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- Volume 56, 2005
Annual Review of Medicine - Volume 56, 2005
Volume 56, 2005
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Myelodysplastic Syndrome
Vol. 56 (2005), pp. 1–16More LessDuring the past 15 years, important progress has been made in the understanding of the biology and prognosis of myelodysplastic syndrome (MDS). MDS is a clonal disorder characterized by ineffective hematopoiesis, which can lead to either fatal cytopenias or acute myelogenous leukemia (AML). Risk-adapted treatment strategies were established because of the high median age (60–75 years) of the MDS patients and the individual history of the disease (number of cytopenias, cytogenetic changes, transfusion requirements). Allogeneic bone marrow transplantation currently offers the only potentially curative treatment, but this form of therapy is not available for the typical MDS patient, who is >60 years of age. Therapy with erythropoietin and G-CSF has improved the quality of life of selected patients. The development of small molecules directed against specific molecular targets with minimal adverse effects is the hope for the future. Innovative uses of immunomodulatory agents and the optimizing of cytotoxic treatment should continue to help in the treatment of MDS.
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G Protein Polymorphisms in Hypertension, Atherosclerosis, and Diabetes
Vol. 56 (2005), pp. 17–28More LessA common C825T polymorphism in the gene GNB3, which encodes the β3 subunit of heterotrimeric G proteins, was identified in cell lines from patients with hypertension. The 825T allele is associated with increased intracellular signal transduction. Many population-based and case-control studies in different ethnicities have investigated an association between this polymorphism and hypertension, obesity, and atherosclerosis. A critical assessment of published studies suggests that 825T allele carriers have an increased risk for hypertension combined with features of the metabolic syndrome, such as dyslipidemia, hypercholesterolemia, insulin resistance, and obesity. It is anticipated that this polymorphism will be used in clinical practice to better characterize hypertension and for individualized treatment regimens.
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Post-Transplant Lymphoproliferative Disorders
Vol. 56 (2005), pp. 29–44More LessPost-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication after hematopoietic stem cell or solid organ transplantation. The majority of PTLD is of B-cell origin and associated with Epstein-Barr virus (EBV). During the past decade progress has been made in better understanding the pathogenesis of PTLD, and early detection strategies, such as serial measurement of EBV-DNA load in peripheral blood samples, have assisted in the identification of high-risk patients. In addition, novel immunotherapies have been developed, including the use of monoclonal antibodies and adoptive transfer of EBV-specific T cells. Despite these advances, it remains a major challenge to define indications for preemptive therapies for PTLD and to integrate novel therapeutic approaches with conventional therapies.
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Metabolic Syndrome: A Clinical and Molecular Perspective
Vol. 56 (2005), pp. 45–62More LessThe metabolic syndrome is a cluster of interrelated common clinical disorders, including obesity, insulin resistance, glucose intolerance, hypertension, and dyslipidemia (hypertriglyceridemia and low HDL cholesterol levels). According to recently defined criteria, the metabolic syndrome is prevalent and is associated with a greater risk of atherosclerotic cardiovascular disease than any of its individual components. Primary defects in energy balance that produce obesity (and visceral adiposity in particular) are sufficient to drive all aspects of the syndrome. Increased free fatty acids and lipid accumulation in certain organs are mediators of insulin resistance. Obesity also leads to a proinflammatory and prothrombotic state that potentiates atherosclerosis. Pathways leading directly from adiposity to the genesis of dyslipidemia and hypertension have been elucidated. Recent knowledge implies a role for fat-derived “adipokines,” including TNFα and adiponectin, as pathogenic contributors or protective factors. Current therapies include diet and exercise as well as agents indicated for the treatment of individual components of the syndrome. Future therapies may accrue from the aggressive pursuit of newer molecular drug targets that have the potential to prevent or treat multiple aspects of the metabolic syndrome.
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New Anticoagulant Therapy
Vol. 56 (2005), pp. 63–77More LessThe development of new anticoagulants is expanding the list of drugs that can be used to prevent and treat venous and arterial thrombosis. New parenteral anticoagulants have been developed to overcome the limitations of heparin and low-molecular-weight heparin, whereas novel orally active anticoagulants have been designed to provide more streamlined therapy than vitamin K antagonists. This review identifies the molecular targets of new anticoagulants, describes the results of clinical trials, and provides clinical perspective on the opportunities for new anticoagulants.
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Endothelial Progenitor Cells*
Vol. 56 (2005), pp. 79–101More LessEndothelial progenitor cells are a circulating, bone marrow–derived cell population that appears to participate in both vasculogenesis and vascular homeostasis. Questions persist regarding their functional characteristics, as well as the precise panel of cell surface markers that uniquely define this newly described progenitor cell population. We review experimental results obtained from both animal studies and recent clinical trials that suggest this cell type may have tremendous therapeutic potential for a wide range of human diseases.
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Aromatase Inhibitors: Rationale and Use in Breast Cancer
Vol. 56 (2005), pp. 103–116More LessConsiderable data implicate estrogens in breast cancer carcinogenesis and progression. In the postmenopausal woman, estrogens are produced in breast tissues and many other sites throughout the body when androgen precursors are converted into estrogens via the enzyme aromatase. Inhibition of this enzyme with aromatase inhibitors (AIs) has demonstrated reductions in systemic as well as intratumoral estrogens. These drugs have now been utilized in large phase 3 randomized trials and have led to greater improved clinical benefit than the “gold standard,” tamoxifen. Questions remain about the long-term side effects and safety profile of AIs. They are associated with increasing incidence of osteoporosis and bone fractures. Nevertheless, AIs add to our armamentarium for therapy and possible prevention of breast cancer.
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Andropause: Is Androgen Replacement Therapy Indicated for the Aging Male?*
Vol. 56 (2005), pp. 117–137More LessThe number of men in the United States ≥65 years of age is projected to increase from 14,452,000 in 2000 to 31,343,000 in 2030. Approximately 30% of men 60–70 years of age and 70% of men 70–80 years of age have low bioavailable or free testosterone levels. Symptoms and findings of testosterone deficiency are similar to those associated with aging. They include loss of energy, depressed mood, decreased libido, erectile dysfunction, decreased muscle mass and strength, increased fat mass, frailty, osteopenia, and osteoporosis. Several small clinical trials indicate that testosterone replacement therapy can improve many of these findings; however, the studies have not been powered to assess potential risks, such as the need for invasive treatment of benign prostatic hyperplasia, development of a clinical prostate cancer, or cardiovascular events. Thus, the benefit/risk ratio of testosterone replacement therapy in aging men is not known.
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Surgical Therapy for Metastatic Disease to the Liver
Vol. 56 (2005), pp. 139–156More LessThe liver is a common site of hematogenous metastasis. In the past, patients with liver metastases were often deemed inoperable, and medical therapy conferred only minor survival benefit. However, advances in surgical techniques and chemotherapeutic agents during the past two decades have led to effective treatments for selected patients with metastases to the liver. Up to ∼80% of the liver can be resected, and partial hepatectomy is now routinely performed with a perioperative mortality rate of <5%. Surgical resection of colorectal cancer metastatic to the liver results in a 5-year survival rate of 40%. These results are expected to improve even further with multimodality approaches that include newer chemotherapy regimens. Liver metastases from other primary tumors, such as neuroendocrine carcinoma and genitourinary tumors, are also treated effectively with liver resection. The indications for surgical treatment of liver metastases are broadening as a variety of novel therapies are being developed, including hepatic artery embolization, hepatic artery infusion of chemotherapy, and radiofrequency ablation.
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New Strategies in the Treatment of the Thalassemias
Vol. 56 (2005), pp. 157–171More LessIn addition to the severe beta thalassemias, hematologists have begun to recognize the more severe forms of alpha thalassemia, namely hemoglobin (Hb) H disease and Hb H/Hb Constant Spring, as well as the beta compound heterozygote, beta thalassemia/HbE. Clinically, variably severe anemia becomes apparent in the first year accompanied by occasionally massive expansion of erythropoiesis. The most anemic patients require regular red blood cell transfusions to avoid death from cardiac failure. However, the inevitable iron accumulation leads to dysfunction, primarily involving the heart, liver, and endocrine system; thus, regularly transfused patients require iron chelation. A major discovery was that allogeneic bone marrow (stem cell) transplantation in severely affected subjects with both alpha and beta thalassemia could result in cure. Current work deals with specific complications, such as iron overload and endocrine, cardiopulmonary, thrombophilic, and osteopenic problems. The thalassemias are likely to benefit in the future from specific gene therapy. There are also important advances in genetic counseling based on results of early fetal diagnosis.
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New Concepts in Von Willebrand Disease
Vol. 56 (2005), pp. 173–191More LessVon Willebrand factor (VWF) behaves as an extracellular adapter molecule, linking platelets to the extracellular matrix at sites of vascular injury. These interactions are crucial for hemostasis. Too little platelet adhesion causes bleeding that is typical of von Willebrand disease, whereas too much platelet adhesion may cause thrombotic thrombocytopenic purpura. Mutations in VWF or platelet glycoprotein Ib can either reduce or increase the affinity of platelet binding. Paradoxically, affinity changes in either direction cause bleeding. Crystallographic studies now suggest molecular explanations for all of these phenotypes. Clinical investigations of von Willebrand disease type 1 are defining the relationship between plasma VWF level and the risk of bleeding or thrombosis. Emerging data suggest that VWF level is a useful biomarker for the risk of either bleeding or thrombosis and could be incorporated into a comprehensive approach to treat or prevent these adverse events.
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Genetics of Longevity and Aging
Jan Vijg, and Yousin SuhVol. 56 (2005), pp. 193–212More LessLongevity, i.e., the property of being long-lived, has its natural limitation in the aging process. Longevity has a strong genetic component, as has become apparent from studies with a variety of organisms, from yeast to humans. Genetic screening efforts with invertebrates have unraveled multiple genetic pathways that suggest longevity is promoted through the manipulation of metabolism and the resistance to oxidative stress. To some extent, these same mechanisms appear to act in mammals also, despite considerable divergence during evolution. Thus far, evidence from population-based studies with humans suggests the importance of genes involved in cardiovascular disease as important determinants of longevity. The challenge is to test if the candidate longevity genes that have emerged from studies with model organisms exhibit genetic variation for life span in human populations. Future investigations are likely to involve large-scale case-control studies, in which large numbers of genes, corresponding to entire gene functional modules, will be assessed for all possible sequence variation and associated with detailed phenotypic information on each individual over extended periods of time. This should eventually unravel the genetic factors that contribute to each particular aging phenotype.
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Progress Toward an HIV Vaccine
Vol. 56 (2005), pp. 213–223More LessThe development of an HIV vaccine is proving to be an unprecedented challenge. The difficulty in creating this vaccine arises from the enormous genetic variation of the virus and the unusual importance of cytotoxic T lymphocytes (CTL) in controlling its spread. Whereas traditional vaccine strategies are unlikely to confer safe and effective HIV protection, novel strategies for eliciting CTL have provided substantial clinical benefits in nonhuman primate model systems. These vaccine strategies, including plasmid DNA and live recombinant vectors, are currently being evaluated in human clinical trials.
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Therapeutic Intervention and Targets for Sepsis*
Vol. 56 (2005), pp. 225–248More LessSepsis syndrome, a systemic response to infection, can beget devastating outcomes even in previously normal individuals. Recent research in septic patients has led to the discovery that early goal-directed resuscitation guided by continuous monitoring of mixed venous hemoglobin saturation, along with moderate doses of corticosteroids, can reduce mortality. An improved understanding of the complex interaction between the inflammatory and coagulant systems in sepsis pathophysiology has resulted in novel treatments, such as recombinant human activated protein C, which improves survival in patients with severe sepsis and a high risk of death. However, despite an increased understanding of the complex pathophysiology of this syndrome and the discovery of new, effective treatments, severe sepsis still results in significant morbidity and mortality. Consequently, investigations continue into additional therapeutic agents directed against novel targets. Following a review of recent advances in sepsis treatment, we briefly discuss a few of the new, promising therapeutic strategies currently being investigated.
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Management of Peripheral Vascular Disease
Vol. 56 (2005), pp. 249–272More LessThe management of patients with peripheral arterial occlusive disease (PAD) has to be planned in the context of natural history, epidemiology, and apparent risk factors that predict deterioration. The ankle-brachial index to date has proved to be the most effective, accurate, and practical method of PAD detection. Given that PAD is a powerful indicator of systemic atherosclerosis and (independent of symptoms) is associated with an increased risk of myocardial infarction and stroke, as well as a six times greater likelihood of death, the prevalence and demographic distribution of measurable PAD becomes particularly relevant. Reliable information on interventions to confer symptom relief is much weaker and reflects discrepancies between published reports from centers of excellence and the experience of patients routinely treated in communities around the world. The impact of newer treatment modalities, such as complex endovascular procedures and therapeutic angiogenesis, has been a subject of recent controversy.
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Role of Magnetic Resonance Imaging and Immunotherapy in Treating Multiple Sclerosis*
Vol. 56 (2005), pp. 273–302More LessSignificant advances in magnetic resonance imaging (MRI) technology and treatment of multiple sclerosis (MS) have been made during the past decade. These advances have revealed evidence of profound heterogeneity in MS. There is a clear need to revisit the key issues in MS pathogenesis and treatment strategies, taking new data into consideration. This paper provides an overview of recent progress in MS research, including (a) a review of clinical, pathologic, and immunologic aspects of MS, (b) a discussion of the mechanism of action of currently available disease-modifying drugs for MS, (c) an account of the role of MRI in clinical management and clinical trials in MS, and (d) an overview of some emerging treatments for MS.
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Definition and Clinical Importance of Haplotypes
Vol. 56 (2005), pp. 303–320More LessAdvances in genotyping and sequencing technologies, coupled with the development of sophisticated statistical methods, have afforded investigators novel opportunities to define the role of sequence variation in the development of common human diseases. At the forefront of these investigations is the use of dense maps of single-nucleotide polymorphisms (SNPs) and the haplotypes derived from these polymorphisms. Here we review basic concepts of high-density genetic maps of SNPs and haplotypes and how they are typically generated and used in human genetic research. We also provide useful examples and tools available for researchers interested in incorporating haplotypes into their studies. Finally, we discuss the latest concepts for the analysis of haplotypes related to human disease, including haplotype blocks, the International HapMap Project, and the future directions of these resources.
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Approaches to Therapy of Prion Diseases
Vol. 56 (2005), pp. 321–344More LessDevising approaches to the therapy of transmissible spongiform encephalopathies, or prion diseases, is beset by many difficulties. For one, the nature of the infectious agent, the prion, is understood only in outline, and its composition, structure, and mode of replication are still shrouded in mystery. In addition, the mechanism of pathogenesis is not well understood. Because clinical disease affects mainly the brain parenchyme, therapeutic agents must be able to traverse the brain-blood barrier (BBB) or have to be introduced directly into the cerebrospinal fluid or brain tissue. And finally, because the disease is usually recognized only after onset of severe clinical symptoms, the question arises as to whether the neurodegenerative processes can be reversed to any extent after a successful eradication of the agent.
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Endometriosis: New Genetic Approaches and Therapy
Vol. 56 (2005), pp. 345–356More LessEndometriosis is a relatively common condition in women of reproductive age and is associated with considerable morbidity. Despite an extensive literature describing its multiple clinical manifestations, their management, and many aspects of the biology of endometriotic lesions, the pathophysiological mechanisms involved remain poorly understood. A genetic component in endometriosis is now recognized, and several groups have taken up the challenge of using genetic techniques to identify the aberrant molecular and cellular mechanisms in endometriosis with the intention of providing much-needed insights that might, in turn, lead to new therapies. The techniques that have been applied include expression profiling, tumor genetic studies, functional candidate gene studies, and linkage studies that can adopt a hypothesis-free approach. This review describes the current status of these studies and explores the prospects for new therapies.
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Severe Acute Respiratory Syndrome (SARS): A Year in Review
Vol. 56 (2005), pp. 357–381More LessSevere acute respiratory syndrome (SARS) emerged from China as an untreatable and rapidly spreading respiratory illness of unknown etiology. Following point source exposure in February 2003, more than a dozen guests infected at a Hong Kong hotel seeded multi-country outbreaks that persisted through the spring of 2003. The World Health Organization responded by invoking traditional public health measures and advanced technologies to control the illness and contain the cause. A novel coronavirus was implicated and its entire genome was sequenced by mid-April 2003. The urgency of responding to this threat focused scientific endeavor and stimulated global collaboration. Through real-time application of accumulating knowledge, the world proved capable of arresting the first pandemic threat of the twenty-first century, despite early respiratory-borne spread and global susceptibility. This review synthesizes lessons learned from this remarkable achievement. These lessons can be applied to re-emergence of SARS or to the next pandemic threat to arise.
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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)