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.

Nitric oxide is a unique biological messenger molecule. It is produced by endothelial cells to mediate blood vessel relaxation; it mediates, in part, the immune functions of activated macrophages; and in the central and peripheral nervous system it serves as a neurotransmitter. In the nervous system, nitric oxide may regulate neurotransmitter release, it may play a key role in synaptic plasticity and morphogenesis, and it may regulate sexual and aggressive behavior. Under conditions of excessive formation, nitric oxide is emerging as an important neurotoxin.

X-linked severe combined immunodeficiency (XSCID) is an inherited disease characterized by profoundly diminished cell-mediated and humoral immunity. XSCID was found to result from mutations in the interleukin-2 (IL-2) receptor γchain. Knowledge of the genetic defect has important implications for prenatal and postnatal diagnosis, carrier female identification, and the possibility of gene therapy. The fact that the phenotype and clinical manifestations in XSCID are more severe than the abnormalities found in humans or mice deficient in IL-2 led to the speculation and subsequent confirmation that the IL-2 receptor is not the only receptor to contain the γ chain. Instead, the γ chain is also a component of the receptors for IL-4, IL-7, IL- 9, and IL-15 and is now denoted as the common cytokine receptor γ chain, γc. The role of γc in signaling and lymphoid development and the implications of a shared receptor component are discussed.

Fatigue is a prominent symptom in patients with chronic heart failure, limiting physical activity and impairing quality of life. Although the underlying mechanisms are not clearly identified, alterations associated with peripheral adaptation in heart failure appear to play an important role, including a variably impaired peripheral perfusion during exercise, reduced oxidative capacity of skeletal muscle, impaired muscle strength, and possibly reflex mechanisms associated with alterations in the metabolism of skeletal muscle. Exercise training can, in part, reverse these peripheral alterations, improve exercise capacity, and alleviate fatigue.

Hepatitis E has a worldwide distribution and causes substantial morbidity and mortality in some developing countries, particularly among pregnant women. Hepatitis E virus (HEV) has recently been cloned and sequenced and new diagnostic tests have been developed; these tests have been used to begin to characterize the natural history and epidemiologic features of HEV infection. Experimental vaccines have also been developed that offer the potential to prevent hepatitis E. However, to develop effective strategies to prevent this disease, much remains to be learned about HEV, including the vehicles of transmission, the reservoir(s) of the virus, and the natural history of protective immunity.

High-altitude pulmonary edema (HAPE) occurs in unacclimatized individuals who are rapidly exposed to altitudes in excess of 2450 m. It is commonly seen in climbers and skiers who ascend to high altitude without previous acclimatization. Initial symptoms of dyspnea, cough, weakness, and chest tightness appear, usually within 1–3 days after arrival. Common physical signs are tachypnea, tachycardia, rales, and cyanosis. Descent to a lower altitude, nifedipine, and oxygen administration result in rapid clinical improvement. Physiologic studies during the acute stage have revealed a normal pulmonary artery wedge pressure, marked elevation of pulmonary artery pressure, severe arterial unsaturation, and usually a low cardiac output. Pulmonary arteriolar (precapillary) resistance is elevated. A working hypothesis of the etiology of HAPE suggests that hypoxic pulmonary vasoconstriction is extensive but not uniform. The result is overperfusion of the remaining patent vessels with transmission of the high pulmonary artery pressure to capillaries. Dilatation of the capillaries and high flow results in capillary injury, with leakage of protein and red cells into the alveoli and airways. HAPE represents one of the few varieties of pulmonary edema where left ventricular filling pressure is normal.

The capacity for malignant growth is acquired by the stepwise accumulation of defects in specific genes regulating cell growth and tissue homeostasis. Although several hundred genes are known to control growth, molecular genetic studies in cancer show that few of these are consistently involved in the natural history of human cancer, and those typically in only certain types of malignancy. Prospects for development of molecular-based diagnostic and therapeutic strategies with widespread application did not look promising, until it was realized that the p53 tumor suppressor gene was defective in approximately half of all malignancies. This discovery generated research efforts of unparalleled intensity to determine how p53 functions at the molecular level, and how to apply this knowledge to clinical ends.

Two important types of antineutrophil cytoplasmic antibodies (ANCA) have been identified: anti-proteinase 3 and anti-myeloperoxidase antibodies. In the appropriate clinical setting, the presence of either is virtually diagnostic of the subset of vasculitis that includes Wegener's granulomatosis, microscopic polyangiitis (microscopic polyarteritis), the Churg-Strauss syndrome, idiopathic pauci-immune necrotizing and crescentic glomerulonephritis, and related and overlapping forms of these vasculitidies. The finding of ANCA throughout this group identifies these syndromes as belonging to a single category or spectrum of disease.

Vascular endothelium is strategically located at the interface between tissue and blood. It is pivotal for protecting against vascular injury and maintaining blood fluidity. Normal endothelium releases prostacyclin and nitric oxide, potent inhibitors of platelet and monocyte activation and vasodilators. Their syntheses are governed by isoforms of enzymes. Normal endothelial surface expresses ecto-adenosine diphosphatase, which degrades adenosine diphosphate and inhibits platelet aggregation; thrombomodulin, which serves as a binding site for thrombin to activate protein C; and heparin-like molecules, which serve as a cofactor for antithrombin III. Normal endothelium secretes tissue plasminogen activator, which activates the fibrinolysis system. Endothelium produces and secretes von Willebrand factor, which mediates platelet adhesion and shear-stress-induced aggregation. Injury to endothelium is accompanied by loss of protective molecules and expression of adhesive molecules, procoagulant activities, and mitogenic factors, leading to development of thrombosis, smooth muscle cell migration, and proliferation and atherosclerosis.

Many studies are in progress worldwide to elucidate the genetics of complex diseases. Nevertheless, few articles are available that provide the scientific rationale and give guidelines for such ambitious endeavours. We describe the methodology and background necessary to study the genetics of complex disease and discuss how to analyze the data. We also provide a table of some ongoing studies. In particular, we wish to emphasize the analysis of intermediate, heritable, quantitative traits as a means of dissecting the genetic basis of a complex trait.

Five species of Bartonella have been found to infect humans, henselae, quintana, elizabethae, bacilliformis, and vinsonii. The most common of these in North America are Bartonella quintana and Bartonella henselae, the agents of trench fever, bacillary angiomatosis, and parenchymal peliosis, and in the case of B. henselae cat-scratch disease. B. bacilliformisis endemic in Peru and Ecuador, where it causes oroya fever or Carrion's disease. New methods of diagnosing Bartonella infections have resulted in increased recognition of the many manifestations of these infections. Early recognition is crucial, as these are potentially fatal opportunistic infections that usually respond rapidly to appropriate antimicrobial therapy.

Nitric oxide (NO), the biologically active component of endothelium-derived relaxing factor, has critical roles in the maintenance of vascular homeostasis. Decreased endothelial NO production, as a result of endothelial dysfunction, occurs in the early phases of atherosclerosis. NO appears to inhibit atherogenesis by inhibiting leukocyte and platelet activation and by inhibiting smooth muscle cell proliferation. Endothelial denudation is a prominent feature of vascular injury associated with percutaneous angioplasty, and decreased NO production appears to contribute to the restenosis process. Manipulation of the NO/cGMP signal transduction system may provide novel therapeutic approaches for limiting atherogenesis and neointimal proliferation in the future.

Goodpasture's, or anti-glomerular basement membrane, disease is an uncommon, usually severe disease caused by autoimmunity to a component of certain basement membranes. Alport's syndrome is an inherited, degenerative disorder that affects specific basement membranes. The two are linked by the involvement of type-IV collagen (basement membrane collagen) in their pathogenesis.

Alzheimer's disease (AD) is unique in medicine in that millions of people suffer from what appears to be the same form of disease, and unlike most other late-onset diseases, the genetic etiologies have been well identified. Three early onset forms of AD inherited as autosomal dominant traits account for less than 2% of prevalent AD. A major susceptibility locus, apolipoprotein E (APOE, gene; apoE, protein) is associated with risk and age of onset distributions for the common familial and sporadic late-onset AD. The identification of additional genetic susceptibility genes in the etiology of AD and the metabolic mechanisms leading to differences in age of onset and disease pathogenesis are active areas of current research.

Risk factor intervention is a useful strategy for prevention of poorly understood diseases. Fifteen studies have examined the relation of glucocorticoid and nonsteroid antiinflammatory treatments and onset or progression of Alzheimer's disease (AD). Fourteen of these studies suggest that such treatments (especially nonsteroidal agents) prevent or ameliorate symptoms of AD. Abundant circumstantial evidence implicates inflammation in the pathogenesis of AD. Inhibition of cyclooxygenases, the central action of nonsteroidal antiinflammatory drugs (but not a prominent effect of steroids), limits inflammation, but it may also alter neural metabolic pathways, resulting in cell death from excitotoxicity or oxidative stress. Randomized controlled trials are needed to determine whether steroids, nonsteroidal antiinflammatory drugs, or both can prevent or treat the symptoms of AD.

Peripheral blood leukocytes interact with the vascular endothelium in a wide range of physiologic and pathophysiologic situations. A current working concept is that activation of vascular endothelium is an important event during the inflammatory response, conferring spatial and temporal localization and leukocyte-type selectivity to the recruitment process. This chapter highlights recent advances in our understanding of the endothelial-dependent molecular mechanisms that mediate recruitment of mononuclear leukocytes (lymphocytes and monocytes) and discusses these advances in the context of chronic inflammatory diseases and their potential therapeutic interventions.

Lipoprotein(a) [Lp(a)] represents an important independent risk factor for atherosclerotic cardiovascular disease. Lp(a) constitutes a class of low-density lipoprotein-like particles that are structurally heterogenous due to variability within the distinguishing apoprotein, apolipoprotein(a) [Apo(a)]. Apo(a) bears a high degree of homology to the fibrinolytic zymogen, plasminogen, the parent molecule of the serine protease plasmin. Apo(a) contains a variable number of tandemly repeated triple-loop units called kringles, which appear to mediate Lp(a)'s interactions with fibrin and cell surface receptors. Although the mechanism of its atherogenicity is unknown, Lp(a) has been implicated in the delivery of cholesterol to the injured blood vessel, in blockade of plasmin generation on fibrin and cell surfaces, and as a stimulus for smooth muscle cell proliferation. In addition, new members of the plasminogen/Apo(a) gene family have been defined, creating a potential link between Lp(a) and the control of angiogenesis in both health and disease. Pharmacologic therapy of elevated Lp(a) levels has been only modestly successful; apheresis remains the most effective therapeutic modality.

The diagnosis of endogenous Cushing's syndrome requires demonstration of an increased cortisol secretion rate, best achieved by urinary free cortisol excretion determinations. In borderline or confusing cases, loss of diurnal cortisol rhythmicity, a combined dexamethasone/corticotropin releasing hormone (CRH) test, or close monitoring of the patient for a few months will be helpful in ruling out pseudo- Cushing's. Primary adrenal Cushing's syndrome can be ruled out on the basis of a normal or elevated basal and/or CRH-stimulated plasma adrenocorticotropin (ACTH) and a negative adrenal computed tomography. ACTH-dependent Cushing's syndrome can then be differentiated on the basis of a CRH test and imaging procedures. A discrete pituitary lesion on magnetic resonance imaging and a standard CRH test with results consistent with such a lesion are sufficient to proceed to transsphenoidal surgery. If no discrete pituitary lesion is present, or if the CRH test is equivocal, bilateral simultaneous inferior petrosal sinus sampling with CRH administration is necessary to distinguish between a pituitary and an ectopic source. Surgery is the treatment of choice for all types of Cushing's syndrome. In the few cases in which transsphenoidal surgery fails or the disease recurs, repeat transsphenoidal surgery, or radiation therapy in association with mitotane treatment, is a reasonable alternative. Bilateral adrenalectomy effectively cures hypercortisolism if resection of the ACTH-secreting tumor is unsuccessful and radiation/medical therapy fails.

This article describes the use of probability in reasoning about diagnostic test results and the importance of accurate measures of test performance. Most studies of test performance are retrospective analyses of unplanned observations. Retrospective studies are likely to result in biased estimates of test performance. This article shows how to adjust for biases in the results of retrospective studies and how to design a prospective study that will accurately measure the sensitivity and specificity of a test.

Recent national epidemiologic studies have provided data on the number of people in the United States with mental and addictive disorders. Many of these people receive their care in the general medical care sector. This has important implications for diagnosis and treatment of mental and addictive disorders.

Cellular immune reactions play a major role in the host reaction to growing cancers. Tumor infiltrating lymphocytes (TIL) can be isolated from melanomas and can specifically recognize unique tumor antigens. The adoptive transfer of TIL plus interleukin-2 can mediate tumor regression in patients with metastatic melanoma. TIL capable of mediating tumor regression have been used to clone and sequence a variety of the genes that encode the tumor-regression antigens recognized by these TIL. This information has opened new opportunities for the development of cancer immunotherapies. These gene products can be used to generate lymphocytes, in vitro, with improved antitumor activity for use in adoptive transfer. Active immunization can be performed using either the immunodominant peptides present in these proteins or by incorporating the tumor antigen genes into recombinant viruses. Cancer vaccine trials using many of these approaches have recently begun. Attempts to apply a similar strategy to epithelial tumors such as breast and ovarian cancer are underway.

The persistence of cigarette smoking despite widespread awareness of adverse health effects results from an underlying addiction to nicotine. Unaided attempts to quit smoking are generally unsuccessful. This article discusses nicotine addiction and therapeutic techniques that have been or are being developed to relieve smoking withdrawal symptoms and promote abstinence from smoking. These techniques include nicotine chewing gum, skin patches, nasal sprays, and inhalers, as well as pharmacotherapies such as mecamylamine and clonidine, serotonergic treatments such as buspirone, and antidepressants such as buproprion. A nondrug approach using cigarette substitutes that mimic the airway sensations produced by cigarette smoke is also discussed.

Both genetic and environmental factors contribute to the etiology of non-insulin-dependent diabetes. The genetic component is heterogeneous and in some patients is probably complex, involving multiple genes. Specific genetic defects have been identified for rare monogenic forms of NIDDM: maturity-onset diabetes of the young, or MODY (which is due to glucokinase mutations in about 40% of families), syndromes of extreme insulin resistance (which often involve the insulin receptor), and diabetes-deafness syndromes (with defects in mitochondrial genes). In contrast, the genes involved in common forms of NIDDM are still uncertain. Mutations have been extensively searched in genes regulating insulin signaling and secretion. Some evidence of involvement has been produced for insulin-receptor substrate-1, glycogen synthase, the glucagon receptor, a ras-related protein (Rad), histocompatibility antigens, PC-1, and fatty acid binding protein, but the contribution of these genes to NIDDM is probably small. Other candidate genes (e.g. insulin, insulin receptor, glucose transporters) have been excluded as major diabetogenes. New insights are expected in the near future from the systematic scanning of the genome for linkage with NIDDM.

Lupus anticoagulants and anticardiolipin antibodies have been strongly associated with the risk of thrombosis, recurrent fetal loss, thrombocytopenia, and a number of other clinical manifestations that together have been referred to as the antiphospholipid syndrome. Despite growing evidence of the significance of this relationship, the pathogenetic mechanisms involved are largely unknown. Recent data suggest strongly that lupus anticoagulants (LACs) and anticardiolipin antibodies (ACAs) are antibodies to protein-phospholipid complexes rather than to phospholipids, as had originally been thought, and that other protein-phospholipid complexes, not recognized by standard assays for LACs or ACAs, may also exist in patients with the antiphospholipid syndrome. Although very recent experimental data may lead to new therapeutic approaches in this syndrome, at present we can only deal with the thrombotic risk by the use of long-term anticoagulation. This chapter reviews current methods of diagnosis, concepts of pathogenesis, and the basis for an approach to anticoagulation in patients at risk for thrombosis or other manifestations of the antiphospholipid syndrome.

Acute promyelocytic leukemia, formerly a highly lethal disease, was recently shown to be highly responsive to treatment with the natural retinoid, all-trans retinoic acid. This compound induces terminal differentiation of the malignant cells and produces complete remission in most patients with this disease. The clinical response is due in part to the presence of a chromosomal break that occurs in a gene that encodes a nuclear retinoic acid receptor.