Humoral regulation of somatic and hematopoietic cell growth has been intensely investigated during the past decade. Growth hormone is unique because it regulates the size of the person within the constraints of the genetic program. The somatomedins and insulin growth factors are low molecular weight polypeptides believed to mediate some functions of growth hormone. Epithelial growth factor and nerve growth factor are well-characterized polypeptides that influence the growth and differentiation of epithelial and neural tissues and interact with specific cell surface receptors. The hematopoietins are a family of polypeptide hormones that specifically regulate the proliferation and differentiation of stem cells giving rise to erythrocytes, granulocytes, monocytes, megakaryocytes, and B and T lymphocytes. Platelet-derived growth factor modulates the proliferation of fibroblasts in vitro and may have a role in the development of atherosclerosis and myelofibrosis. New knowledge on the biochemistry and physiology of growth factors will probably have a substantial impact on our understanding of human diseases involving abnormal cell growth.

The clinical involvement of membrane receptors for hormones, neurotransmitters, and other molecules of interest is reported with increasing frequency. In this review, the terminology of the hormone-receptor field is defined, and the current concepts of the participation of membrane receptors in the mechanism of hormone action are outlined. Several major developing concepts of receptor regulation and function, including spare receptors and down regulation of receptor number, provide a basis for understanding the physiology and pathophysiology of cellular sensitivity to specific hormones. The relation of these concepts to the pathophysiology of various metabolic disorders is discussed. Clinical disorders in which membrane receptors play a central role are reviewed, including Graves' disease and myasthenia gravis, which involve antireceptor antibodies, and familial hypercholesterolemia and various conditions of hormone resistance that often involve a marked decrease in receptor number as the primary pathogenic factor. The significance of receptor physiology in other selected areas of clinical medicine is discussed.

Viral hepatitis is still the most serious post-transfusion complication. Despite the routine screening of donor blood for the hepatitis type B surface antigen in the United States, post-transfusion hepatitis develops in approximately 7% of blood recipients. Type B hepatitis accounts for only 10% to 15% of cases; non-A, non-B hepatitis constitutes the remainder. Non-A, non-B hepatitis is usually asymptomatic and anicteric but often runs a prolonged course manifested by persistent or intermittent elevations of alanine aminotransferase levels. The risk of developing non-A, non-B hepatitis is increased considerably when blood from paid rather than volunteer donors is transfused. Although there are currently no definitive preventive measures that can be used to reduce the attack rate, the possibility of developing a serologic test fot the non-A, non-B agent is under active investigation.

Recent advances in understanding the physiologic and biochemical bases for recruitment of phagocytes to inflammatory sites has led to the recognition of patients who have recurrent infections because of abnormalities of phagocyte chemotaxis. In some of these patients there is abnormal chemoattractant mediator production or regulation, whereas in others there are defects in phagocytic cell function. The cellular defects in chemotaxis can be characterized as either intrinsic defects of the cellular motility apparatus or acquired defects from mediators influencing cell function or from shifts in circulating phagocyte subpopulations. Systematic study of these defects has resulted in functional, biochemical, and ultrastructural characterization of abnormal phagocyte chemotaxis in certain patients, and in some patients study has led to rational approaches for treatment. Clinical trials assessing the efficacy of such pharmacologic agents are underway.

Patients with active sarcoidosis (acute and chronic) have a depression in systemic cell-mediated immunity manifested by a reduction in the number of circulating T cells and impaired responses of these cells to polyclonal mitogens and recall antigens. These abnormalities are absent in patients with resolved disease and contrast with heightened B-cell activity. The latter includes elevated serum immunoglobulins and the presence of autoantibodies and circulating immune complexes. Similarly, many humoral abnormalities (for example, immune complexes) are absent in patients with resolved disease. Studies of bronchoalveolar cells have revealed changes that are opposite to what is found in peripheral blood. The number of lymphocytes recovered by bronchoalveolar lavage is increased. This is mainly due to an increase in the number of T cells and a subpopulation of activated T cells. These findings suggest that the lung (when involved) is the site of an immune inflammatory response.

Pemphigus is an autoimmune intraepidermal bullous disease involving the skin and mucous membranes. There are four clinically recognized variants of this disease. The histopathologic hallmark is acantholysis, which is disruption of normal cell-to-cell adhesion. Patients produce an IgG antibody directed against an antigen present in the intercellular substance of the epidermis. The antibody binds to the intercellular spaces in vivo and can be frequently detected in patients' sera. Immunofluorescent examination of perilesional tissue and serum is an extremely valuable diagnostic technique. Recently, pemphigus-like lesions have been produced in skin explants grown in tissue culture media enriched with pemphigus serum. Before corticosteroid therapy was available, pemphigus was a fatal disease. Steroids, and more recently immunosuppressive agents, have drastically improved the prognosis.

A penicillin-aminoglycoside regimen is accepted therapy for enterococcal endocarditis, but use of combinations of antibiotics in other forms of bacterial endocarditis is controversial. This review analyzes in-vitro, experimental animal model, and clinical studies of combination "synergistic" antibiotic treatment for enterococcal, viridans streptococcal, staphylococcal, and gram-negative aerobic bacillary endocarditis. Current recommendations for treatment of these entities are discussed.

The roles of changes in cellular redox, interorgan lactate flux and balance, and quantitative aspects of lactate metabolism in the pathogenesis of lactic acidosis are discussed. Altered metabolism of pyruvate is central to the development of lactic acidosis and hyperlactatemia. Lactic acidosis occurs as a result of a relative or absolute imbalance in lactate production and utilization. Lactate utilization for oxidative purposes and for the resynthesis of glucose is essential for the maintenance of acid-base balance. Because of its role in lactate homeostasis the liver may play a central role in acid-base balance. Impairment of hepatic utilization of lactate may produce lactic acidosis.

Clonidine represents the prototype of a new class of centrally acting antihypertensive agents, classed as partial alpha-adrenergic antagonists. Blood pressure reduction is characterized, hemodynamically, by reduced cardiac output with unchanged peripheral vascular resistance at rest. Reflex control of blood pressure during orthostasis and exercise appears to be unimpaired, and orthostatic hypotension is uncommon. As with most other antihypertensive agents, satisfactory reduction of blood pressure with clonidine given as a sole agent is limited to patients with relatively mild hypertension; an additive or synergistic effect of diuretic administration has been well documented. Abrupt withdrawal of clinidine has been reported to be followed, within 24 to 36 h, by rebound hypertension, tachycardia, cardiac arrhythmias, and other changes suggestive of sympathetic overactivity. The incidence and clinical significance of rebound hypertension after abrupt cessation of clonidine therapy, and indeed the profile of blood pressure responses to varying physical activity during therapy, remain to be evaluated.

Thalassemia major is a severe and transfusion-dependent anemia that occurs in persons homozygous for a mutation that affects the capacity for synthesis of the beta-globin subunit of hemoglobin. Characterization of the molecular defects that cause beta-thalassemia is providing insight into the mechanism of globin gene regulation. Newer approaches to the management of thalassemia major include more effective chelation by use of subcutaneous desferrioxamine and attempts to obtain young erythrocytes with a longer potential for survival in recipient patients. Development of more effective chelators that may be given orally is an ongoing effort. Noninvasive evaluation of cardiac structure and function in patients with thalassemia major suggests that myocardial iron deposits begin at an early age, causing functional impairment long before the onset of clinical symptoms. Prevention or reversal of these cardiac abnormalities remains the goal of chelation therapy.

Ibuprofen was introduced in England in 1967 and in the United States in 1974 as an anti-inflammatory drug in humans. It has weak but definite anti-inflammatory properties similar to those of aspirin, milligram for milligram, but with considerably less adverse effect on the stomach. Ibuprofen is chemically related to fenoprofen and naproxen, but lack of effect for any one in this chemical class of propionic-acid derivatives does not necessarily mean lack of effect for any other in an individual patient. The drug has analgesic properties, probably related to its anti-inflammatory effect. It inhibits prostaglandin synthesis and has no effect on the adrenopituitary axis, making it a nonsteroidal agent. Ibuprofen has been shown to be effective in rheumatoid arthritis and osteoarthritis and is probably effective in ankylosing spondylitis, gout, and Bartter's syndrome.

A fundamental abnormality in acute myeloid leukemia is a block in cell differentiation with resultant accumulation of immature leukocytes. This abnormality can be studied in continuously growing leukemic cell lines that differentiate with simple chemical signals. Surface antigenic modulation occurring with cell differentiation can be monitored by specific antisera. These antisera have great potential as diagnostic and therapeutic reagents. More than 90% of patients with acute lymphoblastic leukemia and more than 70% of patients with acute myeloid leukemia can achieve remission of disease with aggressive multiagent chemotherapy. Long-term, disease-free survival is obtainable in about one half of patients with acute lymphoblastic leukemia but in less than 15% of patients with acute myeloid leukemia. The future directions of research for achieving cure of acute leukemia seem to be well defined.

Molecular analysis of normal and abnormal human globin genes and their gene products has recently provided information on the precise genetic events that result in hemoglobinopathies. In the case of structurally abnormal hemoglobins, the following mechanisms can be invoked: single nucleotide base substitutions leading to amino acid replacement or chain termination variants; nucleotide deletions (or additions) leading to deletion and frameshift variants; and nonhomologous crossing over leading to the production of fused globin chains. The molecular basis of the thalassemia syndromes, disorders characterized by absent or decreased synthesis of alpha- or beta-globin chains, is quite heterogeneous. In some cases globin gene deletions have been demonstrated; whereas in others there is probably either a defect in globin gene transcription or a defect in nuclear globin messenger RNA (mRNA) processing, mRNA transport or globin mRNA stability. In one form of beta(0)-thalassemia a nonsense mutation has recently been demonstrated, and other cases are also associated with some as yet undetermined functional abnormality of beta-globin mRNA.

Interferons, cell glycoproteins synthesized in response to viral infections and various nonviral inducers, have proved therapeutically effective for viral infections in experimental models and in humans. Current evidence suggests interferons may also prove effective as antitumor agents in humans. Potent effects on cellular function result from interferons. Cell surface structure and enzyme levels are altered. Immunologic responses thought to be important in tumor immunity are augmented. Interferons have antiproliferative effects on the replication of normal and neoplastic cells. Interferons are effective in animals against tumors of both viral and nonviral origin. Clinical trials in cancer have been limited by the availability and cost of human interferons. However, results in small numbers of patients have been encouraging. This paper review experimental and clinical findings regarding the rationale for use of interferons in neoplastic disease.

Coronary artery spasm is an important pathogenetic mechanism in some forms of myocardial ischemic disease. Factors that may be important in the genesis of spasm include the autonomic nervous system, prostaglandins, endoperoxides, thromboxanes, and the calcium availability to the contractile apparatus. Spasm results in myocardial ischemia with attendant chest pain and electrocardiographic and hemodynamic changes; it is the primary pathogenetic mechanism in Prinzmetal's variant angina and has been found in association with classic angina pectoris and acute myocardial infarction. Diagnosis of coronary artery spasm is firmly made only by coronary angiography. Treatment includes the use of both short- and long-acting nitrates and the slow-channel blocking agents such as verapamil, nifedipine, and perhexiline.

The size and molecular composition of circulating immune complexes depend on various factors, including the concentrations and valences of antigens and antibodies and the antigen-antibody ratio. The composition and biological properties of circulating immune complexes, in turn, influence their fate in vivo as well as the likelihood of their detection by various assays. Several assays clearly detect circulating immune complexes, but no single assay has yet been shown to be the most sensitive and the most specific for the entire spectrum of circulating immune complexes. Assays correlate poorly with each other, but this may be desirable if we are to determine which circulating immune complexes have diagnostic, prognostic, or pathogenic importance. Circulating immune complexes are found in numerous rheumatologic disorders and infectious diseases. Their presence in the circulation statistically correlates with disease activity; however, the assays currently used have limited value for diagnosing or aiding in therapeutic decisions. Nevertheless, the future holds promise for such uses.

After approximately 5 years of clinical use in Great Britain and other European countries, trimethoprim-sulfamethoxazole in fixed-dose combination was introduced into the United States in 1973. As a result of sequential blockade in the biosynthesis of tetrahydrofolic acid, the antimicrobial activity of the combination exceeds that of either agent alone. Although the drug is approved for use in only chronic urinary-tract infection, otitis media, shigellosis, and Pneumocystis carinii pneumonia, many experimental clinical trials suggest that this agent may be useful in a number of other infectious disorders. Trimethoprim-sulfamethoxazole is generally well tolerated even with long-term administration, but its potential for hematologic toxicity and nephrotoxicity must be monitored.

A remarkable development in primary care is the recent emergence of a new class of health professional: nurse practitioners and physician's assistants. These practitioners diagnose and treat a wide variety of medical problems, usually with supervision by physicians. Their clinical competence has been evaluated in over 40 studies. Twenty-one studies in which care given by nurse practitioners or physician's assistants was directly compared with that given by physicians are analyzed. These studies show that nurse practitioners and physician's assistants provide office-based care that is indistinguishable from physician care. Because these studies were limited in scope, there is no experimental basis for extending this conclusion to care given outside the office, care that is unsupervised, or care of the seriously ill patient.

Recently developed radioligand binding techniques permit direct investigation of the alpha- and beta-adrenergic receptors for catecholamines in a wide variety of tissues. These techniques allow the receptors to be quantitated, characterized, and studied under varying conditions of physiologic and pathophysiologic interest. They are providing fresh insights into the mechanisms by which endogenous catecholamines and other hormones regulate the properties of the adrenergic receptors and, in turn, control tissue sensitivity to catecholamine action.