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- Volume 52, 2001
Annual Review of Medicine - Volume 52, 2001
Volume 52, 2001
- Review Articles
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Regulation of Leukotrienes in the Management of Asthma: Biology and Clinical Therapy
Vol. 52 (2001), pp. 1–14More Less▪ AbstractLeukotrienes (LTs) are the ultimate synthetic product resulting from the intracellular hydrolysis of membrane phospholipid at the nuclear envelope in inflammatory cells. Activated cytosolic phospholipase (cPLA2) catalyzes the production of arachidonic acid, which is converted by cyclooxygenases into leukotriene A4 (LTA4) and subsequently into the chemotaxin LTB4, which has no direct bronchoconstrictor activity. In certain inflammatory cells, LTA4 is converted into the cysteinyl leukotriene (cysLT) LTC4, which is converted into LTD4 and finally to LTE4 after extracellular transport. All cysLTs occupy the same receptors and are extremely potent bronchoconstricting agents that are pathogenetic in both asthma and allergy. With the identification of the structure of the cysLT receptor, antileukotriene therapies have been developed that either (a) inhibit synthesis of leukotriene (through 5-lipoxygenase inhibition) or (b) block the cysLT receptor. Preliminary investigations indicate that corticosteroids also may partially block the synthesis of cysLT and that cysLTs may be chemotactic for other inflammatory cells, e.g. eosinophils, by a mechanism that has not yet been defined. Currently, anti-LT therapies are approved by the US Food and Drug Administration (FDA) only for patients with asthma. These drugs generally are moderately efficacious agents, although they are highly efficacious in aspirin-induced asthma (AIA). In other forms of asthma, inhaled corticosteroid (ICS) therapy has been more effective than anti-LT therapy in improving air flow obstruction. However, anti-LT agents are additive to beta-adrenoceptor and ICS in their effects. Accordingly, anti-LT therapies are used frequently as supplemental treatments in asthmatic patients whose asthma is not optimally controlled by a combination of other drugs, including long-acting beta-adrenoceptor drugs and ICS agents. The growth of leukotriene receptor antagonists (LTRAs) has been extraordinary in the United States. The exceptional safety of these agents and their ease of administration as tablets taken once or twice daily has spurred this growth. In the past year, the high-affinity cysLT receptor has been cloned. This holds forth the promise of a second generation of LTRA agents of even greater efficacy and possibly greater duration of action.
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Pathophysiological Role of Cytokines in Congestive Heart Failure
Arnon Blum, and Hylton MillerVol. 52 (2001), pp. 15–27More Less▪ AbstractHeart failure is a complex neurohumoral and inflammatory syndrome. Recent studies have shown that proinflammatory cytokines (interleukin-1, interleukin-2, interleukin-6, interleukin-10, and tumor necrosis factor) are involved in cardiac depression and in the complex syndrome of heart failure. Understanding the involvement of these cytokines may enable us to reverse cardiac depression and heart failure by the use of monoclonal antibodies directed against specific cytokines to block the downhill progression of heart failure.
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Current Treatment Strategies for Chronic Hepatitis B and C
Vol. 52 (2001), pp. 29–49More Less▪ AbstractFor chronic hepatitis B, treatment with a 4-month course of interferon alfa-2b can achieve hepatitis B e antigen seroconversion, normalization of aminotrans-ferase levels, reduced hepatic inflammation, and possibly reduced progression to cirrhosis and improvement in survival in 20%–30% of patients. Similar results can be achieved with a 12-month course of lamivudine, with response rates increasing to 40%–65% after 3 years of therapy. Interferon can also be used in early cirrhotic patients, and lamivudine can be used in advanced cirrhotics and immunosuppressed patients. Combination interferon and lamivudine therapy does not confer additional benefits. For chronic hepatitis C, the combination of interferon alfa-2b and ribavirin is the treatment of choice, offering superior sustained response rates (40%) compared with interferon alone (15%). Therapy should be administered for 12 months to patients with genotype 1 virus but for only 6 months to patients with genotypes 2 and 3. Patients experiencing relapse after 6 months of interferon monotherapy can be re-treated with interferon and ribavirin or high-dose interferon, with 45%–56% sustained response rates. However, relatively few patients who are prior nonresponders to interferon monotherapy will have sustained response to further interferon-based treatments, including combination therapy with ribavirin. Successful therapy not only leads to the eradication of viral RNA but also may delay progression to cirrhosis and hepatocellular carcinoma. Interferon combined with polyethylene glycol (PEG), shows promise as an improved formulation of interferon with yet higher sustained response rates.
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Health Care Workforce for the Twenty-First Century: The Impact of Nonphysician Clinicians
Vol. 52 (2001), pp. 51–61More Less▪ AbstractFor many years, nonphysician clinicians (NPCs) have participated in the care of patients. However, their numbers were small and their licensed prerogatives were narrow. Over the past decade, these characteristics have changed in three important ways. First, training in many of the NPC disciplines has increased substantially, and the growth of these disciplines is accelerating. Second, state laws and regulations have expanded both the practice prerogatives of NPCs and their autonomy from physician supervision. Third, payers have increased their access to reimbursement. As a consequence, NPCs are undertaking many elements of care that previously were provided by physicians. Their participation is generally cost-effective and is met with a high degree of patient satisfaction. This presents both opportunities and challenges to physicians as they forge new relationships with NPCs and as their own spectrum of responsibilities evolves.
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Advances in the Treatment of Lupus Nephritis
Vol. 52 (2001), pp. 63–78More Less▪ AbstractSystemic lupus erythematosus (SLE) is an autoimmune disease that leads to the formation and deposition of immune complexes throughout the body, which are pathogenic for the disease. Different forms of glomerulonephritis can occur in patients with SLE and can contribute significantly to the associated morbidity and, ultimately, mortality from the disease. Over the past two decades, there have been significant strides in our understanding of the disease and in treatments that attempt to control the formation and deposition of anti-DNA auto-antibodies and immune complexes, as well as the subsequent inflammatory cascade mediated through various cellular and humoral pathways leading to progressive renal damage and end-stage renal disease. In this chapter, we review the current understanding of the pathogenesis and treatment of lupus nephritis in its various stages and discuss the experimental and human data regarding some of the potential newer forms of therapy. We discuss data regarding the use of steroids, azathioprine, cyclophosphamide, cyclosporine A, mycophenolate mofetil, gammaglobulin, plasmapheresis, LJP 394, flaxseed oil, bindarit, anti-CD40 ligand, and CTLA4Ig.
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Biomedical Ethics and the Withdrawal of Advanced Life Support
Vol. 52 (2001), pp. 79–92More Less▪ AbstractIt is common for health care providers to deal with the complex and difficult issue of withdrawing advanced life support. The patient is always the key source of authority in these decisions. The most important ingredient in end-of-life decision making is effective communication. It is important to try to ascertain what the patient thought about quality-of-life values before surrogate decisions can be made on the patient's behalf. The concepts of beneficence, nonmaleficence, autonomy, and justice are the foundation of ethical decision making. Numerous legal precedents have laid the groundwork for end-of-life decision making. Most state courts have supported withholding and withdrawing life support from patients who will not regain a reasonable quality of life. The recent Patient Self-Determination Act encourages patients to fill out advance directives that state their desires. When continued intensive care is futile, advanced life support should be withdrawn. However, a narrow definition of futility in this situation is the key, since the concept of futility could lead to inappropriate decisions. It is best to consider a situation futile when the patient is terminally ill, the condition is irreversible, and death is imminent. During the withdrawal of advanced life support, terminal or rapid weaning is preferable to extubation. Combinations of opiates, benzodiazepines, and other agents help provide comfort to patients who are suffering.
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Molecular Genetics and Pathogenesis of Autosomal Dominant Polycystic Kidney Disease
Vol. 52 (2001), pp. 93–123More Less▪ AbstractAutosomal dominant polycystic kidney disease (ADPKD) is a common and systemic disease characterized by formation of focal cysts. Of the three potential causes of cysts, downstream obstruction, compositional changes in extracellular matrix, and proliferation of partially dedifferentiated cells, evidence strongly supports the latter as the primary abnormality. In the vast majority of cases, the disease is caused by mutations in PKD1 or PKD2, and appears to be recessive at the cellular level. Somatic second hits in the normal allele of cells containing the germ line mutation initiate or accelerate formation of cysts. The intrinsically high frequency of somatic second hits in epithelia appears to be sufficient to explain the frequent occurrence of somatic second hits in the disease-causing genes. PKD1 and PKD2 encode a putative adhesive/ion channel regulatory protein and an ion channel, respectively. The two proteins interact directly in vitro. Their cellular and subcellular localization suggest that they may also function independently in a common signaling pathway that may involve the membrane skeleton and that links cell-cell and cell-matrix adhesion to the development of cell polarity.
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Antibody-Targeted Immunotherapy for Treatment of Malignancy
Vol. 52 (2001), pp. 125–145More Less▪ AbstractDespite testing since the mid-1900s, only in the past three years have some monoclonal antibodies provided sufficient efficacy and safety data to support regulatory approval as cancer therapy. Adjuvant-edrecolomab monoclonal antibody was approved in Germany after demonstration of a statistically significant 32% improvement over observation alone in the seven-year mortality rate for patients with colorectal cancer. Similarly, trastuzumab monoclonal antibody combined with chemotherapy prolonged the median time to the progression of breast cancer compared to chemotherapy alone. Unconjugated monoclonal antibodies investigated for the treatment of hematologic malignancies include anti-idiotype, CAMPATH-1, and rituximab. Rituximab was the first such therapy approved in the United States for relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma after demonstration of an overall response rate of 48% and a duration of response of 11.7 months. The radioisotope-conjugated monoclonal antibodies tested as therapy include anti-B1, LYM-1, LL2, anti-CD33, and ibritumomab tiuxetan. Clearly, the full potential of immunotherapy still lies ahead.
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Liver Transplants from Living Related Donors
Vol. 52 (2001), pp. 147–160More Less▪ AbstractLiver transplantation from living related donors was unthinkable until recently, when the safety of modern hepatic surgery became widely appreciated. The first step was the successful demonstration that parts of livers could be transplanted. This technique, termed reduced-size liver transplantation, evolved into reliable procedures to allow parents to donate small parts of their livers to small children. More recently, right hepatectomy, in which up to 70% of the liver is resected for donation, has been performed in adults. As the demand for liver transplantation continues to increase, the development of ethically sound, medically and surgically optimal programs for routine use of living donors has become essential. This chapter provides a broad overview of the evolution and current state of liver transplantation with living donors.
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Novel Platelet Inhibitors
Vol. 52 (2001), pp. 161–184More Less▪ AbstractPlatelet-inhibitory drugs are of proven benefit to individuals who suffer from atherosclerotic cardiovascular disease. Despite substantial effort to identify more potent platelet-inhibitory agents, aspirin, an irreversible inhibitor of platelet cyclooxygenase activity, remains the standard against which other drugs are judged. Drugs that appear to be at least as efficacious as aspirin in specific clinical settings include the thienopyridines ticlopidine and clopidogrel, specific inhibitors of ADP-stimulated platelet function, and the phosphodiesterase 3 inhibitor cilostazol. Ligand binding to the platelet integrin αIIbβ3 (GPIIb-IIIa), a prerequisite for platelet thrombus formation, has been a prominent target for drug development. Currently, three types of αIIbβ3 antagonists are available: the monoclonal antibody Fab fragment abciximab, cyclic peptides based on the Arg-Gly-Asp (RGD) or related amino acid motifs, and RGD-based peptidomimetics. The efficacy of each type of αIIbβ3 antagonist in the setting of acute coronary artery disease has been confirmed in multicenter clinical trials.
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Lung Transplantation at the Turn of the Century
Vol. 52 (2001), pp. 185–201More Less▪ AbstractLung transplantation has become a viable treatment option for patients with end-stage lung disease. Donor selection and organ allocation must follow specific guidelines. Single, bilateral, and living-donor lobar transplantation have all been performed successfully for a variety of diseases. Complications include reimplantation response and airway complications. Rejection may occur in the hyperacute, acute, or chronic settings and requires judicious management with immunosuppression. Infection and malignancy remain potential complications of the commitment to lifelong systemic immunosuppression. Survival statistics have remained encouraging and continue to improve with experience. Improved exercise tolerance and quality of life have been demonstrated in the years following transplantation. Remaining obstacles include limited donor organ availability, long-term graft function, and patient survival. However, ongoing advances in immune tolerance and standardized training of physicians in the care of transplant patients should carry lung transplant forward in the twenty-first century.
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Prevention of Uremic Bone Disease Using Calcimimetic Compounds
Klaus Olgaard, and Ewa LewinVol. 52 (2001), pp. 203–220More Less▪ AbstractThe discovery, characterization, and cloning of the calcium-sensing receptor (CaR) in 1993 was soon followed by the creation of a new type of drug, the calcimimetics—NPS R-568 and NPS R-467—which are small phenylalkylamine derivative compounds that act as CaR agonists and increase the sensitivity of the CaR to activation by extracellular calcium (Ca2+). As expected, these compounds turned out to have a significant effect on the Ca2+/parathyroid hormone (PTH) relationship, resulting in a dramatically greater suppression of the PTH level than would otherwise occur at the actual extracellular Ca2+ levels. Renal osteodystrophy (RO) due to secondary hyperparathyroidism (HPT) in chronic renal failure was an obvious target for studying the effects of NPS R-568. In a study on experimental animals, the results clearly showed that this first generation of calcimimetics, NPS R-568, had an acute dose-dependent and short-lived suppressive effect on PTH secretion from the parathyroid glands. A similar effect was found in patients with chronic renal failure and secondary HPT. At the same time, the calcimimetics induced a slight degree of hypocalcemia. Such a significant suppressive effect on PTH secretion would be expected to result in therapeutic potential for a preventive or therapeutic effect on the RO accompanying chronic uremia. Administration would probably be in close concert with present strategies, phosphate binders and vitamin D analogs. A wide distribution of CaRs have now been demonstrated in the body, and an important question is how calcimimetics will affect the function of different tissues and organs when used for long-term treatment or prevention of secondary HPT and RO. Although relatively few experimental and clinical investigations have been completed, they clearly confirm the suppressive effect of calcimimetics on PTH secretion. In rats with experimental chronic renal failure, a significant and beneficial effect on the prevention of RO has been demonstrated. The effect of calcimimetic compounds is presently being evaluated in humans. Besides induction of hypocalcemia, the adverse effects in these mainly short-term studies have been few. Future studies with calcimimetics will further define the physiology and pathophysiology of the CaR and the long-term benefit of calcimimetic compounds in patients with chronic renal failure.
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Acute Respiratory Distress Syndrome: Physiology and New Management Strategies
Vol. 52 (2001), pp. 221–237More Less▪ AbstractThe acute respiratory distress syndrome (ARDS) has been recognized for more than three decades as a cause of respiratory failure in patients with a variety of illnesses. Clinically, it is characterized by pulmonary edema, refractory hypoxemia, diffuse pulmonary infiltrates, and altered lung compliance. Pathologically, it is distinguished by infiltration of the lungs with inflammatory cells, interstitial and alveolar edema, hyaline membrane formation, and ultimately fibrosis. Although we have learned much about the pathophysiology of this inflammatory syndrome since its earliest descriptions, ARDS continues to claim the lives of 40%–70% of its victims. Many treatment strategies have been used to prevent or treat ARDS, but thus far the most encouraging strategy to prevent lung injury and improve survival is mechanical ventilation with low tidal volumes and high levels of positive end-expiratory pressure.
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New Oral Therapies for Type 2 Diabetes Mellitus: The Glitazones or Insulin Sensitizers1
Vol. 52 (2001), pp. 239–257More Less▪ AbstractType 2 diabetes mellitus is a growing problem not only in the United States but also across the world. There is now strong evidence that intensive control of blood glucose can significantly reduce and retard the microvascular complications of retinopathy, nephropathy, and neuropathy. Ultimately however, up to 80% of type 2 diabetics die from macrovascular cardiovascular disease. This increased incidence of atherosclerotic disease is intricately associated with insulin resistance, which is a major pathophysiologic abnormality in type 2 diabetes. There is strong evidence that insulin resistance is involved in the development of not only hyperglycemia, but also dyslipidemia, hypertension, hypercoagulation, vasculopathy, and ultimately atherosclerotic cardiovascular disease. This cluster of metabolic abnormalities has been termed the insulin resistance or cardiovascular dysmetabolic syndrome. The thiazolidinediones (rosiglitazone and pioglitazone), a new class of oral antidiabetic agents, are “insulin sensitizers” and exert direct effects on the mechanisms of insulin resistance. These effects not only improve insulin sensitivity and glycemic control with reduced insulin requirements, but also have potentially favorable effects on other components of the cardiovascular dysmetabolic syndrome. Long-term studies are needed to determine whether the insulin-sensitizing effects of the glitazones can prevent or delay premature atherosclerotic cardiovascular disease, morbidity, and death.
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Salmonella: A Model for Bacterial Pathogenesis
Vol. 52 (2001), pp. 259–274More Less▪ AbstractSalmonellae are gram-negative bacteria that cause gastroenteritis and enteric fever. Salmonella virulence requires the coordinated expression of complex arrays of virulence factors that allow the bacterium to evade the host's immune system. All Salmonella serotypes share the ability to invade the host by inducing their own uptake into cells of the intestinal epithelium. In addition, Salmonella serotypes associated with gastroenteritis orchestrate an intestinal inflammatory and secretory response, whereas serotypes that cause enteric fever establish systemic infection through their ability to survive and replicate in mononuclear phagocytes. This review explores the molecular basis of selected Salmonella virulence strategies, with an emphasis on general themes of bacterial pathogenesis as exemplified by Salmonella.
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Risk-Adjusted Surgical Outcomes1
Vol. 52 (2001), pp. 275–287More Less▪ AbstractMeasures of risk-adjusted outcome are particularly suited for the assessment of the quality of surgical care. The reliability of measures of quality that use surgical outcomes is enhanced by prospective data acquisition and should be adjusted for the preoperative severity of illness. Such measures should be based only on reliable and validated data, and they should apply state-of-the-art analytical methods. The risk-adjusted postoperative mortality rate is useful as a quality measure only in specialties and operations expected to have a high rate of postoperative deaths. Risk-adjusted complications are more common but are limited as a comparative measure of quality by a lack of uniform definitions and data collection mechanisms. In specialties in which the expected postoperative mortality is low, risk-adjusted functional outcomes are promising measures for the assessment of the quality of surgical care. Measures of cost and patient satisfaction should also be incorporated in systems designed to measure the quality and cost-effectiveness of surgical care.
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The Role of Inflammation and Infection in Coronary Artery Disease
Vol. 52 (2001), pp. 289–297More Less▪ AbstractNew insights into atherosclerosis, the most common disease affecting coronary arteries, may change therapeutic strategies from largely symptomatic to causal. Atherosclerotic plaques contain a lipid-related, immune-mediated inflammation, with release of secretory products capable of changing plaque morphology. Plaques prone to complications contain large numbers of inflammatory cells; stable plaques contain little inflammation. Similarly, atherectomy specimens from patients with coronary syndromes revealed more inflammatory cells in unstable than in stable patients. These observations, and the fact that acute coronary syndromes are associated with increased blood levels of inflammatory markers, have renewed interest in the possible relationship between infection and atherogenesis. Of all potential candidate antigens, Chlamydia pneumoniae presently is considered the most likely because a substantial number of patients with unstable syndromes contain C. pneumoniae–reactive T cells, both in blood and within the atherosclerotic plaque, suggesting enhancement of intraplaque inflammation.
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Evolving Treatment Strategies for Inflammatory Bowel Disease
Vol. 52 (2001), pp. 299–318More Less▪ AbstractCrohn's disease and ulcerative colitis are idiopathic inflammatory bowel diseases characterized by dysregulated intestinal immune responses in genetically susceptible hosts. Conventional approaches to the medical therapy of ulcerative colitis and Crohn's disease can now be directed at either induction or maintenance of remission to improve therapeutic efficacy while minimizing complications. Newer approaches have expanded the utility of conventional therapies by improving both safety and efficacy and highlight the importance of specific targets along the immunoinflammatory pathways. The combination of conventional and novel approaches now offers the potential of modifying the natural history of these diseases.
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Irritable Bowel Syndrome
Vol. 52 (2001), pp. 319–338More Less▪ AbstractThe irritable bowel syndrome (IBS) is a functional gastrointestinal disorder whose hallmark is abdominal pain or discomfort associated with a change in the consistency or frequency of stools. In the western world, 8% to 23% of adults have IBS and its socioeconomic cost is substantial. Research-generated insights have led to the understanding of IBS as a disorder of brain-gut regulation. The experience of symptoms derives from dysregulation of the bidirectional communication system between the gastrointestinal tract and the brain, mediated by neuroendocrine and immunological factors and modulated by psychosocial factors. The biopsychosocial model integrates the various physical and psychosocial factors that contribute to the patient's illness. This model and the recently revised symptom-based criteria (i.e. the “Rome II criteria”) form the basis for establishing a comprehensive and effective approach for the diagnosis and management of the disorder.
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Effects of Neuropeptides and Leptin on Nutrient Partitioning: Dysregulations in Obesity
Vol. 52 (2001), pp. 339–351More Less▪ AbstractBody weight homeostasis is maintained via a series of complex interactions that occur between the brain (particularly the hypothalamus) and the periphery, notably via the hormone leptin, which is synthesized in and secreted from adipose tissue. Under normal conditions, a dynamic equilibrium exists between anabolic neuropeptides (orexigenic peptides), which favor food intake, decrease energy expenditure, and facilitate fat storage, and catabolic ones (anorexigenic peptides), which decrease food intake, increase energy expenditure, and facilitate the loss of fat stores. Secreted leptin, although it may have some direct peripheral effects, exerts its action principally within the brain. Following its transport through the blood-brain barrier, leptin reaches the hypothalamic area, where it binds to its long receptor isoform. After a specific signaling cascade, leptin inhibits many of the orexigenic neuropeptides while favoring many of the anorexigenic ones. Thus, leptin decreases food intake and body weight, and it increases fat oxidation and energy expenditure, ultimately favoring leanness. Lack of leptin secretion, the inability of leptin to reach the brain, or the inability of leptin to interact with hypothalamic leptin receptors, prevent leptin's effects and lead to obesity.
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Mixed Chimerism and Transplantation Tolerance
Vol. 52 (2001), pp. 353–370More Less▪ AbstractAchieving transplanatation tolerance is an important goal in the effort to reduce long-term morbidity and mortality in organ transplant recipients. Robust, lifelong, donor-specific tolerance can be reliably achieved by induction of mixed chimerism in various animal models. To date, the clinical application of these proto-cols has been impeded partly by the potential toxicity of the required host conditioning regimens and the lack of successful studies in large animals. This article reviews the progress achieved in recent years in developing considerably milder conditioning protocols in rodents, and in extending some of these models to achieve permanent mixed chimerism and tolerance in large animals. Advances in the induction of xenogeneic tolerance through mixed chimerism are also discussed.
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Genetic Testing for Cancer Predisposition
Vol. 52 (2001), pp. 371–400More Less▪ AbstractClinical cancer genetics is becoming an integral part of the care of cancer patients. This review describes the clinical aspects, genetics, and clinical genetic management of most of the major hereditary cancer susceptibility syndromes. Multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and familial adenomatous polyposis are examples of syndromes for which genetic testing to identify at-risk family members is considered the standard of care. Genetic testing for these syndromes is sensitive and affordable, and it will change medical management. Cancer genetic counseling and testing is probably beneficial in other syndromes, such as the hereditary breast cancer syndromes, hereditary nonpolyposis colorectal cancer syndrome, Peutz-Jeghers syndrome, and juvenile polyposis. There are also hereditary cancer syndromes for which testing is not yet available and/or is unlikely to change medical management, including Li-Fraumeni syndrome and hereditary malignant melanoma. Thorough medical care requires the identification of families likely to have a hereditary cancer susceptibility syndrome for referral to cancer genetics professionals.
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Current Concepts in the Polycystic Ovary Syndrome
Vol. 52 (2001), pp. 401–419More Less▪ AbstractOver the past 20 years, it has been clearly documented that the polycystic ovary syndrome (PCOS) has major metabolic sequelae related to insulin resistance and that insulin resistance plays an important role in the pathogenesis of the reproductive disturbances of the disorder. Family studies have indicated a genetic susceptibility to PCOS. Polycystic ovaries and hyperandrogenemia are present in ∼50% of sisters of affected women. Increased androgen secretion and insulin resistance persist in cultured theca cells and skin fibroblasts, respectively, from women with PCOS; this finding suggests that these are intrinsic, presumably genetic, defects. Insulin resistance and elevated low-density lipoprotein (LDL) levels also cluster in the sisters of women with PCOS, consistent with genetic traits. Moreover, the brothers of women with PCOS have insulin resistance and elevated dehydroepiandrosterone sulfate (DHEAS) levels, which supports a genetic basis for these findings. Family-based studies of linkage and association have implicated several genes in the pathogenesis of PCOS. The strongest evidence to date points to a gene in the region of the insulin receptor. Insulin-sensitizing therapy mitigates the reproductive disturbances of PCOS.
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Renal Artery Stenosis: A Common, Treatable Cause of Renal Failure?
Vol. 52 (2001), pp. 421–442More Less▪ AbstractChronic azotemic renovascular disease is common in patients with atherosclerosis. Its prevalence appears to be increasing in the aging population. How often it is the primary cause of end-stage renal disease (ESRD) is not yet certain. Some studies suggest that 10%–40% of elderly hypertensive patients with newly documented ESRD and no demonstrable primary renal disease have significant renal artery stenosis (RAS). Atherosclerotic vascular occlusive disease of the renal arteries does progress, but current rates of progression and occlusion are lower than those reported a decade ago. Methods of identifying patients whose renal function is at true risk from vascular occlusive disease and determining who will benefit from intervention remain elusive. The presence of RAS in an azotemic patient can be assessed with noninvasive and risk-free radiologic techniques, including Duplex doppler velicometry and magnetic resonance angiography. Functional tests that predict the change in renal function after revascularization are not yet available. However, a renal length of greater than 7.5 cm in the absence of renal cysts and a short history of renal functional deterioration indicate a good prognosis. Patients with recent deterioration in renal function, those with bilateral renal artery stenosis or stenosis to a single functioning kidney, those with flash pulmonary edema, advanced chronic renal failure, or ESRD (who have much to gain), those with reversible azotemia during angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor antagonist (ARB) therapy, and those whose conditions cannot be managed medically should be considered for revascularization. Results from recent controlled clinical trials of the response to percutaneous transluminal renal artery angioplasty (PTRA) and stenting indicate that improvement in blood pressure control or renal function is not a predictable outcome of renal revascularization. In azotemic groups, 25%–30% of patients achieve important recovery of renal function. Thus, significant progress has been made recently in determining whether RAS is a frequent, treatable cause of renal failure. The decision to recommend revascularization remains a difficult balance between the risks and expense of the procedure and the undoubted benefits that accrue if renal function is successfully stabilized.
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Tissue Engineering: Current State and Prospects
Vol. 52 (2001), pp. 443–451More Less▪ AbstractOrgan shortage and suboptimal prosthetic or biological materials for repair or replacement of diseased or destroyed human organs and tissues are the main motivation for increasing research in the emerging field of tissue engineering. No organ or tissue is excluded from this multidisciplinary research field, which aims to provide vital tissues with the abilities to function, grow, repair, and remodel. There are several approaches to tissue engineering, including the use of cells, scaffolds, and the combination of the two. The most common approach is biodegradable or resorbable scaffolds configured to the shape of the new tissue (e.g. a heart valve). This scaffold is seeded with cells, potentially derived from either biopsies or stem cells. The seeded cells proliferate, organize, and produce cellular and extracellular matrix. During this matrix formation, the starter matrix is degraded, resorbed, or metabolized. First clinical trials using skin or cartilage substitutes are currently under way. Both the current state of the field and future prospects are discussed.
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Kaposi's Sarcoma–Associated Herpesvirus: A New DNA Tumor Virus
C. Boshoff, and Y. ChangVol. 52 (2001), pp. 453–470More Less▪ AbstractKaposi's sarcoma–associated herpesvirus (KSHV) is a newly identified gammaherpesvirus associated with all clinical forms of Kaposi's sarcoma (KS), body-cavity–based, primary effusion lymphomas (PELs), and a subset of Castleman's disease (CD). Sequence analysis of the KSHV genome demonstrates an extensive array of genes with homology to cellular genes involved in cell cycle regulation, cell proliferation, apoptosis, and immune modulation. Functional studies indicate that these genes may modify the host cell environment, contributing to the pathogenesis of KSHV-associated disorders. Several KSHV genes have been found to cause dysregulated cell proliferation or to interfere with established tumor suppressor pathways. The epidemiologic association of KSHV with malignancies and the coding features of its genome suggest that it is a new DNA tumor virus.
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Hereditary Distal Renal Tubular Acidosis: New Understandings
Vol. 52 (2001), pp. 471–484More Less▪ AbstractThe primary or hereditary form of distal renal tubular acidosis (dRTA), although rare, has received increased attention recently because of dramatic advances in the understanding of its genetic basis. The final regulation of renal acid excretion is effected by various acid/base transporters localized in specialized cells in the cortical collecting and outer medullary collecting tubules. Inherited defects in two of the key acid/base transporters involved in distal acidification, as well as mutations in the cytosolic carbonic anhydrase gene, can cause dRTA. The syndrome is inherited in both autosomal dominant and recessive patterns; patients with recessive dRTA present with either acute illness or growth failure at a young age, sometimes accompanied by deafness, whereas dominant dRTA is usually a milder disease and involves no hearing loss.
The AE1 gene encodes two Cl−/HCO3− exchangers that are expressed in the erythrocyte and in the acid-secreting intercalated cells of the kidney. AE1 contributes to urinary acidification by providing the major exit route for HCO3− across the basolateral membrane. Several mutations in the AE1 gene cosegregate with dominant dRTA. The modest degree of hypofunction exhibited in vitro by these mutations, however, does not explain the abnormal distal acidification phenotype. Other AE1 mutations have been linked to a recessive syndrome of dRTA and hemolytic anemia in which hypofunction can be discerned by in vitro studies. Several mutations in the carbonic anyhdrase II gene are associated with the autosomal recessive syndrome of osteopetrosis, renal tubular acidosis, and cerebral calcification. Some of these individuals present with deafness of the conductive type. By contrast, more recent studies have shown that mutations in ATP6B1, encoding the B-subtype unit of the apical H+ ATPase, are responsible for a group of patients with autosomal recessive dRTA associated with sensorineural deafness. Thus, the presence of deafness and the type provide an important clue to the genetic lesion underlying hereditary dRTA.
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Gene Transfer for Angiogenesis in Coronary Artery Disease
Vol. 52 (2001), pp. 485–502More Less▪ AbstractAngiogenesis is a promising novel therapeutic strategy to provide new venues for blood flow in patients with severe ischemic heart and peripheral vascular disease, who are not candidates for standard revascularization strategies. We describe the underlying mechanisms involved in physiologic and therapeutic angiogenesis, underscoring the relative importance of vasculogenesis, angiogenesis, and arteriogenesis. We then present the various gene transfer vectors including plasmid, viral, and cell-based vectors, and various delivery modalities. The available preclinical data are presented, followed by a description of preliminary clinical experience, with an emphasis on the preliminary nature of these results, which address safety and not efficacy. Finally, we discuss the promises and pitfalls of clinical angiogenesis and gene transfer studies, stressing the importance of proper design of clinical trials and adequate protection of research subjects.
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Atypical Antipsychotics: New Directions and New Challenges in the Treatment of Schizophrenia
Vol. 52 (2001), pp. 503–517More Less▪ Abstract“Atypical” antipsychotics represent a new generation of antipsychotics with a significantly lower incidence of extrapyramidal side effects (EPS), as well as little or no effect on prolactin elevation. These advantages constitute a major improvement in the treatment of patients with schizophrenia. The exact mechanisms that make these drugs atypical is not clear. However, a preferential action on serotonin 5-HT2 or D4 receptors, or a more rapid dissociation from the dopamine D2 receptor, may account for atypicality. Although the atypical antipsychotics have overcome EPS, other side effects such as weight gain and impaired glucose tolerance/lipid abnormalities have come to the fore. Thus, the challenges are far from over. The current atypicals are much more effective against the psychosis of schizophrenia than against the other, more enduring aspects of this disorder, e.g. negative symptoms and cognitive dysfunction. At present, the atypicals use a “pharmacological shotgun” strategy to treat aspects of the disease in all patients. A more sophisticated and perhaps effective approach to schizophrenia may lie in independently targeting the pathophysiological mechanisms of each clinical dimension (i.e. positive, negative, cognitive, and affective) with more selective drugs that can be combined and individually titrated to the needs of each patient.
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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)