiple assignment randomized (SMAR) trial. Designers of clinical trials might find the ATS concept useful in improving the efficiency and ecological relevance of clinical trials.
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Antiretroviral Drug–Based Microbicides to Prevent HIV-1 Sexual Transmission
Vol. 59 (2008), pp. 455–471More LessThe development of a vaginal (and perhaps a rectal) microbicide would be of major benefit for slowing the global spread of human immunodeficiency virus type 1 (HIV-1). A microbicide is a gel or related device that, when inserted vaginally or rectally, acts to prevent infection of a woman or a man by HIV-1 during sexual intercourse. A practical microbicide must be not only effective, safe, and user-friendly but also economically affordable in the developing world. To date, the performance of microbicide candidates in efficacy trials has been disappointing, but next-generation concepts now in or approaching clinical trials offer improved prospects for efficacy. The most plausible approaches involve topical application of antiretroviral agents with specific activity against HIV-1, compounds similar to drugs used to treat HIV-1 infection. How these inhibitors are applied may also be critical, with sustained-release formulations and vaginal ring delivery systems now becoming a high priority.
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The Challenge of Hepatitis C in the HIV-Infected Person
Vol. 59 (2008), pp. 473–485More LessHepatitis C virus (HCV) coinfection occurs in an estimated one quarter of HIV-infected persons in Europe, Australia, and the United States. As use of highly active antiretroviral drugs has markedly reduced opportunistic infections, HCV-related liver disease has emerged as a leading cause of death. HIV infection adversely affects both the natural history and the treatment of hepatitis C. Because there are no experimental models of coinfection and because the pathogenesis of each infection is incompletely understood, how HIV infection alters hepatitis C is not clear. This review considers the epidemiology, natural history, treatment, and pathogenesis of hepatitis C in HIV-infected persons.
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Hide-and-Seek: The Challenge of Viral Persistence in HIV-1 Infection
Vol. 59 (2008), pp. 487–501More LessThe success of highly active antiretroviral therapy (HAART) for HIV-1 infection has sparked interest in mechanisms by which the virus can persist despite effectively suppressive therapy. Latent HIV-1 reservoirs established early during infection not only prevent sterilizing immunity but also represent a major obstacle to virus eradication. When HIV-1 gains a foothold in the immunologic memory or in certain inaccessible compartments of the human body, it cannot be easily purged by HAART and is able to replenish systemic infection on treatment interruption. Because latently infected cells are indistinguishable from uninfected cells, deliberate activation of latent infection combined with intensified HAART seems to be the best strategy to combat latent infection. Initial hypothesis-driven clinical trials did not achieve their ultimate goal, although they provided valuable insight for the design of future eradication protocols. A more detailed understanding of the basic mechanisms underlying the establishment and long-term maintenance of HIV-1 reservoirs will be critical in developing new eradication approaches.
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Advancements in the Treatment of Epilepsy
B.A. Leeman, and A.J. ColeVol. 59 (2008), pp. 503–523More LessDiagnostic tools and treatment options for epilepsy have expanded in recent years. Imaging techniques once confined to research laboratories are now routinely used for clinical purposes. Medications that were unavailable a few years ago are now first-line agents. Patients with refractory seizures push for earlier surgical intervention, consider treatment with medical devices, and actively seek nonpharmacologic alternatives. We review some of these recent advances in the management of epilepsy.
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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)