Annual Review of Medicine - Volume 48, 1997

Regulation of the homeostatic balance between cell proliferation and cell death is essential for development and maintenance of multicellular organisms. Physiologic, or programmed, cell death is dependent on a genetically encoded and evolutionarily conserved pathway that induces a form of cellular suicide known as apoptosis. In the past decade, it has become clear that the regulatory mechanisms controlling programmed cell death are as fundamental, and as complex, as those regulating cell proliferation. Perturbation of the signaling cascades regulating apoptosis, whether by extracellular triggers, acquired or germline genetic mutations, or viral mimicry of signaling molecules, can result in a wide variety of human diseases. Analysis of these regulatory pathways has led to a better understanding of the etiology and pathogenesis of many human diseases, notably cancers, infectious diseases including AIDS, autoimmune diseases, and neurodegenerative/neurodevelopmental diseases. Our understanding of the regulation of programmed cell death in health and disease is far from complete, and the challenge of converting that understanding into new therapeutic modalities has only begun to be approached.

A small new population of patients in cardiology, the grown-up (adult) congenital hearts (GUCH), need superspecialist care and expertise, particularly those patients with complex defects previously operated on in childhood or who were not operated on. Arrhythmias are the most common cardiologic reason for admission to the hospital, and atrial flutter is the most frequent disorder of rhythm, usually related to hemodynamic disturbances. The GUCHs need solutions to problems of transition of care, ideally an adolescent area for the younger patients, knowledge of which and when to investigate each anomaly, expertise in cardiac catheterization and interventions, cardiac surgeons experienced in congenital as well as adult disease since one in five admissions are for cardiac surgery, at-risk pregnancy service, counseling on life's problems, and most of all a few dedicated centers with cardiologists and surgeons trained in this subspecialty. The profession needs to achieve optimal care for these precious patients, particularly those with complicated lesions and complex surgery, particularly with valve replacements. Although small in number and high in expense, GUCH patients should be centralized so expertise and experience can be concentrated despite the need to cross barriers of finance and bureaucracy. Currently, with the exception of a few expert centers, these patients receive suboptimal medical management.

Mitral valve reconstruction offers patients an important alternative to the traditional method for treating severe mitral regurgitation—mitral valve replacement. Over the last 15 years, surgical techniques have evolved for treating mitral regurgitation occurring from various anatomic mechanisms—annular dilatation, abnormal leaflet motion due to a variety of causes, or leaflet perforation. Currently, over 90% of regurgitant mitral valves of varying etiologies are amenable to nonreplacement therapy by reconstruction, with good intermediate- and long-term results. Reconstruction obviates the need for long-term anticoagulation, and thus, there has evolved a trend toward reconstruction earlier in the course of this disease, before fixed atrial fibrillation and ventricular dilatation occur.

Brown adipose tissue is distinguished by its unique capacity for uncoupled mitochondrial respiration, which is highly regulated by sympathetic nerve activity. Because of this, energy expenditure in brown fat is capable of ranging over many orders of magnitude. The fact that the function of brown adipose tissue is impaired in obese rodents and that transgenic mice with decreased brown fat develop obesity demonstrates the importance of brown fat in maintaining nutritional homeostasis. However, the role of brown fat in humans is less clear. β3-Adrenergic receptors are found on brown adipocytes, and treatment with β3-selective agonists markedly increases energy expenditure and decreases obesity in rodents. Whether β3-selective agonists will be effective anti-obesity agents in humans is presently under investigation.

Initial management of patients with temporal lobe epilepsy is with antiepileptic drugs, but these control seizures in only half the patients. Patients refractory to drugs should be evaluated for resective surgery. That evaluation requires identification of a focus of onset of seizures, as well as establishing that the focus is in an area of the brain that can be removed with a low risk of new neurologic deficits. Techniques used in that evaluation, including electroencephalography, imaging, recording from intracranial electrodes, use of the intracarotid amobarbitol perfusion test, and the role of specialized studies such as positron emission tomography, are reviewed, along with the correlation of the findings on that evaluation to the control of seizures after surgery. The different surgical techniques for temporal lobe resections are also reviewed, along with the risks of surgery, particularly to recent memory, and the changes in quality of life following surgery.

Safe and efficient treatment of drinking water has been one of the major public health advances of the twentieth century. People in developed countries generally take for granted that their water is safe to drink, a luxury the majority of the world's population does not have. The leading cause of infant mortality in the developing world is infectious diarrhea, and the prevalence of diarrheal pathogens is largely influenced by the quality and quantity of clean water available for drinking and washing. Until recently, modern water treatment had all but eliminated these concerns in developed nations. Over the past two decades, however, the safety of our water supply has been threatened by the emergence of Cryptosporidium parvum, a protozoal pathogen. The hearty oocysts of this organism survive chlorination and filtration to cause a diarrheal illness that, while unpleasant enough in healthy people, is devastating in immunocompromised individuals. The 1993 Milwaukee outbreak, in which 403,000 people developed diarrhea from drinking water that met all the updated federal safety standards, demonstrated the tremendous public health importance of this organism. While earlier attention had focused on Giardia and amebic infections, the other "emerging" protozoan besides Cryptosporidium is Cyclospora. This review discusses the protozoal pathogens, including Cryptosporidium parvum, Giardialamblia, Entamoebahistolytica, and Cyclospora cayetanensis, that cause waterborne diarrheal outbreaks and the threats they pose to the public.

Orally administered autoantigens suppress autoimmunity in animal models, including experimental allergic encephalomyelitis, collagen and adjuvant-induced arthritis, uveitis, and diabetes in the non-obese diabetic mouse. Low doses of oral antigen induce antigen-specific regulatory T-cells in the gut, which act by releasing inhibitory cytokines such as transforming growth factor-β, interleukin-4, and interleukin-10 at the target organ. Thus, one can suppress inflammation at a target organ by orally administering an antigen derived from the site of inflammation, even if it is not the target of the autoimmune response. Initial human trials of orally administered antigen have shown positive findings in patients with multiple sclerosis and rheumatoid arthritis. A double-blind, placebo-controlled, phase III multi-center trial of oral myelin in 515 relapsing-remitting multiple sclerosis patients is in progress, as are phase II clinical trials investigating the oral administration of type II collagen in rheumatoid arthritis, S-antigen in uveitis, and insulin in type I diabetes.

The taxane class of antimicrotubule anticancer agents is perhaps the most important addition to the chemotherapeutic armamentarium against cancer over the past several decades. After only a brief period, the taxanes have not only demonstrated a unique ability to palliate the symptoms of many types of advanced cancers, including carcinoma of the ovary, lung, head and neck, bladder, and esophagus, they have also demonstrated effectiveness in the initial therapy of earlier stages of cancer, a setting in which any new therapy is likely to make its greatest impact. The challenge now facing investigators is to develop strategies to maximize therapeutic benefits with the taxanes in the early stages, as well as the advanced stages, of many cancers. This review describes the preclinical features and clinical results of the two major taxanes, paclitaxel (Taxol®, Bristol-Myers Squibb) and docetaxel (Taxotere®, Rhone-Poulenc Rhorer).

Cholesterol embolization (CE), usually occurring in males in their sixth or seventh decade of life, can affect multiple organ systems, including the kidney. Interventive diagnostic procedures and aortic surgery greatly increase the risk of CE. Rapid or insidious progression of renal failure in association with surgical or diagnostic radiologic procedures should suggest this diagnosis. Progressive renal insufficiency in older patients with generalized arterial disease should suggest ischemic nephropathy secondary to bilateral renal artery stenosis, renal CE, or both. Recent worsening of hypertension is characteristic of either diagnosis. A number of clinical conditions can simulate renal CE, and final differentiation may be possible only by renal biopsy. Aggressive, supportive management of renal CE is warranted because renal function may stabilize and, in a limited number of cases, may even improve.

Volume reduction surgery is based on the removal of volume-occupying but nonfunctioning emphysematous lung, which is thought to improve pulmonary elastic recoil. The reduction in thoracic volume may also improve thoracic cage and inspiratory muscle function. In addition, dyspnea is lessened, exercise tolerance is increased, and measured pulmonary function is improved. Alveolar gas exchange may also be improved. Selection criteria include marked airway obstruction secondary to emphysema, marked hyperinflation of the chest wall, and regional heterogeneity in the distribution of the emphysema. The best results are obtained with a bilateral procedure utilizing stapling resection. The two surgical approaches are median sternotomy and video-assisted thoracic surgery.

Progress in treatment of pulmonary hypertension has been impaired by the lack of formal clinical trials. This is now beginning to change, and the impact on our approach to treating patients with pulmonary hypertension is substantial. As with other relatively uncommon medical disorders, randomized, controlled, multi-center trials are needed to assess the safety and efficacy of potential therapeutic modalities. Treatments showing promise at the level of small pilot studies within a single center should be studied more rigorously.

Identification of RET gene mutations in patients at-risk for the development of the hereditary forms of medullary thyroid carcinoma has simplified management and expanded the scope of indications for surgical intervention. Patients who carry this mutation can be offered thyroidectomy at a very young age, hopefully at a point when the cancer has not yet developed or spread. Those who are found not to have inherited the mutation are spared further genetic and biochemical screening. This achievement marks a new paradigm in surgery—the recommendation that an operation be performed based on the result of a genetic test. Experience with management of patients with multiple endocrine neoplasia types 2A and 2B and with familial, non–multiple endocrine neoplasia medullary thyroid carcinoma will provide information that will aid in the future management of patients with other hereditary cancers.

Spousal bereavement is a common event in later life and, not infrequently, an important cause of psychiatric and medical morbidity. Depression (along with suicide), anxiety, substance abuse, and symptoms of “complicated” grief are among the more important psychiatric sequelae of spousal bereavement. They may represent, in part, forms of abnormal reaction to the stress of loss and the challenges of adaption to becoming widowed. This paper summarizes current knowledge about the clinical phenomenology of the psychiatric sequelae to late-life attachment bereavment, some of the hypothesized antecedents of abnormal stress response to bereavement, psychobiologic correlates of bereavement-related depression, and the long-term course (including preliminary evidence on response to treatment with psychotherapy and antidepressant medication).

The acute respiratory distress syndrome (ARDS) is a relatively common, inflammatory lung disorder that is associated with major morbidity and high mortality. The pathogenesis of ARDS is complex, and unfortunately, the development of ARDS in an individual patient is difficult to anticipate. In this chapter, we outline the rationale for why accurately predicting the development of ARDS would be valuable. We also review the accumulated data on approaches for predicting ARDS and discuss the potential difficulties in establishing predictive markers.

The recent inclusion of research criteria for premenstrual dysphoric disorder in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders should help physicians recognize women with symptoms of irritability, tension, dysphoria, and lability of mood that seriously interfere with their lifestyle. Premenstrual dysphoric disorder can be differentiated from premenstrual syndrome, which is primarily reserved for milder physical symptoms and minor mood changes. The use of criteria from the Diagnostic and Statistical Manualin conjunction with prospective daily charting for at least two menstrual cycles is now accepted as common practice in confirming the diagnosis. Treatment options range from the conservative (lifestyle and stress management) to treatment with psychotropic medications and hormonal or surgical interventions to eliminate ovulation for the more extreme cases. Results from several randomized, placebo-controlled trials have clearly demonstrated that selective serotonin reuptake inhibitors, as well as medical or surgical oophorectomy, are effective in treating premenstrual dysphoric disorder. Taken together, these data indicate that treatment may be accomplished by either eliminating the hormonal trigger or by reversing the sensitivity of the serotonergic system.

Discovery of the gene encoding the protein dystrophin delineated not only the cause of Duchenne dystrophy but also an expanding family of at least eight different dystrophin-associated muscle proteins. These include two that span the membrane (the dystroglycans), at least five within the membrane (the sarcoglycans), and a submembrane protein (utrophin). In recent years, defects in the genes for several of these proteins have been identified in several different muscular dystrophies. The spectrum of clinical deficits associated with these genetic lesions is broad, but typically it encompasses both milder proximal myopathies characteristic of limb-girdle dystrophy and more severe disorders reminiscent of Duchenne dystrophy. These discoveries will provide the basis both for improved understanding of physiology of this complex of proteins at the muscle membrane and for new strategies in the treatment of muscular dystrophy.

Recent clinical studies of acute renal failure in adults have focused attention on the biocompatibility of the dialysis membrane as a possible factor influencing patient morbidity and mortality. In this article, we review the concept of dialysis membrane biocompatibility and highlight the difficulty of finding an ideal definition. We then expand on the possible roles of complement and neutrophil activation by dialysis membranes, which may prolong the recovery from acute renal failure. The results of several clinical studies analyzing the impact of dialysis membranes on the course and outcome of acute renal failure are discussed. Finally, the possible relevance of biocompatibility in continuous renal replacement therapies is emphasized.

Alcoholism affects nearly 12.5 million Americans and is responsible for annual costs of over $130 billion from loss of job productivity, deleterious health effects, and direct treatment expenses. Research on treating alcoholism from the standpoint of relapse prevention using psychosocial interventions alone has produced only modest results. Studies on the efficacy of adjunctive medications using multiple medications in placebo-controlled and open trials combined with psychosocial interventions have shown mixed results. Recently, a safe and well-tolerated opiate antagonist, naltrexone, was approved by the Food and Drug Administration (FDA) for the adjunctive treatment of alcoholism. This review describes the pertinent preclinical and clinical research that led to the FDA's approval. Details are provided describing the subjects, methods, and results of the two pivotal human studies that led to the FDA review for this indication. Clinical therapeutic guidelines, appropriate patient selection, and future directions are also elucidated.

The product of nitric oxide (NO) synthase is the most potent endogenous vasodilator known. NO not only is a potent vasodilator, it also inhibits platelet adherence and aggregation, reduces adherence of leukocytes to the endothelium, and suppresses proliferation of vascular smooth muscle cells. A number of disorders are associated with reduced synthesis and/or increased degradation of vascular NO. These include hypercholesterolemia, diabetes mellitus, hypertension, and tobacco use. The endothelial dysfunction caused by these disorders contributes to the alterations in vascular function and structure observed in these conditions. A reduction in the activity of vascular NO likely plays a significant role in the development of atherosclerosis. Insights into the mechanisms by which NO production or activity is altered in these states will lead to new therapeutic strategies in the treatment of a number of vascular disorders, including hypertension, atherosclerosis, restenosis, and thrombosis.