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- Volume 59, 2008
Annual Review of Medicine - Volume 59, 2008
Volume 59, 2008
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The FDA Critical Path Initiative and Its Influence on New Drug Development*
Vol. 59 (2008), pp. 1–12More LessSocietal expectations about drug safety and efficacy are rising while productivity in the pharmaceutical industry is falling. In 2004, the US Food and Drug Administration introduced the Critical Path Initiative with the intent of modernizing drug development by incorporating recent scientific advances, such as genomics and advanced imaging technologies, into the process. An important part of the initiative is the use of public-private partnerships and consortia to accomplish the needed research. This article explicates the reasoning behind the Critical Path Initiative and discusses examples of successful consortia.
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Reversing Advanced Heart Failure by Targeting Ca2+ Cycling
Vol. 59 (2008), pp. 13–28More LessHeart failure is a major cardiovascular disease, characterized by considerable morbidity and mortality. Despite major advances in the pharmacotherapy of heart failure, the options for patients with severe end-stage symptoms remain limited. However, recent developments in the identification of the molecular basis for the progressive nature of heart failure have identified a number of potentially important new therapeutic targets. In particular, key components of the cardiomyocyte calcium-handling pathway show characteristic changes in heart failure. A body of research examining the effect of restoration of these defects in experimental models of heart failure, whether in genetically engineered mouse models or by myocardial gene transfer, very strongly supports the calcium-handling pathway as a target for clinical intervention.
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Tissue Factor and Factor VIIa as Therapeutic Targets in Disorders of Hemostasis
Ulla Hedner, and Mirella EzbanVol. 59 (2008), pp. 29–41More LessFor hemophilia patients with inhibitors against FVIII or FIX, the development of recombinant factor VIIa (rFVIIa) raises the possibility of a therapeutic alternative whose availability and convenience of treatment are comparable to those of FVIII or FIX. In support of this new concept for the treatment of bleeding episodes, pharmacological doses of FVIIa have been shown to induce hemostasis. Pharmacological doses of rFVIIa enhance thrombin generation on thrombin-activated platelets, thereby facilitating the formation of strong, well-structured fibrin plugs resistant to premature proteolysis. Modified rFVIIa molecules with a stronger hemostatic potential have been produced. Inhibition of the FVII-TF-dependent pathway (TFPI and rFVIIai) has been tried in attempts to prevent thrombosis, with promising results in animal models so far not confirmed in clinical trials.
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Therapy of Marfan Syndrome
Vol. 59 (2008), pp. 43–59More LessMarfan syndrome is a common inherited disorder of connective tissue caused by deficiency of the matrix protein fibrillin-1. Effective surgical therapy for the most life-threatening manifestation, aortic root aneurysm, has led to a nearly normal lifespan for affected individuals who are appropriately recognized and treated. Traditional medical therapies, such as beta-adrenergic receptor blockade, are used to slow pathologic aortic growth and decrease the risk of aortic dissection by decreasing hemodynamic stress. New insights regarding the pathogenesis of Marfan syndrome have developed from investigation of murine models of this disorder. Fibrillin-1 deficiency is associated with excess signaling by transforming growth factor beta (TGFβ). TGFβ antagonists have shown great success in improving or preventing several manifestations of Marfan syndrome in these mice, including aortic aneurysm. These results highlight the potential for development of targeted therapies based on discovery of disease genes and interrogation of pathogenesis in murine models.
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Preeclampsia and Angiogenic Imbalance
Vol. 59 (2008), pp. 61–78More LessPreeclampsia is a systemic syndrome of pregnancy that originates in the placenta and is characterized by widespread maternal endothelial dysfunction. Until recently, the molecular pathogenesis of preeclampsia was largely unknown, but recent work suggests a key role for altered expression of placental antiangiogenic factors. Soluble Flt1 and soluble endoglin, secreted by the placenta, are increased in the maternal circulation weeks before the onset of preeclampsia. These antiangiogenic factors produce systemic endothelial dysfunction, resulting in hypertension, proteinuria, and the other systemic manifestations of preeclampsia. The molecular basis for placental dysregulation of these pathogenic factors remains unknown, and the role of angiogenic proteins in early placental vascular development is just beginning to be explored. These discoveries have exciting clinical implications and are likely to transform the detection and treatment of preeclampsia in the future.
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Management of Lipids in the Prevention of Cardiovascular Events
Vol. 59 (2008), pp. 79–94More LessLipid-modifying therapy has been proven to significantly reduce cardiovascular events and total mortality. Most of the data have come from statin trials. Statin therapy is generally well-tolerated and safe, and for patients who are at higher than average risk of cardiovascular disease, the benefit of lipid-modifying therapy far exceeds the risk. Careful risk assessment is a critical component of effective lipid-modifying therapy. In the foreseeable future, low-density lipoprotein cholesterol (LDL-C) will remain the primary therapeutic target, and combination therapy is likely to become the norm. The major questions are how low to treat and how to achieve increasingly aggressive targets in lipid-lowering therapy. Many patients on LDL-lowering therapy continue to have abnormalities of the triglyceride–high-density lipoprotein (TG-HDL) axis, so additional drug therapy is often considered for such patients. In this review, we briefly discuss new developments in cardiovascular risk assessment, then discuss recent developments in treatment to reduce LDL, and finally discuss current concepts regarding therapy targeting the TG-HDL axis.
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Genetic Susceptibility to Type 2 Diabetes and Implications for Antidiabetic Therapy
Vol. 59 (2008), pp. 95–111More LessDespite major advances in our knowledge of glycemic pathophysiology and the availability of multiple therapeutic options to confront type 2 diabetes, unraveling the complex link between genetic risk and environmental factors in this burgeoning epidemic has proven difficult. Linkage approaches have clarified the etiology of monogenic diabetic syndromes and congenital lipodystrophies, and candidate gene association studies have identified a number of common variants implicated in type 2 diabetes. This year we have witnessed the advent of genome-wide association scanning: As many as nine genetic loci have now been reproducibly associated with type 2 diabetes in five genome-wide scans. Of particular interest are preliminary explorations of the connections between genetic risk and pharmacologic response. An improved understanding of genetic mechanisms should allow us to test whether behavioral or pharmacologic therapies can be tailored and thus the tremendous disease burden inflicted by type 2 diabetes alleviated.
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Array-Based DNA Diagnostics: Let the Revolution Begin
Vol. 59 (2008), pp. 113–129More LessAdvances in the fabrication of DNA microarrays as well as transformations in detection chemistries have vastly increased the throughput for genotyping, DNA sequencing, and array-based copy number analysis (ABCNA). Rapid changes in technology are not only affecting research but also revolutionizing DNA diagnostics. Here we focus on the application of high-throughput ABCNA and genotyping. Targeted and genome-wide ABCNA has led to the discovery of extensive DNA copy number variation in the population and the delineation of many previously unrecognized submicroscopic chromosomal aberrations (genomic disorders). High-throughput single-nucleotide polymorphism (SNP) genotyping is being widely applied in genome-wide association studies (GWASs) with recent successes in identification of common variants that confer risk for common adult diseases. Future applications of high-throughput genotyping and array-based DNA sequencing technology will undoubtedly involve research and diagnostic analyses of rare mutations and perhaps ultimately enable full individual genome sequencing.
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Inherited Mitochondrial Diseases of DNA Replication*
Vol. 59 (2008), pp. 131–146More LessMitochondrial genetic diseases can result from defects in mitochondrial DNA (mtDNA) in the form of deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These mutations may be spontaneous, maternally inherited, or a result of inherited nuclear defects in genes that maintain mtDNA. This review focuses on our current understanding of nuclear gene mutations that produce mtDNA alterations and cause mitochondrial depletion syndrome (MDS), progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). To date, all of these etiologic nuclear genes fall into one of two categories: genes whose products function directly at the mtDNA replication fork, such as POLG, POLG2, and TWINKLE, or genes whose products supply the mitochondria with deoxynucleotide triphosphate pools needed for DNA replication, such as TK2, DGUOK, TP, SUCLA2, ANT1, and possibly the newly identified MPV17.
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Childhood Obesity: Adrift in the “Limbic Triangle”
Vol. 59 (2008), pp. 147–162More LessThe prevalence and severity of childhood obesity have increased steadily over the past three decades. The human species evolved to rigorously defend its lower limit for weight and adiposity but is tolerant of the upper limit, which, until recent times, was rarely approached. Neuroendocrine mechanisms within the limbic core of the brain prevent starvation (ventromedial hypothalamus), heighten reward (ventral tegmental area and nucleus accumbens), and attenuate stress (amygdala), in order to promote food-seeking and ingestive behavior and to conserve energy output. In a stressful modern environment with ready access to calorie-dense, highly palatable foods and limited venues for activity, normal, reflexive responsiveness to these three drives makes weight gain all but inevitable. The obesity that ensues often engenders insulin resistance, which undermines the ability of normal hunger and satiety signals to accurately modulate energy intake versus expenditure. Obesity interventions that rely on cognitive information alone cannot free children from this “limbic triangle.” Integrated multidisciplinary family- and community-based education, effective stress reduction, and a societal commitment to alter the food and built environments are all necessary components to battle the global obesity epidemic.
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Expanded Newborn Screening: Implications for Genomic Medicine
Vol. 59 (2008), pp. 163–175More LessNewborn screening (NBS) represents the largest volume of genetic testing. The 45-year history of NBS has demonstrated its benefits, as well as the importance of an evidence base. The recent addition of tandem mass spectrometry (MS/MS) resulted in a fivefold increase in the number of tests. Experience with MS/MS also showed that laboratory tests are just one part of the NBS system. The lessons learned from NBS will provide important insights as we move into the predictive, preventive, and personalized era of genomic medicine.
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Is Human Hibernation Possible?
Vol. 59 (2008), pp. 177–186More LessThe induction of hypometabolism in cells and organs to reduce ischemia damage holds enormous clinical promise in diverse fields, including treatment of stroke and heart attack. However, the thought that humans can undergo a severe hypometabolic state analogous to hibernation borders on science fiction. Some mammals can enter a severe hypothermic state during hibernation in which metabolic activity is extremely low, and yet full viability is restored when the animal arouses from such a state. To date, the underlying mechanism for hibernation or similar behaviors remains an enigma. The beneficial effect of hypothermia, which reduces cellular metabolic demands, has many well-established clinical applications. However, severe hypothermia induced by clinical drugs is extremely difficult and is associated with dramatically increased rates of cardiac arrest for nonhibernators. The recent discovery of a biomolecule, 5′-AMP, which allows nonhibernating mammals to rapidly and safely enter severe hypothermia could remove this impediment and enable the wide adoption of hypothermia as a routine clinical tool.
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Advance Directives
Vol. 59 (2008), pp. 187–198More LessMost patients want some control over their medical care, including—or even especially—when they are too sick to participate in decisions. Clinicians who have to make decisions for patients who are unable to participate often would appreciate guidance from patients’ wishes. Advance care planning responds to these needs. The process provides for discussions about goals in different scenarios and allows inclusion of the family and physician as well as the patient. It helps to have the patient and family complete validated worksheets that walk them through the various considerations and result in expressions of preference that are clinically meaningful. For the clinician, scenario-based goals for care and personal thresholds for when desired care shifts from primarily cure-oriented to primarily palliative are the most useful features to know about. The patient and family should do most of the discussing on their own time; the physician and team should coordinate to screen for problems and ensure agreement. Ideally, this should occur over the course of regular clinical encounters, with some dedicated time for the topic at suitable intervals.
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Genetic Determinants of Aggressive Breast Cancer
Vol. 59 (2008), pp. 199–212More LessThe development and spread of breast and other human cancers are caused by the overexpression, mutation, and/or deletion of specific genes that drive these events. Finding genetic and molecular differences between cancerous and healthy cells can reveal the genetic determinants of cancer. This knowledge results in a better understanding of the carcinogenic process and improved predictive power, with implications for identifying new drug targets, designing novel therapies, and improving preclinical and clinical studies. We review the concepts of biomarker, genetic marker, and genetic determinant in cancer, with particular focus on the most aggressive and lethal form of breast cancer, termed inflammatory breast cancer (IBC). Using IBC as an example, we describe in detail the approaches to identify the genes that are responsible for—and not merely associated with—this disease.
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A Role for JAK2 Mutations in Myeloproliferative Diseases
Vol. 59 (2008), pp. 213–222More LessMyeloproliferative disorders (MPDs) are characterized by a clonal expansion of myeloid cells. Over the past two years, the identification of the JAK2V617F mutation in most cases of polycythemia vera (PV) as well as ∼50% of patients with essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF) has greatly advanced our understanding of MPDs. The JAK2V617F mutation alters the JAK2 tyrosine kinase to confer constitutive activation and affect downstream signaling pathways. Data from mouse models demonstrate that the mutation is sufficient for development of PV, but additional work is needed to better understand how this allele functions in ET and IMF. Regardless of the various pathologies, the JAK2V617F discovery highlights the importance of JAK-STAT signaling in myeloid differentiation and focuses effort on developing a clinically relevant JAK2 inhibitor.
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Appropriate Use of Cervical Cancer Vaccine
Vol. 59 (2008), pp. 223–236More LessHuman papillomavirus (HPV) is a necessary, though not sufficient, cause of cervical cancer. Two vaccines have been developed that prevent two HPV types associated with 70% of cervical cancers. One of the vaccines (a quadrivalent vaccine) also prevents two HPV types associated with 90% of genital warts. Both HPV vaccines have shown very good efficacy and safety. This review summarizes the guidelines for use of the quadrivalent vaccine published by the Advisory Committee on Immunization Practices, presents data on vaccine efficacy and safety, and gives an overview of the findings of cost-effectiveness studies. In addition, we summarize the research on the attitudes of parents and health care providers toward HPV vaccine and critically evaluate controversial and challenging issues surrounding HPV vaccination, including concerns about sexual disinhibition and potential obstacles to vaccine distribution and uptake.
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A Decade of Rituximab: Improving Survival Outcomes in Non-Hodgkin's Lymphoma
Vol. 59 (2008), pp. 237–250More LessThe anti-CD20 monoclonal antibody rituximab, first approved for clinical use in 1997, has changed the standard of care for many patients with non-Hodgkin's lymphoma (NHL). Recent data from large randomized clinical trials confirm that the addition of rituximab to standard chemotherapy regimens (chemoimmunotherapy) improves both response rates and survival outcomes in patients with follicular NHL and diffuse large B cell lymphoma (DLBCL), the two most common subtypes of NHL. Population-based analyses have found substantial improvements in NHL survival over the past decade; studies indicate that rituximab has favorably altered the long-term prognosis of follicular NHL and DLBCL patients. This review discusses the clinical development of rituximab-based therapies for patients with low-grade or follicular NHL and newly diagnosed DLBCL, highlighting recent key randomized trials with a focus on survival outcomes.
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Nanotechnology and Cancer
Vol. 59 (2008), pp. 251–265More LessThe biological picture of cancer is rapidly advancing from models built from phenomenological descriptions to network models derived from systems biology, which can capture the evolving pathophysiology of the disease at the molecular level. The translation of this (still academic) picture into a clinically relevant framework can be enabling for the war on cancer, but it is a scientific and technological challenge. In this review, we discuss emerging in vitro diagnostic technologies and therapeutic approaches that are being developed to handle this challenge. Our discussion of in vitro diagnostics is guided by the theme of making large numbers of measurements accurately, sensitively, and at very low cost. We discuss diagnostic approaches based on microfluidics and nanotechnology. We then review the current state of the art of nanoparticle-based therapeutics that have reached the clinic. The goal of the presentation is to identify nanotherapeutic strategies that are designed to increase efficacy while simultaneously minimizing the toxic side effects commonly associated with cancer chemotherapies.
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Cancer Epigenetics: Modifications, Screening, and Therapy
Vol. 59 (2008), pp. 267–280More LessDeregulation of gene expression is a hallmark of cancer. Although genetic lesions have been the focus of cancer research for many years, it has become increasingly recognized that aberrant epigenetic modifications also play major roles in the tumorigenic process. These modifications are imposed on chromatin, do not change the nucleotide sequence of DNA, and are manifested by specific patterns of gene expression that are heritable through many cell divisions. We review these modifications in normal and cancer cells and the evolving approaches used to study them. Additionally, we outline advances in their potential use for cancer diagnostics and targeted epigenetic therapy.
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T Cells and NKT Cells in the Pathogenesis of Asthma
Vol. 59 (2008), pp. 281–292More LessAsthma is an immunological disease with multiple inflammatory and clinical phenotypes, characterized by symptoms of wheezing, shortness of breath, and coughing due to airway hyperreactivity (AHR) and reversible airway obstruction. In allergic asthma, the most common form of asthma, airway inflammation is mediated by adaptive immune recognition of protein allergens by Th2 cells, resulting in airway eosinophilia. However, in other forms of asthma, inflammation is associated with immune responses to respiratory infections and airway neutrophilia. A central feature common to all forms of asthma is AHR, the heightened responsiveness of the airways to nonspecific stimuli. AHR has been shown recently in animal models of asthma to require the presence of CD1d-restricted, invariant T cell receptor-positive, natural killer T (iNKT) cells. Although allergen-specific Th2 cells and iNKT cells have many phenotypic similarities (e.g., expression of CD4 and production of Th2 cytokines), they have complementary activities, such as production of Th2 cytokines under different conditions, differential sensitivity to corticosteroids, and responsiveness to different classes of antigen (proteins versus glycolipids). We hypothesize that Th2 cells and iNKT cells interact synergistically to induce asthma but that different forms of asthma result from distinct roles of CD4+iNKT cells versus Th2 cells.
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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 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)