Annual Review of Medicine - Volume 50, 1999

Arrhythmogenic right ventricular dysplasia (ARVD) is a new form of cardiomyopathy probably more frequent than commonly reported. It is a rare but important cause of sudden arrhythmic death in young, otherwise healthy persons, as well as a subtle cause of congestive heart failure. It may lead to temporary incapacitation with catastrophic consequences. Proper electrocardiographic criteria, echocardiography, nuclear medicine, or magnetic resonance imaging could identify most of these individuals. With the exception of full-thickness histological examination of the right ventricular free wall, contrast ventriculography remains the most definitive standard for a positive diagnosis. The wide clinical spectrum of arrhythmogenic right ventricular cardiomyopathies/dysplasia appears to be the result of one or possibly two factors: (a) replacement of most of the right ventricular myocardium by fat and (b) genetic susceptibility to environmental agents (myocarditis). Current treatment modalities include drug therapy, catheter or surgical ablative techniques, and modern treatments of congestive heart failure. Heart transplant is exceptional. Implantable defibrillators, used alone or in combination with drug therapy, will probably play an increasing role in ARVD and related cardiomyopathies.

Pseudo-obstruction syndromes are increasingly recognized in clinical practice. They result from impairment of intrinsic neuromuscular or extrinsic control of gut motility. Typically, pseudo-obstruction syndromes result in features suggestive of mechanical obstruction and bowel dilatation in the absence of any demonstrable obstruction or mucosal disease. The syndrome may affect any region of the gut. Less severe variants without bowel dilatation are diagnosed by measurement of gastrointestinal transit and pressure profiles. The aims of treatment are restoration of nutrition and hydration, symptom relief, normalization of intestinal propulsion with prokinetics, and suppression of bacterial overgrowth. Surgery plays a limited role, adjunctive to medical treatment, facilitating enteral nutrition and decompression by means of jejunostomy. Infrequently, resection of localized disease or intestinal transplantation are indicated. The roles of intestinal pacemakers (interstitial cells of Cajal) and genetic mutations in the etiology of pseudo-obstruction, as well as the cost-benefit ratio of transplantation for pseudo-obstruction, will be clarified in the future.

The ubiquitin-proteasome pathway plays a pivotal role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation. The pathway involves an enzymatic cascade through which multiple ubiquitin molecules are covalently attached to the protein substrate, which is then degraded by the 26S proteasome complex. The pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman's syndroome, and Liddle syndrome), in immune surveillance/viral pathogenesis, and in the pathology of muscle wasting. The molecular mechanisms that underlie these processes are being unraveled at present.

Hibernating myocardium is a state of persistently impaired myocardial and left ventricular function at rest due to reduced coronary blood flows. It can be defined as an exquisitely regulated tissue successfully adapting its activity to prevailing circumstances. It has been documented in patients with angina (chronic stable and/or unstable), acute myocardial infarction, heart failure and/or severe left ventricular dysfunction, and anomalous left coronary artery from the pulmonary artery. The diagnosis of hibernating myocardium involves (a) documenting left ventricular dysfunction at rest and (b) documenting that there is viable myocardium in the area of dysfunction. Tests commonly used for the latter are dobutamine echocardiography, ²⁰¹Tl isotope studies, and positron image tomography. Revascularization, either by surgery or by interventional catheter techniques, has been shown to improve or normalize the abnormal left ventricular function at rest.

Hereditary hemochromatosis (HHC) is a common autosomal recessive disorder of iron metabolism that results in progressive iron overload and can be fatal if untreated. The hemochromatosis gene (HFE) was identified by positional cloning in 1996. Two missense mutations have been described in HFE. The majority of HHC patients are homozygous for a cysteine-to-tyrosine substitution (C282Y); however, a small number are homozygous for a histidine-to-aspartic-acid substitution (H63D) or are heterozygous for both of these mutations. Mechanisms by which C282Y and H63D may disrupt the normal functioning of HFE have been suggested, but the role of HFE in the process of normal iron metabolism has yet to be clearly defined.

Keeping one's personal fund of knowledge current is one of the most formidable challenges that physicians face. This article considers a few strategies that may help physicians as they struggle to keep their knowledge up-to-date. Physicians need to develop their own goals for staying current, systematically and periodically search the literature for high-quality material relevant to the topics on their agendas, become facile with critical appraisal of the literature, and schedule time for reading. One of the responsibilities of any professional is to maintain expertise, and this responsibility is probably nowhere more critical, or more difficult, than in the profession of medicine.

Virtually all cells in humans depend on mitochondrial oxidative phosphorylation to generate energy, accounting for the remarkable diversity of clinical disorders associated with mitochondrial DNA mutations. However, certain tissues are particularly susceptible to mitochondrial dysfunction, resulting in recognizable clinical syndromes. Mitochondrial DNA mutations have been linked to seizures, strokes, optic atrophy, neuropathy, myopathy, cardiomyopathy, sensorineural hearing loss, diabetes mellitus, and other clinical features. Mitochondrial DNA mutations also may play an important role in aging, as well as in common age-related neurodegenerative disorders such as Parkinson's disease. Therefore, it is becoming increasingly important for clinicians to recognize the clinical syndromes suggestive of a mitochondrial disorder, and to understand the unique features of mitochondrial genetics that complicate diagnosis and genetic counseling.

The past decade has seen many important advances in the pathogenesis, clinical and laboratory diagnosis, and management of heparin-induced thrombocytopenia (HIT), one of the most common immune-mediated adverse drug reactions. HIT is caused by IgG antibodies that recognize complexes of heparin and platelet factor 4, leading to platelet activation via platelet FcγIIa receptors. Formation of procoagulant, platelet-derived microparticles, and, possibly, activation of endothelium generate thrombin in vivo. Thrombin generation helps to explain the strong association between HIT and thrombosis, including the newly recognized syndrome of warfarin-induced venous limb gangrene. This syndrome occurs when acquired protein C deficiency during warfarin treatment of HIT and deep venous thrombosis leads to the inability to regulate thrombin generation in the microvasculature. The central role of HIT antibodies in causing HIT, as well as refinements in laboratory assays to detect these antibodies, means that HIT should be considered a clinicopathologic syndrome. The diagnosis can be made confidently when one or more typical clinical events (most frequently, thrombocytopenia with or withoutt thrombosis) occur in a patient with detectable HIT antibodies. The central role of thrombin generation in this syndrome provides a rationale for the use of anticoagulants that reduce thrombin generation (danaparoid) or inhibit thrombin (lepirudin).

Cystitis is caused by a relatively small number of bacterial species. To colonize and grow in the urinary tract, these organisms have developed and acquired special properties (virulence factors) that allow them to overcome the defences of the urinary tract, particularly clearance by urine flow. These virulence factors are unlikely to be required during transmission from host to host, and sometimes their constitutive expression may actually be disadvantageous. Such factors are therefore regulated by the environment and in a coordinate manner to ensure their most appropriate expression for the conditions encountered. This review focuses on the biology of the urinary tract and the bacterial properties necessary to cause cystitis. The regulation of virulence factors at the different stages of the infection is considered, and a general model for the pathogenesis of urinary tract infection is proposed.

Most ventricular tachycardias encountered in clinical practice occur in patients who have structural heart disease. Idiopathic ventricular tachycardia refers to those arrhythmias that occur in patients without structural heart disease, metabolic/electrolyte abnormalities, or the long QT syndrome. Three commonly recognized forms of idiopathic ventricular tachycardia include: (a) ventricular tachycardia associated with mitral valve prolapse, (b) ventricular tachycardia originating from the right ventricular outflow tract, and (c) ventricular tachycardia originating from the left ventricle. Recently, a fourth type of idiopathic ventricular tachycardia, termed the Brugada syndrome, has been identified as responsible for some cases of cardiac arrest in persons without apparent structural heart disease. Each form of ventricular tachycardia may be considered a discrete syndrome based on its electrocardiographic characteristics, mechanisms, responses to pharmacologic intervention, and prognosis (good in most cases). Ventricular tachycardias range from the common to the exotic, but all represent syndromes with which the internist and general cardiologist should be familiar.

Malaria still kills some 0.5–2.5 million people per year in the tropics. Resistance to the cheap, most commonly used antimalarials continues to spread alarmingly and could outpace drug development. The artemisinin derivatives have had an important clinical impact both on the treatment of resistant falciparum malaria and on the incidence of disease in low-transmission areas. A few promising new antimalarials are being tested clinically but there is an imperative need for cheap, well-tolerated drugs that can be used in short courses, and for strategies to delay the onset of drug resistance. Bed nets have been shown to reduce the incidence of severe malaria in many areas but an effective vaccine is urgently needed.

Early referral of the patient with chronic renal failure will give the nephrologist time to fit the treatment to the patient. Planning for dialysis and transplantation should be undertaken concurrently. If the patient is not of advanced age and is not afflicted with severe comorbid illness, renal transplantation is the preferred form of renal replacement therapy. Living donor transplantation is preferred to cadaveric transplantation. For the patient who awaits or who cannot undergo transplantation, either peritoneal dialysis or hemodialysis may be chosen. Although the mortality rate for peritoneal dialysis appears to be higher than that for hemodialysis, especially among elderly diabetic patients, peritoneal dialysis remains an acceptable therapy for the highly motivated patient. In the United States, the mortality rate for chronic dialysis patients is high. We expect mortality rates for both peritoneal dialysis and hemodialysis to fall, however, as we strive to achieve optimal solute clearance and to more effectively treat comorbid illness.

Controversy over screening for prostate cancer involves both scientific and policy considerations. The principal scientific questions are whether tumors detected by screening are clinically significant, whether screening generates too many false-positive results, and whether early detection lowers morbidity or mortality. Both screening and treatment of prostate cancer can be harmful, making the tradeoff between benefits and risks especially relevant. Studies suggest that this judgment is highly personal, depending on the relative importance that individuals assign to potential outcomes. Opinions and policy considerations also influence views about the appropriateness of screening. Chief among these are personal beliefs about benefits and harms, medicolegal concerns, patient expectations, resource constraints, and opportunity costs. Appropriate policy must discriminate between what is best for populations and for individual patients. The lack of evidence of benefit and the potential harms argue against a societal policy of routine screening. Individual patients who could benefit from screening should be informed about the potential benefits and harms and invited to make a personal choice based on their priorities and concerns.

Coagulase-negative staphylococci have long been regarded as apathogenic but their important role as pathogens and their increasing incidence have been recognized and studied in recent years. Although specific virulence factors are not as clearly established as they are in Staphylococcus aureus, it seems clear that factors such as bacterial polysaccharide components are involved in attachment and/or persistence of bacteria on foreign materials. Coagulase-negative staphylococci are by far the most common cause of bacteremia related to indwelling devices. Most of these infections are hospital-acquired, and studies over the past several years suggest that they are often caused by strains that are transmitted among hospitalized patients. Other important infections due to coagulase-negative staphylococci include central nervous system shunt infections, native or prosthetic valve endocarditis, urinary tract infections, and endophthalmitis. Intravenous treatment of systemic infections is usually required because coagulase-negative staphylococci have become increasingly resistant to multiple antibiotics.

Tumor-induced osteolysis or lytic bone disease is mediated by osteoclast activation. Osteoclasts can be activated directly by products produced by tumors or indirectly through other nonmalignant cells. By reducing osteoclastic activity, bisphosphonates inhibit bone resorption. Since these agents were shown effective in treating other diseases associated with increased bone resorption, including cancer-related hypercalcemia and Paget's disease of bone, studies have been initiated to explore the use of bisphosphonates in patients with osteolytic bone metastases. Recent large randomized double-blind studies show the efficacy of these agents in reducing skeletal complications in patients with bone metastases from both breast cancer and multiple myeloma.

Indices of heart rate variability (HRV) provide a window onto autonomic modulation of the heart. HRV indices, determined in either the time or frequency domain, are closely related and reflect parasympathetic, mixed sympathetic, and parasympathetic and circadian rhythms. In population studies, decreased HRV has had predictive value for mortality among healthy adults. It is a well-established risk factor for arrhythmic events and mortality among post-myocardial-infarction patients but has only moderate sensitivity and specificity. Decreased HRV has had mixed predictive success in congestive heart failure. Reduced HRV identifies diabetic patients with autonomic neuropathy. HRV in combination with other risk stratifiers, e.g. ejection fraction, can identify cardiac patients at especially high risk of mortality. Many but not all interventions associated with increased HRV are also associated with better survival rates.

Hereditary peripheral neuropathies, among the most common genetic disorders in humans, are a complex, clinically and genetically heterogeneous group of disorders that produce progressive deterioration of the peripheral nerves. This group of disorders includes hereditary neuropathy with liability to pressure palsies, Charcot-Marie-Tooth disease, Dejerine-Sottas syndrome, and congenital hypomyelinating neuropathy. Our understanding of these disorders has progressed from the description of the clinical phenotypes and delineation of the electrophysiologic and pathologic features to the identification of disease genes and elucidation of the underlying molecular mechanisms.

Prior to the advent of nuclear magnetic resonance (NMR) spectroscopy, human glucose metabolism was studied through tracer and tissue biopsy methodology. NMR spectroscopy now provides a noninvasive means to monitor metabolic flux and intracellular metabolite concentrations continuously. ¹³C NMR spectroscopy has shown that muscle glycogen synthesis accounts for the majority of insulin-stimulated muscle glucose uptake in normal volunteers and that defects in this process are chiefly responsible for insulin resistance in type 1 and type 2 diabetes mellitus, as well as in other insulin resistant states (obesity, insulin-resistant offspring of type 2 diabetic parents, elevation of plasma FFA concentrations). Furthermore, using ³¹P NMR spectroscopy to measure intracellular glucose-6-phosphate, it has been shown that defects in insulin-stimulated glucose transport/phosphorylation activity are primarily responsible for the insulin resistance in these states.

Three interferon β preparations (Betaseron^®, Avonex^®, and Rebif^®) have shown efficacy in the treatment of relapsing-remitting multiple sclerosis (MS). Attack frequency is reduced by 30% and major attacks to an even greater extent. Accumulating disease burden as measured by annual T2-weighted magnetic resonance imaging is markedly lessened, and disease activity as measured by serial gadolinium-enhanced MRI scanning is reduced by over 80%. A fourth preparation, Copaxone^®, a basic copolymer of four amino acids, lessens MS attack frequency by 30% and also lessens disease activity as measured by gadolinium-enhanced MRI. Betaseron^® lessens accumulation of disability in MS patients with secondary progressive disease regardless of the severity of disability at the time treatment is commenced. MS is now a treatable disease.