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- Volume 57, 2006
Annual Review of Medicine - Volume 57, 2006
Volume 57, 2006
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Hemochromatosis: Genetics and Pathophysiology
Vol. 57 (2006), pp. 331–347More LessA number of genetic disorders can result in the accumulation of excess iron in the body. These causes of hereditary hemochromatosis include defects in genes encoding HFE, transferrin receptor 2, ferroportin, hepcidin, and hemojuvelin. Hepcidin, with its cognate receptor, ferroportin, has emerged as a central regulator of iron homeostasis; all of the known causes of hemochromatosis appear to prevent this system from functioning normally. The most common form of primary hemochromatosis is that caused by C282Y mutation of the HFE gene. This mutation is most prevalent among Northern Europeans. Although the frequency of the homozygous genotype is approximately 5 per 1000, the disease itself is quite rare because the clinical penetrance of the genotype is very low.
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Therapeutic Use of Calcimimetics
Vol. 57 (2006), pp. 349–364More LessIt has long been recognized that the secretion of PTH by chief cells in the parathyroid gland is regulated by extracellular ionized calcium. The molecular mechanism by which extracellular Ca2+ performs this feat was deduced by the cloning of the extracellular calcium-sensing receptor (CaSR) in 1993 in the laboratories of Brown and Hebert. The CaSR is a G protein–coupled cell surface receptor that belongs to family 3 of the GPCR superfamily. The CaSR senses the extracellular ionic activity of the divalent minerals Ca2+ and Mg2+ and translates this information, via a complex array of cellular signaling pathways, to modify cell and tissue function. Genetic studies have demonstrated that the activity of this receptor determines the steady-state plasma calcium concentration in humans by regulating key elements in the calcium homeostatic system. CaSR agonists (calcimimetics) and antagonists (calcilytics) have been identified and have provided both current and potential therapies for a variety of disorders. Calcimimetics can effectively reduce PTH secretion in all forms of hyperparathyroidism. They are likely to become a major therapy for secondary hyperparathyroidism associated with renal failure and for treatment of certain patients with primary hyperparathyroidism. On the therapeutic horizon are calcilytics that can transiently increase PTH and may prove useful in the treatment of osteoporosis.
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Toward a Unified Theory of Renal Progression
Vol. 57 (2006), pp. 365–380More LessVarious disciplines within nephrology investigate the mechanisms by which kidneys fail. Progress in the areas of glomerular hemodynamics, proteinuria, tubular biology, interstitial nephritis, fibroblast formation, and fibrosis have added kernels of information that together support a unified theory of renal progression. Prevention of progression to end-stage disease has largely focused on control of systemic and glomerular hypertension. Current success in delaying a decline in glomerular filtration rate underlines the promise of a more comprehensive approach. New knowledge about the cell biology of progression also suggests that other adjunctive therapies may be possible. We describe the progress and highlight those spheres where new-targeted interventions may arise.
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CD4+CD25+ Regulatory T Cells and Their Therapeutic Potential
Vol. 57 (2006), pp. 381–402More LessThe human immune system mounts specific responses to a vast array of antigens. Although this is clearly beneficial in fighting off harmful infections and cancerous cells, the system must be carefully controlled to ensure that normal self-antigens are not targeted. A recently characterized subset of T cells, identified by their cell surface expression of CD4 and CD25, is critical in regulating the function of other immune cells and preventing potentially harmful autoimmune responses. This article reviews what is currently known about these so-called regulatory T cells and discusses the therapeutic potential of these cells to modulate human immune-based diseases.
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Umbilical Cord Blood Transplantation and Banking
Vol. 57 (2006), pp. 403–417More LessUmbilical cord blood transplantation (UCBT) is an expanding practice for both pediatric and adult patients. Rapid availability, low risk of infectious disease transmission, lower risk of graft-versus-host disease, and lack of risk for the donor makes UCB an attractive alternative source of hematopoietic stem cells for transplantation. We review the state of the art of pediatric and adult UCBT and important aspects of UCB banking. Current strategies to improve clinical results and expand access to UCBT to a larger number of adult patients are discussed. New approaches to enhance hematopoietic recovery by the use of accessory cells or direct intra-bone marrow injection are also reviewed.
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Current Concepts in Thrombotic Thrombocytopenic Purpura
Vol. 57 (2006), pp. 419–436More LessRecent advances have demonstrated that thrombotic thrombocytopenic purpura (TTP), characterized by widespread thrombosis in the arterioles and capillaries, is caused by deficiency of a circulating zinc metalloprotease, ADAMTS13. Two types of TTP are recognized: autoimmune TTP, caused by inhibitory antibodies of ADAMTS13, and hereditary TTP, caused by genetic mutations of ADAMTS13. This article reviews the characteristics and function of ADAMTS13, the mechanism by which ADAMTS13 deficiency may lead to thrombosis, and the causes of ADAMTS13 deficiency. It also discusses how the new knowledge may improve the diagnosis and treatment of this previously mysterious disorder.
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Use of Stents to Treat Extracranial Cerebrovascular Disease
Vol. 57 (2006), pp. 437–454More LessStent-assisted carotid angioplasty (CAS) is increasingly utilized for hemodynamically significant stenoses of the extracranial carotid artery. Carotid endarterectomy (CEA) is still considered the gold standard in the management of symptomatic hemodynamically significant carotid stenoses. However, endovascular device technology is rapidly evolving and the recent introduction of embolic filtration devices (EFD) proved to reduce periprocedural stroke rates in CAS considerably. Several randomized multicenter trials are currently recruiting patients to compare CAS with EFD to carotid endarterectomy in different cohorts, such as patients at high surgical risk for CEA and those with asymptomatic stenosis. The review presents current developments in CAS.
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New Directions in Cardiac Transplantation
Vol. 57 (2006), pp. 455–471More LessMore than three decades of clinical experience in cardiac transplantation resulted in the spread of the procedure worldwide with a wealth of knowledge and advancements. Developments included liberalization of recipient and donor selection criteria, improved surgical techniques, novel immunosuppressive drugs and protocols, new rejection surveillance techniques, and better understanding of the pathophysiology of cardiac allograft vasculopathy to direct interventions for prevention and treatment.
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Exercise-Induced Ventricular Arrhythmias in Patients with No Structural Cardiac Disease
Vol. 57 (2006), pp. 473–484More LessWe review the clinical and genetic disorders associated with exercise-induced ventricular arrhythmias in patients with normal hearts. Foremost are those with catecholaminergic polymorphic ventricular tachycardia due to abnormalities in either the ryanodine receptor 2 genes (RyR2) or the calsequestrin genes (CASQ). These patients manifest ventricular premature beats and polymorphic ventricular tachycardia in response to exercise or on exposure to catecholamines. A great deal of basic information has been accumulated suggesting that these arrhythmias are caused by abnormalities in Ca2+ metabolism. The ensuing cytosolic Ca2+ overload results in delayed after-depolarizations and extrasystolic Ca2+ waves, leading to polymorphic ventricular tachycardia. Most of these patients will respond to beta-blocker therapy but a significant minority (30%) will require a defibrillator. Advances in genetic testing allow better understanding of this syndrome.
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Cardiotoxicity Induced by Chemotherapy and Antibody Therapy
Vol. 57 (2006), pp. 485–498More LessModern cancer therapy employs a combination of chemotherapy, antibody-based therapy, radiotherapy, and surgery to prolong life and provide cure. However, many of the chemotherapy agents and antibodies, either singly or in combination, can affect the cardiovascular system. Common cardiovascular manifestations of these therapies include heart failure, ischemia, hypotension, hypertension, edema, QT prolongation, bradyarrhythmia, and thromboembolism. The patient's age, underlying cardiovascular status, and genetic background, as well as the route of drug administration and dosage, can all contribute to the development of cardiotoxicity. Strategies to monitor for and to manage these effects are discussed in this review.
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“Sundowning” and Other Temporally Associated Agitation States in Dementia Patients
Vol. 57 (2006), pp. 499–511More LessThe behavioral and neuropsychiatric symptoms of dementia and Alzheimer's disease have become an increasingly important focus of clinical research. These symptoms also pose a tremendous challenge to families and caregivers. The late afternoon/evening exacerbation of behavioral symptoms in dementia has been recognized by clinicians for >60 years. Researchers have utilized a variety of increasingly sophisticated tools to examine the circadian, hormonal, physiological, and epidemiological correlations with sundowning behavior. Although treatment remains largely empirical, an improved understanding of the complex relationships that drive sundowning behavior should lead to more effective therapies in the future.
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Current Pharmacotherapy for Alzheimer's Disease
Vol. 57 (2006), pp. 513–533More LessAlzheimer's disease (AD) is an age-related neurodegenerative disease that affects approximately 4.5 million people in the United States. The mainstays of current pharmacotherapy for AD are compounds aimed at increasing the levels of acetylcholine in the brain, thereby facilitating cholinergic neurotransmission through inhibition of the cholinesterases. These drugs, known as acetylcholinesterase inhibitors (AChEIs), were first approved by the U.S. Food and Drug Administration (FDA) in 1995 based on clinical trials showing modest symptomatic benefit on cognitive, behavioral, and global measures. In 2004 the FDA approved memantine, an NMDA antagonist, for treating dementia symptoms in moderate to severe AD cases. In clinical practice, memantine may be co-administered with an AChEI, although neither drug individually or in combination affects the underlying pathophysiology of dementia. Dementia in AD results from progressive synaptic loss and neuronal death. As knowledge of the mechanisms responsible for neurodegeneration in AD increases, it is anticipated that neuroprotective drugs to slow or prevent neuronal dysfunction and death will be developed to complement current symptomatic treatments.
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New Treatments for Neuropathic Pain
Vol. 57 (2006), pp. 535–551More LessExisting treatments for neuropathic pain deliver inadequate pain relief, unacceptable side effects, or both. The unmet medical need for more effective treatment is driving a large volume of research to discover new drugs. Most existing treatments are drugs introduced to treat other pain conditions or other medical conditions, such as antidepressants and anticonvulsants, which were found empirically to be effective for neuropathic pain. Only recently have drug discovery efforts have become mechanistically driven, addressing targets identified by a molecular neurobiological approach to the pathophysiology of neuropathic states.
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Plant, Synthetic, and Endogenous Cannabinoids in Medicine
Vol. 57 (2006), pp. 553–574More LessAlthough used for more than 4000 years for recreational and medicinal purposes, Cannabis and its best-known pharmacologically active constituents, the cannabinoids, became a protagonist in medical research only recently. This revival of interest is explained by the finding in the 1990s of the mechanism of action of the main psychotropic cannabinoid, Δ9-tetrahydrocannabinol (THC), which acts through specific membrane receptors, the cannabinoid receptors. The molecular characterization of these receptors allowed the development of synthetic molecules with cannabinoid and noncannabinoid structure and with higher selectivity, metabolic stability, and efficacy than THC, as well as the development of antagonists that have already found pharmaceutical application. The finding of endogenous agonists at these receptors, the endocannabinoids, opened new therapeutic possibilities through the modulation of the activity of cannabinoid receptors by targeting the biochemical mechanisms controlling endocannabinoid tissue levels.
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The Health Insurance Portability and Accountability Act of 1996 (HIPAA) Privacy Rule: Implications for Clinical Research
Vol. 57 (2006), pp. 575–590More LessIn the short time since it became effective for health care organizations, a privacy regulation issued under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) has had a significant adverse impact on the conduct of clinical research in the United States, without a substantial corresponding increase in privacy protection for research participants. Some of the problems associated with HIPAA have been resolved through revisions since the regulation's initial promulgation in December 2000, and other problems can be addressed by better educating health care providers and researchers about its requirements and available alternatives for compliance; however, considerable structural challenges remain. These constitute substantial barriers to research and resulting medical advances. Additional revisions to HIPAA based on the principles and trade-offs reflected in the Common Rule—which responsibly balances an individual's interest in privacy protection with the public interest in gaining knowledge through biomedical research—can go a long way to remedying remaining flaws in the system.
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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)