Annual Review of Medicine - Volume 47, 1996

Transfer of new genetic material to hematopoietic stem cells and expression of the gene product in daughter cells of various lineages is an exciting approach to the treatment of congenital and acquired human diseases. This review summarizes the current status of retroviral and adeno-associated viral vectors for gene transfer to human hematopoietic cells, including extensive preclinical data as well as preliminary results from ongoing clinical trials.

In the phenomenon termed "ischemic preconditioning," a brief period of ischemia prior to a more prolonged one improves myocardial function (after reperfusion) and diminishes infarction. This phenomenon has been described extensively in experimental animals and now in humans. It is triggered by several agents released by ischemic cells and can be reproduced by infusion of agonists coupled to protein kinase C (PKC), e.g. adenosine, angiotensin, phenylephrine, bradykinin, and endothelin. The intracellular signaling pathway involves a phospholipase, either C or D, which metabolizes membrane phospholipids to produce diacylglycerol, a necessary endogenous cofactor for PKC activation. Which protein(s) is phosphorylated by PKC is not yet known, nor is the identity of the end-effector that actually mediates protection of the ischemic cell. Identification of the end-effector may make it possible in the routine treatment of patients with ischemic heart disease to precondition and thereby salvage ischemic myocardium and improve survival.

Video technology allows surgeons to offer patients operations through small incisions. While these minimally invasive techniques have been employed for a wide range of operations for many years, only recently has a laparoscopic cholecystectomy been possible. Compared to the same operation performed via laparotomy, it is deemed the “gold standard.” Overall mortality after laparoscopic cholecystectomy ranges from 0–1%, and the rate of major complications is less than 5%. As a group, general surgeons are beyond their initial learning curve for laparoscopic cholecystectomy, but the majority of iatrogenic injuries can be successfully avoided by appreciating the limitations and pitfalls of laparoscopic surgery, and by carefully dissecting the hepatocystic triangle before dividing any structure. Early identification and management of complications will minimize potentially devastating complications of small, unrecognized injuries. Physicians need to accurately advise patients of the proposed advantages and potential problems of laparoscopic cholecystectomy before referring them to a surgeon.

How lithium works in manic-depressive illness is unknown. Recently, however, a powerful hypothesis has been gaining momentum. Distinguished by its testability and clinical implications, the inositol depletion hypothesis of lithium action is relevant to treatment of lithium side effects, to the development of new compounds with the clinical profile of lithium, and to new experimental treatment of depression.

Endocrine tumors of the gastrointestinal tract produce a variety of secretory products that cause unique clinical syndromes. Diagnosis, which is often delayed, requires a strong index of suspicion and must be confirmed by biochemical tests. Precisely where these tumors originate remains a topic of controversy. However, several growth factors that may be involved in tumor development have been identified, and genetic abnormalities in patients with multiple endocrine neoplasia have been described. New pre- and intraoperative localization techniques have greatly increased the ability to identify and resect these tumors. The long-acting somatostatin analogue octreotide is frequently useful as a tracer to localize tumors and as symptomatic therapy for limiting release of secretory products produced by the tumors. In some instances it may also have direct anti-tumor activity.

Type-II (non-insulin-dependent) diabetes mellitus (NIDDM) is a heterogeneous disease resulting from insulin resistance and β-cell dysfunction. β-Cell dysfunction in Type-II diabetes is characterized by a specific lack of first-phase glucose-induced insulin secretion. This defect is readily reversible upon normalization of blood glucose levels. Chronic hyperglycemia itself is harmful to the β-cell and affects both insulin biosynthesis and exocytosis. No unique intracellular defect has been demonstrated to be responsible for all common forms of the disease. However, mutations of the glucokinase gene have been identified in maturity onset diabetes in the young, a particular form of NIDDM.

Since its initial application in 1980, the implantable cardioverter defibrillator (ICD) has evolved into a highly sophisticated device that offers programmable tiered therapy (antitachycardia pacing, cardioversion, and defibrillation) for ventricular tachyarrhythmias and backup pacing for bradycardia. It also provides diagnostic information about detected events. Successful implantation of nonthoracotomy systems is now routine. The availability of nonthoracotomy systems has reduced perioperative morbidity and mortality as well as hospital costs. Although the ICD has virtually eliminated sudden cardiac death in recipients, overall cardiac mortality remains considerable in these patients. Several prospective randomized clinical trials comparing ICD therapy to antiarrhythmic drug therapy are under way.

It is now recognized that most clinically nonfunctioning pituitary tumors express gonadotropin hormones or their subunits in vitro, and sometimes in vivo. Many of these tumors are diagnosed by sensitive imaging techniques while patients are still asymptomatic. We outline an overview of the diagnosis and clinical management of these tumors.

How reproductive technologies are used has consequences not just for immediate users but for others as well. This article discusses issues that should be taken into consideration in coming to decisions about whether or not it is appropriate to use a particular reproductive technology, or whether to use a technology in a particular way.

Pulmonary disease is a major source of morbidity and mortality in HIV-infected persons. Pneumocystis carinii pneumonia has decreased substantially during the last eight years, but in the United States it remains the most common disorder that announces the onset of AIDS. In contrast, tuberculosis is by far the most important AIDS-associated indicator disease in developing countries. Community-acquired acute bacterial penumonia is a common HIV-linked complication throughout the world; pneumonia occurs at all levels of immune suppression but increases in frequency as CD4 counts decrease. Fungal infections mainly afflict persons who live or have lived in the various endemic areas. AIDS-related Kaposi's sarcoma and lymphoma generally do not involve the lungs until the malignancies are advanced. The increasing use of successful chemoprophylaxis against many important HIV-associated infections is increasing the incidence of other end-stage complications such as cytomegalovirus and disseminated MAC disease.

Laxative abuse is an uncommon but clinically important cause of chronic diarrhea, a condition often associated with other gastrointestinal symptoms, as well as with disturbances in electrolyte and acid-base balance. A high index of suspicion, a detailed history, and the detection of laxative in stool and/or urine will establish the diagnosis once routine laboratory, endoscopic, and radiologic investigations have excluded common causes of chronic diarrhea. Confirmation of the diagnosis may rule out the need for more extensive, invasive, and costly investigations. However, management is frequently difficult owing to the laxative abuser's complex underlying psychopathology.

The electrical activity of cardiac tissue is determined by the highly regulated flow of ions across the cell membrane during the cardiac action potential. Ion channels are pore-forming proteins through which these electric currents flow. In this review, the ion currents that underlie the action potential are first described. Then, the way in which expression of individual ion-channel genes results in such ion currents is discussed. Finally, the concept that arrhythmias may be due to abnormalities of structure, function, or number of ion channels, or the way in which they respond to abnormalities in their environment (such as acute ischemia), is reviewed. Further understanding of the molecular mechanisms underlying normal and abnormal cardiac electrophysiologic behavior should allow the development of safer and more effective antiarrhythmic interventions.

Disparities in the relationships between alcohol consumption and various cardiovascular conditions are now evident, with complex interrelationships between conditions. An inverse relationship of alcohol use to coronary heart disease is supported by many population studies. Interpretation of these data as a protective effect of alcohol against coronary disease is strengthened by plausible mechanisms. Although some experimental data suggest the hypothesis that wine, in particular, has additional protective benefit, prospective studies show no consensus on this point. Strong, consistent epidemiologic data support a relationship of heavier drinking to hypertension. Intervention studies show a pressor effect of alcohol, which appears and regresses within several days, but a mechanism has not yet been established. As with most aspects of alcohol and health effects, the data do not suggest monotonic relationships of alcohol with these conditions. Thus, amount of alcohol taken is a crucial consideration. Advice to concerned persons needs to take into account individual factors in drinkers or potential drinkers.

This brief review highlights the rise in asthma mortality witnessed in many countries. It outlines the multifactorial character of this phenomenon, which in most instances is a complex interplay between physician, patient, and environment. The pathophysiology of airflow obstruction and in particular the role of hyperinflation are outlined. These data may allow better prediction of who is at risk of fatal asthma (FA). Finally, potential approaches to the prevention of FA are outlined.

Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, and Klebsiella pneumoniae have become increasingly resistant to antimicrobial agents. This chapter reviews the epidemiology of this resistance, its detection in the laboratory, the mechanisms of resistance, and the options for therapy and infection control.

Sunlight exposure produces a variety of adverse cutaneous effects. Erythema, photosensitivity, and immunologic alterations represent acute events, whereas photoaging and carcinogenesis are long-term consequences. These adverse cutaneous sequelae can be minimized by photoprotection in the form of sun avoidance, regular cover-up with clothing, and sunscreen application. This chapter reviews the diagnosis and treatment of sun-related skin disorders and recommendations for reducing photodamage.

The placebo effect yields beneficial clinical results in 60–90% of diseases that include angina pectoris, bronchial asthma, herpes simplex, and duodenal ulcer. Three components bring forth the placebo effect: (a) positive beliefs and expectations on the part of the patient; (b) positive beliefs and expectations on the part of the physician or health care professional; and (c) a good relationship between the two parties. Because of the heavily negative connotations of the very words “placebo effect,” the term should be replaced by “remembered wellness.” Remembered wellness has been one of medicine's most potent assets and it should not be belittled or ridiculed. Unlike most other treatments, it is safe and inexpensive and has withstood the test of time.

In recent years, a completely new mechanism of mutation has emerged in a number of disorders that display perplexing and paradoxical features of genetic inheritance. This mechanism involves the expansion and intergenerational instability of stretches of consecutive identical nucleotide triplets that also exist as shorter stable segments on normal chromosomes. The unstable nature of the trinucleotide segments has solved many of the genealogic puzzles in these disorders and has provided a new tool for predictive testing. Treatments for the disorders await a better understanding of the different pathogenic processes that are triggered by various expanded repeats. The existence of numerous other disorders with peculiarities of genetic inheritance suggests that this mutational mechanism may be a major cause of human inherited disease.

It is important to understand the management of patients with melanoma because of a rising incidence of this cancer in the United States. The most important prognostic factor is tumor thickness. Patients with early melanoma (thickness <1.0 mm) have an excellent prognosis and are effectively treated with narrow local excision (1-cm radius). Those with advanced melanomas (tumor thickness >4.0 mm) have a high risk of metastases and are treated with a wider local excision (2–3 cm). Controversies surrounding the management of patients with intermediate-thickness melanoma (thickness 1–4 mm) center on the issues of local excision and management of regional lymph nodes. Randomized trials have shown that a 2-cm radius of excision will minimize the risk for local recurrence. Although retrospective analyses have indicated a survival advantage for elective regional lymph node dissection, two randomized trials have not shown a benefit for the early removal of lymph nodes. Two more randomized trials are in progress. Techniques are now available to identify the sentinel lymph node, which will help to limit lymph node dissections to those patients with nodal metastases. Postoperative surveillance for recurrence is most effectively performed with a combination of patient self-examination and regular physician examinations rather than frequent X-rays and laboratory tests. Adjuvant therapy has not been proven effective for melanoma patients; however, many investigational trials are available.