Current Drug Targets - Cardiovascular & Hematological Disorders

Publisher: Bentham Science Publishers

Description

Current Drug Targets - Cardiovascular & Hematological Disorders aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in cardiovascular and hematological disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in cardiovascular and hematological disorders. As the discovery, identification, characterization and validation of novel human drug targets for cardiovascular and hematological drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development. Discontinued. Continued as Cardiovascular & Haematological Disorders - Drug Targets (1871-529X).

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  • Website
    Current Drug Targets - Cardiovascular & Hematological Disorders website
  • Other titles
    Current drug targets., Cardiovascular & hematological disorders, Cardiovascular & haematological disorders, Cardiovascular and hematological disorders, Cardiovascular and haematological disorders, Current drug targets., Current drug targets., Current drug targets
  • ISSN
    1568-0061
  • OCLC
    55201041
  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Bentham Science Publishers

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    • Author can archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
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    • 12 months (unless federal, government, funding agencies or local policy mandates for the author's institute a different policy on self-archiving)
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    • On authors personal or authors institutions server
    • Published source must be acknowledged
    • Must link to journal home page
    • Publisher's version/PDF cannot be used
    • Articles in all journals can be made Open Access on payment of additional charge
  • Classification
    ​ yellow

Publications in this journal

  • Current Drug Targets - Cardiovascular & Hematological Disorders 01/2013; 3(1):24.
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    ABSTRACT: Mature human atherosclerotic plaques are frequently characterized by a lipid-rich core covered by a fibrous cap composed of fibrillar collagens, elastin, proteoglycans and smooth muscle cells (SMC). Most sudden deaths due to acute myocardial infarction are caused by rupture of coronary atheroma, leading to a prothrombotic response followed by rapid occlusion of the artery. The accumulation of macrophage-derived foam cells in vulnerable shoulder regions of atherosclerotic plaques correlates with increased local release of matrix-degrading metalloproteinases (MMPs) and weak fibrous cap tissue. These findings suggest a potential role of macrophage-derived MMPs in the weakening and ultimate rupture of plaque structures. Consequently, several studies have focussed on the hypothesis that inhibiting MMP activity would reduce plaque volume and prevent plaque rupture and therefore would be useful in the treatment of atherosclerosis. However, current synthetic MMP inhibitors are not very specific and clinical results have so far been inconclusive. The development of selective inhibitors and focal gene transfer approaches may be better suited for the treatment of atherosclerosis.
    Current Drug Targets - Cardiovascular & Hematological Disorders 01/2006; 5(6):541-8.
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    ABSTRACT: Despite significant protection from cardiovascular events by HMG-CoA reductase inhibitors (statins), the extent of event reduction is incomplete and persistent lipid abnormalities remain prevalent. As such, the use of combination lipid modification regimens is a clinical reality. While we await large, randomized clinical outcomes trials assessing the benefits of combination or novel lipid management therapies, non-invasive imaging tests such as B-mode ultrasound to measure carotid intima-media thickness (CIMT), coronary computed tomography (CT) and cardiovascular magnetic resonance imaging (CMR) are increasingly being utilized to accurately assess the impact of lipid modifying therapies on atherosclerosis. Based on knowledge that atherosclerosis progression is a validated surrogate for increased cardiovascular risk, use of atherosclerosis imaging surrogates in studies allows for smaller sample sizes, shortens study duration, demonstrates clinically meaningful changes prior to clinical event and provides potentially useful pathophysiologic information. CIMT measurement is currently the most studied and validated non-invasive imaging study used to assess atherosclerosis longitudinally in response to lipid modification therapies. Quantification of coronary calcium using coronary CT has been utilized to study atherosclerosis longitudinally, however, calcium scoring to assess response to lipid modifying therapies is not recommended due to several limitations of this assessment of the atherosclerosis process. These include the fact that non-calcified atherosclerosis is not quantified, that the calcification process in atherosclerosis is diverse and that the effects of statins on tissue calcification are complex. Use of contrast coronary CT to image non-calcified coronary atherosclerosis is promising. Modern CMR imaging, aided by high reproducibility and image resolution, is rapidly advancing and early studies imaging non-coronary and coronary atherosclerosis are impressive.
    Current Drug Targets - Cardiovascular & Hematological Disorders 01/2006; 5(6):557-64.
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    ABSTRACT: The incidence of diabetes is increasing at an alarming rate to the point where it is becoming an epidemic. An ageing population, sedentary lifestyle and an unhealthy diet are considered to have contributed toward this. What we must now consider is not only the burden of the disease but the complications that arise from diabetes, in particular kidney and heart disease. Foremost, more than half of the diabetic population will die from cardiovascular-related causes. Whilst diabetes is most often associated with hypertension, dyslipidaemia and obesity, these factors do not fully account for the increased burden of cardiovascular disease in people with diabetes. This strengthens the need for comprehensive studies investigating the underlying mechanisms mediating diabetic cardiovascular disease, and more specifically, diabetes-associated atherosclerosis. In addition to the recognised metabolic abnormalities associated with diabetes, upregulation of putative pathological pathways such as advanced glycation endproducts, renin-angiotensin system, oxidative stress and increased expression of growth factors and cytokines have been observed in the setting of diabetes. All of these have been shown to play a causal role in atherosclerotic plaque formation and thus may explain the increased risk of macrovascular complications in those patients with diabetes. In this review the effect of inhibiting the renin-angiotensin system with angiotensin converting enzyme inhibition and a comparison to angiotensin II receptor antagonism is discussed, with the results of clinical trails reflecting the more recently discovered, non-haemodynamic, proatherogenic actions of angiotensin II. The need for experimental models of diabetes-associated atherosclerosis will be covered, with particular emphasis given to the streptozotocin-diabetic apolipoprotein E knockout mouse. Finally, growth factors, including vascular endothelial growth factor and platelet-derived growth factor are discussed in detail.
    Current Drug Targets - Cardiovascular & Hematological Disorders 01/2006; 5(6):503-12.
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    ABSTRACT: The Liver X Receptors, LXRalpha and LXRbeta are members of the nuclear hormone receptor superfamily which have recently been implicated as novel pharmacological targets for the treatment of cardiovascular diseases. The identification of natural and synthetic ligands for LXRs and the generation of LXR-deficient mice have been crucial for our understanding of the function of these receptors and for the identification of LXR-regulated target genes, particularly with respect to the role of LXRs in regulating cholesterol homeostasis. Synthetic LXRalpha/beta agonists induce cholesterol efflux and reverse cholesterol transport, improve glucose metabolism, inhibit macrophage-derived inflammation, and suppress the proliferation of vascular smooth muscle cells. By regulating the expression of multiple genes involved in these pathways, LXR agonists prevent the development and progression of atherosclerosis and inhibit neointima formation following angioplasty of the arterial wall. In this review, we will summarize the important roles of LXR in metabolism and vascular biology and discuss its implications as potential molecular drug target for the treatment of cardiovascular diseases.
    Current Drug Targets - Cardiovascular & Hematological Disorders 01/2006; 5(6):533-40.
  • Current Drug Targets - Cardiovascular & Hematological Disorders 01/2006; 5(6):431-2.
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    ABSTRACT: Over the past decades, lowering of LDL-cholesterol (LDL-c) levels has been established as the foundation for preventing atherosclerotic disease. It is, however, widely accepted that additional risk reduction has to come from modifying other risk factors than LDL-c. In this context, increasing HDL-cholesterol (HDL-c) levels by pharmacological inhibition of the cholesteryl ester transfer protein (CETP) is currently under intense investigation. Two small-molecule compounds, JTT-705 and Torcetrapib, have been shown to effectively increase HDL-c levels in humans, without inducing clinically significant side effects when used as monotherapy or combined with statins. Whether this approach will translate into a reduction in risk of atherosclerotic disease has not yet been established. Data from studies focusing on genetic CETP deficiency as well as those studying the relationship between CETP plasma levels and risk of atherosclerosis do not provide clear answers. Several long-term clinical studies addressing this crucial issue have recently been initiated, results of which will follow within the next few years. This review focuses on CETP, its role in human lipid metabolism and its relation to atherosclerotic disease. Furthermore, it summarizes the currently available data regarding pharmacological CETP inhibition. Finally, it will highlight a number of issues basic to the considerations of whether CETP inhibition will fulfill its promises.
    Current Drug Targets - Cardiovascular & Hematological Disorders 01/2006; 5(6):481-8.
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    ABSTRACT: Overweight and obesity are recognised as significant risk factors for coronary heart disease (CHD). Weight reduction leads to reduction in associated CHD risk factors. The discovery that endocannabinoid system is involved in regulation of food intake and other reward behaviours has led to development of cannabinoid receptor antagonists. Recent studies with rimonabant, a cannabinoid type 1 receptor (CB(1)) antagonist, demonstrate clinically significant weight loss as well as reduction in metabolic syndromme burden in obese patients.
    Current Drug Targets - Cardiovascular & Hematological Disorders 01/2006; 5(6):549-56.
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    ABSTRACT: Calcium channel blockers and HMG-CoA reductase inhibitors are widely used for the management of hypertension and dyslipidemia, respectively. The use of these agents in the prevention and treatment of cardiovascular disease remains largely based on their actions in lowering blood pressure and lipids. Recent clinical trials, however, indicate that certain members of these two drug classes may slow progression of disease to an extent that cannot be solely attributed to risk factor reduction. The proposed mechanisms for such pleiotropic actions include enhancement of endothelial-dependent nitric oxide bioavailability, anti-inflammatory activity, and inhibition of oxidative stress. To understand the basis for such effects, along with potential synergies, we will review the basic and clinical evidence that indicate a broader opportunity for treatment and protection of cardiovascular events by atheroprotection with these agents beyond risk factor management.
    Current Drug Targets - Cardiovascular & Hematological Disorders 01/2006; 5(6):489-501.
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    ABSTRACT: Epidemiologic and experimental observations suggest high density lipoprotein (HDL) has a protective effect against atherothrombotic vascular disease. These findings have stimulated considerable interest to promote HDL as a potential therapeutic strategy. Several exciting therapeutic strategies have recently emerged and currently are the focus of intense research interest. One approach is the direct administration of HDL or its components such as apolipoprotein A-I (apoA-I). Recently, much attention has focused on a naturally occurring variant of apoA-I, apoA-I(Milano) (apoA-IM) characterized by a cysteine for arginine substitution that is associated with low rates of vascular disease and significant longevity in its carriers, despite markedly reduced HDL and elevated triglyceride levels. The mutation alters the characteristics of the protein resulting in apoA-IM being functionally more effective than normal apoA-I. A number of animal and laboratory studies have demonstrated significant antiatherogenic, antiproliferative, antirestenotic, antiplatelet, antithrombotic, antiinflammatory, and antioxidant properties of apoA-IM. Furthermore, apoA-IM has been shown to promote reverse cholesterol transport, improve endothelial dysfunction and induce rapid mobilization of tissue cholesterol resulting in regression and alteration of plaque composition in animal models of atherosclerosis. Recently, a pilot clinical trial of recombinant apoA-IM demonstrated significant and rapid regression of atherosclerosis as measured by intravascular ultrasound in patients with acute coronary syndromes. These promising data provide the rationale for the development of reconstituted HDL utilizing recombinant apoA-IM as a potential therapeutic approach for atherothrombotic vascular disease in humans.
    Current Drug Targets - Cardiovascular & Hematological Disorders 01/2006; 5(6):471-9.
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    ABSTRACT: The reduction of circulating atherogenic lipoproteins through lifestyle modification and pharmacologic intervention is an important therapeutic goal in patients at risk for acute cardiovascular events. A large number of clinical trials have demonstrated that the reduction of low-density lipoprotein cholesterol (LDL-C) is associated with significant decreases in the incidence of all cause mortality, stroke, fatal and nonfatal myocardial infarction, and the need for revascularization with coronary artery bypass grafting and percutaneous transluminal coronary angioplasty. Therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (i.e., statins) are the agents of choice for treating a variety of dyslipidemias, particularly when LDL-C levels are elevated. The statins are highly efficacious; however, not all patients are able to tolerate the higher doses of these medications due to adverse side-effects such as hepatoxicity and myotoxicity. Moreover, many patients cannot achieve their various lipoprotein targets at even the highest doses of these medications. Ezetimibe is a novel cholesterol absorption inhibitor that blocks the translocation of dietary and biliary cholesterol from the gastrointestinal lumen into the intracellular space of jejunal enterocytes. Ezetimibe undergoes enterohepatic recirculation with minimal systemic exposure and not does not adversely impact the pharmacokinetic profile of statins. Ezetimibe significantly reduces serum LDL-C. It is safe when used as monotherapy or when used in combination with statins. Ezetimibe is indicated in the management of hyperlipidemia, familial hypercholesterolemia, and sitosterolemia and significantly increases the percentage of patients able to reach their lipid-lowering goals.
    Current Drug Targets - Cardiovascular & Hematological Disorders 01/2006; 5(6):455-62.
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    ABSTRACT: Acyl-coenzyme A: cholesterol acyltransferase (ACAT) is an intracellular enzyme that catalyzes the formation of cholesterol esters from cholesterol and fatty acyl-coenzyme A. Animal experiments showed that ACAT inhibitors reduce plasma cholesterol levels by suppressing absorption of dietary cholesterol and by suppressing the assembly and secretion of apolipoprotein B-containing lipoproteins such as very low density lipoprotein in liver and chylomicron in intestine. Moreover, ACAT inhibitors were shown to prevent formation of macrophage-derived foam cells in the arterial walls. However, a recent double-blind, placebo-controlled, randomized trial of a potent ACAT inhibitor, avasimibe, failed to show significant beneficial effects on coronary atherosclerosis assessed by intravascular ultrasound. For clinical application of ACAT inhibitors, development of more potent compounds and improvements of the methods to evaluate their clinical efficacy are strongly needed.
    Current Drug Targets - Cardiovascular & Hematological Disorders 01/2006; 5(6):463-9.
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    ABSTRACT: The last decade has seen a number of important advances in the use of animal models of atherosclerosis progression. Small animal models, particularly mouse knockouts and rabbit models, are finding increasing use. This review discusses those models of particular research utility, highlights their advantages and limitations, and specifically addresses methodologies and current developments, in what is a rapidly changing field.
    Current Drug Targets - Cardiovascular & Hematological Disorders 01/2006; 5(6):433-40.
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    ABSTRACT: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an enzyme that is produced by inflammatory cells, is bound to circulating LDL, and is involved in hydrolyzing polar phospholipids, including those found in oxidized low-density lipoproteins. To date, the biological role of Lp-PLA(2) in atherogenesis has been controversial, with initial reports purporting an atheroprotective effect attributable to the degradation of platelet activating factor and similar molecules. However, more recent studies suggest a proatherogenic role for this enzyme, which is attributed to Lp-PLA(2)-mediated hydrolysis of oxidatively modified low-density lipoproteins that results in the accumulation of proinflammatory products. The liberation of lysophosphatidylcholine and oxidized nonesterified fatty acids from oxidized phospholipids by the action of Lp-PLA(2) results in diverse inflammatory effects on various cell types involved in atherogenesis. This concept is further supported by a number of recently published epidemiology studies suggesting that plasma levels of the enzyme predict future cardiovascular events independent of conventional risk factors. The development of selective inhibitors of Lp-PLA(2) that inhibit enzyme activity in the circulation as well as within human atherosclerotic lesions opens the possibility of therapeutic manipulation of vascular inflammatory processes to reduce residual cardiovascular events in high risk individuals who continue to suffer fatal and nonfatal events despite the current standard of care.
    Current Drug Targets - Cardiovascular & Hematological Disorders 01/2006; 5(6):527-32.
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    ABSTRACT: The peroxisome proliferator-activated receptors (PPARs) alpha, beta/delta and gamma are ligand-activated transcription factors belonging to the nuclear receptor superfamily. PPARs heterodimerize with the retinoid X receptor (RXR) and modulate the function of many target genes. They were originally described as regulators of various metabolic, pathways, but have been recently found to also exert modulating actions in the vascular wall. PPARalpha is activated by endogenous ligands, such as polyunsaturated fatty acids and by synthetic agonists such as the fibrates. PPARalpha is expressed mainly in the liver, kidney and skeletal muscle and is involved in fatty acid oxidation. However, it is also expressed in vascular cells such as the endothelial cells, vascular smooth muscle cells and macrophages, where it exerts anti-inflammatory and antioxidant effects. Since atherosclerosis is both a chronic inflammatory and a lipid disorder and since PPARalpha is expressed in vascular cells and regulates the expression of genes involved in lipid metabolism and inflammation, PPARalpha activators may constitute useful agents for the prevention of atherosclerosis, beyond their effects on lipid metabolism. This review will focus on the functions of PPARalpha on lipid metabolism, on vascular inflammation and its relationship to atherosclerosis. Furthermore, the currently available preclinical and clinical data on PPARalpha activators as well as their future perspectives will be discussed.
    Current Drug Targets - Cardiovascular & Hematological Disorders 01/2006; 5(6):513-23.
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    ABSTRACT: The peroxisome proliferator-activated receptors (PPARs) α, β/δ and γ are ligand-activated transcription factors belonging to the nuclear receptor superfamily. PPARs heterodimerize with the retinoid X receptor (RXR) and modulate the function of many target genes. They were originally described as regulators of various metabolic, pathways, but have been recently found to also exert modulating actions in the vascular wall. PPARα is activated by endogenous ligands, such as polyunsaturated fatty acids and by synthetic agonists such as the fibrates. PPARα is expressed mainly in the liver, kidney and skeletal muscle and is involved in fatty acid oxidation. However, it is also expressed in vascular cells such as the endothelial cells, vascular smooth muscle cells and macrophages, where it exerts anti-inflammatory and antioxidant effects. Since atherosclerosis is both a chronic inflammatory and a lipid disorder and since PPARα is expressed in vascular cells and regulates the expression of genes involved in lipid metabolism and inflammation, PPARα activators may constitute useful agents for the prevention of atherosclerosis, beyond their effects on lipid metabolism. This review will focus on the functions of PPARα on lipid metabolism, on vascular inflammation and its relationship to atherosclerosis. Furthermore, the currently available preclinical and clinical data on PPARα activators as well as their future perspectives will be discussed
    Current Drug Targets - Cardiovascular & Hematological Disorders 11/2005; 5(6):513-525.
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    ABSTRACT: Sudden cardiac death in healthy individuals with structurally normal hearts and a characteristic morphology of the QRS complex resembling a right bundle branch block with elevation of the ST segment in V1 to V3 is known as Brugada syndrome (BrS). Although placement of an implantable cardioverter-defibrillator is considered the only effective therapy for symptomatic patients, some authors have repeatedly reported a beneficial effect of quinidine and isoproterenol in patients with BrS. Also, isolated case reports on the usefulness of cilostazol, sotalol, and mexiletine have been described. The present article reviews the mechanisms by which these drugs may act and their role in the pharmacotherapy of BrS. Other possible agents, mainly I(2) blockers, are also reviewed.
    Current Drug Targets - Cardiovascular & Hematological Disorders 11/2005; 5(5):409-17.
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    ABSTRACT: Atrial fibrillation (AF) is the most common cardiac arrhythmia seen in clinical practice. The understanding of the pathophysiology of AF has changed drastically during the last several decades. Recent observations have challenged the concept of the multiple circuit reentry model in favor of single focus or single circuit reentry models. Atrial electrical dysfunction provides a favorable substrate and transmembrane ionic currents are key determinants. Recent research is focusing increasingly on the atrial structural remodeling, which underlies the development of AF in different pathological conditions. This has led to concepts about how interfering with the substrate might prevent AF development and recurrence. Particular interest has been generated in the role of renin angiotensin system (RAS) blockade in reversing the electrical and structural remodeling of diseased atria. The mechanisms for the preventive effect of angiotensin converting enzyme inhibitors (ACEi) or angiotensin-II (AT-II) type 1 receptor blockers (ARB) in AF are probably complex. They may comprise general haemodynamic changes leading to lower intra-atrial pressure and wall-stress, or reduce in atrial fibrosis, connexin43 over-expression and conduction delay. The promising results of several clinical trials concerning RAS blockade may herald a whole new era of AF treatment, where AF is prevented and treated by modifying its substrate rather than fighting it electrically. This review centers on the pathophysiology of the structural and electrical remodeling in AF, the possible mechanisms by which RAS blockade may reverse electrical and structural remodeling of diseased atria and on the role of ACEi or ARB blockers in AF prevention and treatment that has already been postulated both experimentally and clinically.
    Current Drug Targets - Cardiovascular & Hematological Disorders 11/2005; 5(5):387-403.
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    ABSTRACT: For over 50 years, acetaminophen (paracetamol) has been a staple in industrialized and non-industrialized countries for the treatment of pain and fever. Although its precise mechanisms of action are not known, the drug generates dose-dependent reduction in circulating prostaglandins, inhibits myeloperoxidase and the oxidation of lipoproteins, and appears to confer cardioprotection by blocking the effects of hydroxyl radical, peroxynitrite, and hydrogen peroxide. The drug might inhibit cyclooxygenase, although its ultimate target(s) is (are) still unclear. Sadly, since most investigations of acetaminophen have focused on its analgesic/antipyretic properties and hepatotoxicity, the effects of the drug on other mammalian organ systems, including the heart and circulation, have been ignored. Recently, work in our laboratory has shown acetaminophen to have a protective role in the injured mammalian myocardium. The cardioprotection was first observed in isolated, perfused guinea pig hearts subjected to ischemia-reperfusion injury. Hearts pretreated with acetaminophen recovered greater ventricular function and exhibited improved myofibrillar ultrastructure when compared to vehicle-treated hearts. More recent in vitro investigations have suggested protective roles for acetaminophen in barbiturate-induced arrhythmogenesis and myocardial hypoxia-reoxygenation injury. We have also extended our work to the in vivo arena. There, we found that acetaminophen reduced infarct size in dogs exposed to 60 minutes regional myocardial ischemia and 180 minutes reperfusion. We invite and encourage readers of this review to repeat/duplicate our experiments. Such work is needed to either challenge or support our findings. Further, more clinically-relevant work depends on these basic and related translational experiments.
    Current Drug Targets - Cardiovascular & Hematological Disorders 11/2005; 5(5):419-29.