In the 1970s chemotherapy has been successfully incorporated into curative primary treatment programs for various adult malignancies so that it is no longer solely palliative treatment for advanced disease. For at least three malignancies and tentatively a fourth (breast and colon carcinoma, osteosarcoma, and melanoma), certain groups of patients have had longer disease-free survival produced by the use of chemotherapy after surgical removal of the primary lesion. The potential impact on cancer mortality from these treatment results is obvious. We review here the fundamental laboratory concepts that have led to human trial of multimodal primary therapy regimens. Data from numerous clinical trials are analyzed, with delineation of the problems encountered in the interpretation of their results.

Bretylium tosylate (Bretylol) has recently been approved for parenteral use against resistant ventricular arrhythmias. The pharmacologic action of bretylium is complex, and its antiarrhythmic action differs significantly from other drugs. Bretylium is an adrenergic neuronal blocking agent taken up selectively at peripheral adrenergic nerve terminals, where it initially releases norepinephrine (sympathomimetic effect) and then produces adrenergic neuronal blockade. It has direct cardiac membrane effect to prolong action potential duration and effective refractory period but, unlike other membrane active antiarrhythmic agents, does not depress conduction velocity or automaticity. Bretylium increases ventricular fibrillation threshold and prevents the decrease in ventricular fibrillation threshold associated with myocardial ischemia. It does not depress myocardial contractility. Clinical studies have shown parenteral bretylium to be effective in suppressing ventricular arrhythmias, particularly recurrent, drug resistant ventricular tachycardia or ventricular fibrillation.

Fever appears to have evolved in vertebrate hosts as an adaptive mechanism for controlling infection. This phenomenon is produced by certain exogenous (largely microbial) stimuli that activated bone-marrow-derived phagocytes to release a fever-inducing hormone (endogenous pyrogen). Endogenous pyrogen, in turn, circulates to the thermoregulatory center of the brain (preoptic area of the anterior hypothalamus) where it causes an elevation in the "set-point" for normal body temperature. Warm blooded animals produced fever by increasing heat production (through shivering) or reducing heat loss (by peripheral vasoconstriction), whereas cold blooded animals do so only by behavioral mechanisms (seeking a warmer environment). This paper discusses current concepts that involve the mechanism of endogenous pyrogen production, the role of central transmittors, and the probable function of fever in combating disease.

The introduction of computed tomography has revolutionized neurodiagnosis. This diagnostic procedure makes it possible to define intracranial anatomy by visualizing structures of different radiodensities. Computed tomography may detect and define the underlying pathologic processes more directly than is possible with other diagnostic procedures and has reduced the need for invasive contrast procedures.

Poststreptococcal acute glomerulonephritis is prototypic of the immunologic glomerulonephritides. It most commonly follows streptococcal infection of the pharynx or skin. The diagnosis is usually not difficult when a nephritic clinical presentation (with such manifestations as hematuria, edema, and hypertension) is associated with serologic evidence of recent streptococcal infection and a depressed serum complement concentration. Currently, however, the nephritogenic antigen(s) has not been identified and has not been shown to be the same antigen for all nephritogenic streptococci; it may not even be a part of the infecting organism. The development of a vaccine to prevent this illness from occurring is therefore still not possible. Whether poststreptococcal acute glomerulonephritis progresses to chronic renal failure is still uncertain. Painstaking laboratory research together with careful, prospective long-term follow-up studies of patients with poststreptococcal acute glomerulonephritis may provide some of the answers to these critical questions.

Eosinophils in the cerebrospinal fluid are an uncommon finding that is most often the result of a helminthic infection of the central nervous system. Information from the recorded literature suggests the differential diagnosis of this clinical observation is relatively limited. Therefore, in the appropriate clinical circumstances, cryptic cases of central nervous system disease might be resolved or the diagnostic possibilities at least narrowed by finding these cells in the cerebrospinal fluid.

Patients troubled by symptoms, regardless of the degree of demonstrable disease, are subject to fources that cause them to amplify, focus upon, and worry about these bodily perceptions. These forces are psychological, sociocultural, or part of the medical care process. Optimal management of the symptomatic and somatizing patient thus entails obtaining psychological information about emotional precipitants, relevant childhood experiences, psychiatric disorders, and the personal meaning of the symptom; searching for the somatizing personality themes of masochism and guilt, hostility, and dependence; understanding the patient's goals in obtaining medical care, such as information and explanation, psychological counseling, or social and administrative intervention; and assessing situational stress, secondary gain, and ethnic and cultural forces that foster the amplification of physical symptoms.

Cushing's syndrome is the common clinical presentation of three unique disorders that give rise to hypercortisolism. In most cases neoplasms underly each of these disorders. Clinical features are highly variable and not accounted for by cortisol alone; indeed, the multihormonal basis for much of the clinical syndrome remains uncertain. Demonstration of sustained, excessive cortisol production is essential and depends on a pattern of repeated measurements and several different procedures. Plasma adrenocorticotropin, although not helpful in establishing the diagnosis, has proved valuable in differentiating the three major entities that cause hypercortisolism. The renewed significance of pituitary microadenomas and their improved detection by sella tomography has accompanied recent, impressive advances in transsphenoidal microsurgery. This may become the preferred treatment for pituitary Cushing's syndrome in the adult, particularly where the appropriate equipment and skills are available; for children, external pituitary irradiation seems to offer safe and effective therapy.

A lack of national health goals has allowed physician manpower policy to be dominated by an expansionist philosophy. Scarce resources have been channeled into the production of specialist physicians trained to provide complex and expensive care for uncommon diseases, using other scare and expensive resources and adding to the steep rise in medical care costs. Society seems to want access to primary care--a lack it views with dismay--and simultaneously fears increasing costs of care. Lack of access plus high cost might lead to rash implementation of other inappropriate policies. Success of policy decisions is pure serendipity if made without reliable and relevant information or based on inappropriate data, such as opinions alone. If information is unavailable, then physician manpower decisions should be delayed or, if made, implemented cautiously.

Advances through basic research have elucidated the disturbances of neurotransmitter function in Parkinson's Dopamine has replaced acetylcholine and norepinephrine as the most studied neurotransmitter, with both conceptual and practical developments, exemplified by the hypothesis of cyclic adenosine monophosphate as a "second messenger," and new therapeutic agents. We now have rationally designed in-vitro and in-vivo tests for the evaluation of dopaminergic compounds instead of entirely empiric screening procedures. We are starting to identify different categories of dopaminergic receptors and to manipulate them selectively, with gains in understanding the physiologic input to the striatum. Crucial questions remain, including how dopamine modulates striatal output and what causes the parkinsonian degeneration of the nigrostriatal pathway. Developing knowledge on synaptic physiology and pharmacology may lead to better therapy.

Prospective data at Framingham and elsewhere have shown conclusively that risk of coronary heart disease in persons younger than age 50 is strikingly related to the serum total cholesterol level. Within so-called normal limits risk has been found to mount over a five-fold range. The impact has been found to be augmented by other risk factors. The contribution of the serum total cholesterol to risk has also been found to be determined by its partition in the various lipoprotein fractions. A relatively large amount of cholesterol in the low-density lipoprotein fraction is atherogenic, whereas that in the high-density fraction appears protective. The independent contribution of very-low density lipoprotein and its triglyceride or cholesterol content has, on the other hand, not been established. The previous position that virtually all of the lipid information pertaining to coronary heart disease resided in the serum total cholesterol must be accordingly modified.

Recently acquired knowledge about vitamin D metabolism has improved our understanding in different varieties of osteomalacia. Many new causes of osteomalacia continue to be found. Radiologic and biochemical changes are not always characteristic and may occasionally be misleading. Bone biopsy after a double tetracycline label is helpful in differentiating osteomalacia from high bone turnover conditions and is recommended in most patients with a generalized rarefying skeletal disorder. Even if the underlying disease state cannot be corrected, effective therapy is available in most varieties of osteomalacia. The newer metabolites of vitamin D should soon be generally available to the medical profession. Their use will make treatment of osteomalacia more individualized and specific.

Androgens are effective therapeutic agents in postmenopausal women with metastatic breast cancer. Early studies with testosterone propionate showed objective regression rates of slightly more than 20%. Subsequent work with synthetic androgens has failed to show a significant reduction in toxicity or an increase in therapeutic efficacy over testosterone propionate. Calusterone (7 beta,17 alpha-dimethyltestosterone), in early clinical trials, showed both of these qualities and was believed by some to be the "ideal androgen." As with many new drugs, subsequent work failed to confirm these early findings, and most of the later data gathered on calusterone are inconsistent. We conclude from our knowledge at present that calusterone offers no real advantages or disadvantages over other androgens in the treatment of breast cancer.

Recent advances in development of immunoassay methods for marijuana constituents in body fluids provide a rapid means of detection for forensic purposes and a useful research tool for accurate quantitation of dose-response relation. Therapeutic possibilities of cannabis, such as reduction in intraocular pressure and bronchodilatation, may stimulate development of synthetic cannabinoid derivatives that meet acceptable standards of safety and effiicacy for treatment of glaucoma and asthma. Cannabis use may have harmful short- and long-term impacts on health. Potentially serious short-term effects include predisposition to angina during exercise in patients with coronary artery disease. Even in healthy subjects, marijuana smoking decreases peak exercise performance, possibly because of its chronotropic effect with achievement of maximum heart rate at reduced work loads. Although no conclusive evidence exists for long-term biologic consequences of chronic cannabis use, preliminary evidence, suggesting impairment in pulmonary function and immune responses, requires further investigation with large-scale epidemiologic studies.

For a decade gentamicin has been used extensively because of its antimicrobial efficacy and the relatively low prevalence of clinical toxicity. Recently the more frequent appearance of resistant organisms, reports of increased nephrotoxicity and ototoxicity, and the development of newer aminoglycoside antibiotics have raised doubts about the continued use of this agent. This paper reassesses the role of gentamicin. It is clear that an appreciation of the pharmacokinetics and the clinical use of gentamicin as well as an understanding of the patterns of toxicity in animals and humans can lead to more efficient treatment with this antimicrobial agent. Despite ample competition from a number of newer aminoglycoside antibiotics, gentamicin will probably continue to be used widely in the near future.

Hypothermia, defined as a core temperature less than 35 degrees C, is frequently not recognized, in part because of the inadequacy of standard thermometers. This entity has multiple causes and unique pathophysiologic consequences that complicate diagnosis and treatment. Understanding of the physiology of thermoregulation is important in light of recent advances in therapy using core rewarming. Pathophysiology, etiology and management of the hypothermia syndrome are reviewed.

Phagocytosis is a cellular function relevant for host defense against infection, tissue turnover, and other aspects of human physiology. Phagocytosis is also representative of functions wherein external stimuli activate motile events in the cell. Recognition of suitable objects by the plasma membrane of the phagocyte initiates phagocytosis. Knowledge of serum proteins that coat objects rendering them recognizable is considerable, but understanding of the chemical basis of recognition is meager. The signals activated by recognition are also not known. The work of phagocytosis that causes pseudopodia to enclose objects in vacuoles is ascribable to metabolic energy-dependent interactions between actin filaments and other contractile proteins in the peripheral cytoplasm. These interactions may also regulate the fusion of lysosomes with phagocytic vacuoles, an event important for the processing of ingested objects after phagocytosis.

Giving up in the face of emotional arousal and psychologic uncertainty are conditions conducive both to vasodepressor syncope and sudden death. Under such circumstances there may be simultaneous activation of two emergency biologic regulatory systems, flight-fight and conservation-withdrawal. In the healthy person this may result in vasodepressor syncope, benign arrhythmias, or both. In the presence of factors lowering the threshold for conduction disturbances, dangerous arrhythmias and sudden death rather than, or as well as, vasodepressor syncope may result. Although active myocardial damage by itself may provide the necessary and sufficient conditions for lethal arrhythmias, psychic uncertainty must be considered an additional risk factor. The implications of this concept for patient care and prevention of sudden death are a challenge for future research.