Annual Review of Medicine - Volume 51, 2000

Ductal carcinoma in situ of the breast is a heterogeneous group of lesions with diverse malignant potential. It is the most rapidly growing subgroup in the breast cancer family; it is projected that more than 39,000 new cases will be diagnosed in the United States during 1999. Most new cases are nonpalpable and are discovered mammographically. Treatment is controversial and ranges from excision only, to excision with radiation therapy, to mastectomy. Genetic changes routinely precede morphologic evidence of malignant transformation. Medicine must learn how to recognize these genetic changes, exploit them, and in the future, prevent them.

The clinical gene therapy trials for adenosine deaminase (ADA) deficiency have defined both the potential benefits and the present limitations of gene therapy with hematopoietic stem cells (HSC). Current clinical results indicate that (a) both umbilical cord blood and neonatal bone marrow HSC can be transduced with murine retroviral-based vectors, (b) the transduced HSC can engraft in nonmyeloablated patients, (c) the frequency of HSC transduction/engraftment is low (1/10,000), (d) an in vivo selective advantage can exist for transduced T lymphoid progeny, and (e) the transduced ADA gene is not expressed in nondividing T lymphocytes. Improving the clinical results of gene therapy for ADA deficiency and other genetic diseases involving HSC will require (a) developing new vectors that express the transduced gene in nondividing cells and (b) increasing the frequency of stable HSC transduction.

This chapter reviews the experimental literature on the effects of acupuncture treatment. The review covers the 14 medical conditions for which the National Institutes of Health Acupuncture Consensus Development Panel (NIHCDP) concluded that acupuncture either is effective (2 conditions) or may be useful (12 conditions). My conclusions partially support those of the NIHCDP. There is evidence that acupuncture is effective for the treatment of postoperative and chemotherapyinduced nausea and vomiting. Also, some data indicate that acupuncture may be useful for headache, low back pain, alcohol dependence, and paralysis resulting from stroke (4 of the 12 conditions for which the NIHCDP found that acupuncture may be useful). For most of the remaining conditions, there is little evidence that acupuncture is either effective or ineffective. It is recommended that workers in the field design double blind, sham controlled trials using adequate acupuncture treatment regimens, with specific hypotheses, and sample sizes sufficient to allow both positive and negative conclusions.

The ends of linear chromosomes are capped by specialized nucleoprotein structures termed telomeres. Telomeres comprise tracts of noncoding hexanucleotide repeat sequences that, in combination with specific proteins, protect against degradation, rearrangement, and chromosomal fusion events. Due to the polarity of conventional DNA synthesis, a net loss of telomeric sequences occurs at each cell division. It has been proposed that this cumulative telomeric erosion is a limiting factor in replicative capacity and elicits a signal for the onset of cellular senescence. To proliferate beyond the senescent checkpoint, cells must restore telomere length. This can be achieved by telomerase, an enzyme with reverse-transcriptase activity. This enzyme is absent in differentiated somatic tissues, but telomerase reactivation has been detected in most tumors. Much investigative effort is focusing on telomere dynamics with a view to possible manipulation of cellular proliferative potential. In this article, we review the role of telomeres and telomerase in senescence and tumor progression, and we discuss the potential use of telomerase in diagnosis and treatment.

Coronary artery disease in the transplanted heart limits the long-term success of cardiac transplantation. Intravascular ultrasound studies reveal a dual morphology with donor-transmitted and de novo plaques. Coronary vasomotor dysfunction may occur independently of morphological alterations. The disease is characterized by the interaction of activated T lymphocytes with cytokines and donor epicardial and microvascular endothelium. Various noxious stimuli contribute to the continuing inflammatory response. Consequently, adhesion molecule expression is upregulated, leukocytes migrate into the allograft, thrombocytes accumulate, and growth factors are expressed, finally resulting in functional and morphological chronic allograft lesions. Blocking the activation of T cells, CD4+ cytokines, and adhesion molecules may prevent endothelial injury and subsequent intimal thickening. Strategies to decrease the formation of antiendothelial and anti-HLA-DR antibodies may also be protective, as may antiproliferative drugs, augmentation of endogenous nitric oxide bioactivity, and new immunosuppressive regimens. Revascularization procedures have a limited role in treating significant focal lesions. Retransplantation, the only definitive treatment, remains ethically controversial.

Lower-extremity vascular surgery is most often indicated for patients with critical leg ischemia but has increasingly been used for patients with disabling intermittent claudication. This article reviews indications, follow-up protocols, and procedure-related outcomes including perioperative and late mortality, complications, and long-term patency rates, which vary with patient risk factors, vascular disease severity, and hospital volume. Population-based studies have yet to establish whether rates of limb-preserving bypass surgery are related to overall amputation rates, partly because of the continued high rate of primary amputation. The functional benefits of vascular surgery have been traditionally assessed by treadmill protocols and batteries of physical tests. Claudication treatment is increasingly being measured by both generic and disease-specific functional and health-related quality-of-life questionnaires. Patient self-reported measures of physical functioning and walking ability are reviewed. Finally, conclusions are presented about trends in lower-extremity bypass surgery rates.

The prevalence of autoimmune diseases (ADs) in Western countries is estimated to be from 3–7%, and the treatment of severe, relapsing/refractory cases is still not satisfactory. The concept of utilizing intense immunosuppression followed by allogeneic or even autologous hemolymphopoietic stem cells (HSCs) to treat AD is based on encouraging results in experimental animals and from serendipitous cases of patients with both ADs and malignancies who were allotransplanted for the latter. However, rare unexpected relapses despite donor immune engraftment have been reported following HSC transplantation for AD. Autologous transplantation is a more feasible procedure with lower toxicity than allogeneic transplantation. This article analyzes the experimental basis for stem cell transplantation in AD and discusses the most important clinical results of both allogeneic and autologous HSC transplants.

Surgical treatment of Parkinson’s disease (PD) can provide gratifying symptomatic improvements for many individuals who suffer from persistent disabling symptoms despite the best available medical management. Current surgical therapies include ablative techniques (thalamotomy and pallidotomy), augmentative techniques (nondestructive) (deep brain stimulation), and restorative techniques (tissue transplantation and gene therapy). Ablative procedures can provide substantial clinical benefit, but the current trend is toward deep brain stimulation, which can provide similar symptomatic improvement in a nondestructive manner. Restorative techniques, such as tissue transplantation and gene therapy, are exciting but have significant obstacles to overcome before their promise can be realized. Until the underlying pathological defect of PD can be identified and treated, surgical intervention is likely to remain important in the symptomatic treatment of this disabling disease.

Atherogenic lipids, particularly oxidized low-density lipoprotein, are responsible for a wide range of cellular dysfunctions within the vessel wall. The effects on endothelial cells disrupt normal control of vasomotion, with a reduction of effective nitric oxide activity, the development of a procoagulant surface, chronic low-grade inflammation, and abnormal cell growth. These changes are central not only in the development of atherosclerosis but also in the evolution of both stable and unstable ischemic syndromes. There is growing evidence that these abnormal changes in cell function respond rapidly to changes in the atherogenic lipids. Certain cell functions can improve within hours or days of cholesterol lowering.

The inherited hypercoagulable states can be divided into those that are common and associated with a modest risk of thrombosis (i.e. factor V Leiden and G20210A prothrombin gene) and those that are uncommon but asssociated with a high risk of thrombosis. There is no convincing evidence that, independent of other clinical factors, the presence of factor V Leiden or the prothrombin gene mutation should influence the use of primary prophylaxis or the duration of anticoagulant therapy following an episode of thrombosis. Indrect evidence sugests that the presence of antithrombin, protein C deficiency, or protein S deficiency justifies avoiding additional risk factors for thrombosis, such as estrogen therapy, and justifies use of more aggressive primary prophylaxis when additional risk factors cannot readily be avoided (e.g. pregnancy). The presence of one of these three abnormalities also favors more prolonged anticoagulant therapy following venous thrombosis. However, their presence or absence appears to have less influence on the risk of recurrent venous thromboembolism than whether thrombosis was provoked by a major reversible risk factor, such as surgery.

Neurocysticercosis is now recognized as a common cause of neurologic disease in developing countries and the United States. The pathogenesis and clinical manifestations vary with the site of infection and accompanying host response. Inactive infection should be treated symptomatically. Active parenchymal infection results from an inflammatory reaction to the degenerating cysticercus and will also respond to symptomatic treatment. Controlled trials have not demonstrated a clinical benefit for antiparasitic drugs. Ventricular neurocysticercosis often causes obstructive hydrocephalus. Surgical intervention, especially cerebrospinal fluid diversion, is the key to management of hydrocephalus. Shunt failure may be less frequent when patients are treated with prednisone and/or antiparasitic drugs. Subarachnoid cysticercosis is associated with arachnoiditis. The arachnoiditis may result in meningitis, vasculitis with stroke, or hydrocephalus. Patients should be treated with corticosteroids, antiparasitic drugs, and shunting if hydrocephalus is present.

Tumor necrosis factor α (TNFα) and interleukin-1 (IL-1) are important in mediating inflammation in rheumatoid arthritis (RA). Randomized phase II and III clinical trials of anti-TNF reagents (infliximab and etanercept) have demonstrated an acceptable safety profile and marked clinical efficacy in cases of RA that have not responded adequately to conventional therapy. Combination therapy with methotrexate (MTX) appears to be particularly effective in patients whose disease activity persists despite prior disease-modifying antirheumatic drugs (DMARDs) and ongoing MTX monotherapy. DMARD-recalcitrant disease may become the main indication for the use of anti-TNF drugs in patients with RA. Trials of IL-1 receptor antagonist show a relatively modest anti-inflammatory effect and a possible retardation of joint damage. Whether anti-TNF therapy protects joints from structural damage is under investigation. One anti-TNF reagent has already been approved in the United States for the treatment of RA, and other cytokine antagonists or agonists are under development.

The skin is a complex organ that is difficult to replace when it is irreversibly damaged by burns, trauma, or disease. Although autologous skin transplantation remains the most common form of treatment in patients with significant skin loss, there are now a number of commercially available products that can be used to replace the skin temporarily or permanently. Here we describe several such products under the rubric “artificial skin,” focusing on two types of technology that have been applied to the problem of permanent skin replacement.

Interleukin-6 (IL-6) is a proinflammatory cytokine that is normally tightly regulated and expressed at low levels, except during infection, trauma, or other stress. Among several factors that down-regulate IL-6 gene expression are estrogen and testosterone. After menopause or andropause, IL-6 levels are elevated, even in the absence of infection, trauma, or stress. IL-6 is a potent mediator of inflammatory processes, and it has been proposed that the age-associated increase in IL-6 accounts for certain of the phenotypic changes of advanced age, particularly those that resemble chronic inflammatory disease [decreased lean body mass, osteopenia, low-grade anemia, decreased serum albumin and cholesterol, and increased inflammatory proteins such as C-reactive protein (CRP) and serum amyloid A]. Furthermore, the age-associated rise in IL-6 has been linked to lymphoproliferative disorders, multiple myeloma, osteoporosis, and Alzheimer’s disease. This overview discusses the data relating IL-6 to age-associated diseases and to frailty. Like the syndrome of inappropriate antidiuretic hormone, it is possible that certain clinically important late-life changes are due to an inappropriate presence of IL-6.

Streptococcal toxic shock syndrome (strep TSS) with associated necrotizing fasciitis is a rapidly progressive process that kills 30–60% of patients in 72– 96 h. Violaceous bullae, hypotension, fever, and evidence of organ failure are late clinical manifestations. Thus, the challenge to clinicians is to make an early diagnosis and to intervene with aggressive fluid replacement, emergent surgical debridement, and general supportive measures. Superantigens such as pyrogenic exotoxin A interact with monocytes and T lymphocytes in unique ways, resulting in T-cell proliferation and watershed production of monokines (e.g. tumor necrosis factor α, interleukin 1, interleukin 6), and lymphokines (e.g. tumor necrosis factor β, interleukin 2, and gamma-interferon). Penicillin, though efficacious in mild Streptococcus pyogenes infection, is less effective in severe infections because of its short postantibiotic effect, inoculum effect, and reduced activity against stationary-phase organisms. Emerging treatments for strep TSS include clindamycin and intravenous gamma-globulin.

Recent advances in the drug treatment of inflammatory bowel disease (IBD) have paralleled our understanding of the pathophysiology of ulcerative colitis and Crohn’s disease. Several proinflammatory and immune-regulatory cytokines are upregulated in the mucosa of patients with IBD, and differences and similarities in the cytokine profiles of ulcerative colitis and Crohn’s disease have been elucidated. Several clinical trials involving a chimeric anti-TNF-α (tumor necrosis factor-α) antibody have shown marked clinical benefit in the majority of patients with Crohn’s disease, verifying the importance of TNF-α in the pathogenesis of Crohn’s disease. In preliminary studies, treatment with recombinant human interleukin-10 has been beneficial in Crohn’s disease but not in ulcerative colitis. Future treatment of IBD may include combination or sequential cytokine and anticytokine administration in defined groups of patients based on their mucosal cytokine profiles.

Anorexia nervosa (AN) and bulimia nervosa (BN) are disorders characterized by abnormal patterns of weight regulation and eating behavior and by disturbances in attitudes and perceptions toward weight and body shape. Etiologic research has indicated substantial genetic influence on these disorders, suggesting significant biological contributions to their development. Obsessional, perfectionistic, and anxious personality styles may be premorbid traits that contribute to this pathogenesis. Studies of neuroendocrine, neuropeptide, and neurotransmitter functioning in patients with AN and BN indicate that disturbances of these systems may contribute to the maintenance as well as the etiology of these sometimes fatal disorders. The efficacy of psychological treatments and pharmacotherapy has been more clearly established for BN than for AN.

Progression to irreversible renal parenchymal damage and end-stage renal disease is the final common pathway of chronic proteinuric nephropathies and is relatively independent of the type of initial insult. In animals, a reduction in nephron mass exposes the remaining nephrons to adaptive hemodynamic changes that are intended to sustain renal function but may be detrimental in the long term. High glomerular capillary pressure impairs glomerular permeability to proteins, which are then filtered in excessive quantities and reach the lumen of the proximal tubule. The secondary process of reabsorption of filtered proteins can contribute substantially to renal interstitial injury by activating intracellular events, including upregulation of vasoactive and inflammatory genes. The corresponding molecules formed in excessive amounts by the renal tubules cause an interstitial inflammatory reaction that normally precedes renal scarring and correlates with declining function. In several clinical studies, the increase in urinary protein excretion correlated with the tendency of the renal disease to progress more than it correlated with the underlying renal disease itself. Whenever urinary protein excretion is reduced, the decline in the glomerular filtration rate (GFR) slows or stops. Thus, to the extent that angiotensin-converting enzyme inhibitors lower the rate of urinary protein excretion, they effectively limit the progressive decline in GFR. If treatment is sufficiently prolonged, the GFR decline can be effectively halted or reversed, even in patients with remarkably severe disease, and remission is now achievable in some patients.

Among the large variety of cerebrovascular syndromes, carotid artery dissections remain often under-recognized. Many patients present with minor or transient symptoms, some with local pain only, and some are asymptomatic. A useful rule is that the coincidence of any local pain in neck or face with an ipsilateral Horner’s syndrome preceding transient or persistent retinal or cerebral ischemic symptoms should alert physicians—notably those treating emergencies—to rule out an underlying dissection of the ipsilateral carotid artery. In most cases the extracranial part of the carotid artery is affected; therefore, this review will focus on this main subgroup of patients. We review the pathological anatomy, as well as possible underlying causes, clinical features, diagnostic tools, differential diagnosis, treatment options, and outcome data.