Cisplatin is a coordinate metal complex with significant antineoplastic activity and various effects, including acute anc chronic renal insufficiency and renal magnesium wasting. Nephrotoxicity may occur in as many as 50% to 75% of patients receiving the drug, and is apparently due to renal tubular injury. Although controlled, prospective clinical trials are lacking, the available data indicate that the frequency and severity of cisplatin nephrotoxicity may be reduced by slow infusion rates; hydration before, during, and immediately after administration of cisplatin; and concomitant administration of mannitol. Preliminary animal studies indicate that chloride-containing vehicles such as 0.9% sodium chloride may prevent the aquation or hydroxylation of cisplatin and reduce its toxicity. No information is available on th prevention of cisplatin associated renal magnesium wasting. However, frequent measurement of serum cations and appropriate replacement are recommended.

Although hospitalizations and deaths attributable to peptic ulcer have decreased notably during the past decade, it is not certain whether this decrease is because of reduced incidence of new cases or changes in other factors, such as the severity of the disease. Several genetic traits associated with peptic ulcer have been recognized. Hyperpepsinogenemia I is the most prevalent. Peptic ulcer is a heterogeneous group of disorders with multiple genetic and environmental causes. One manifestation of the diversity of ulcer disease is the variety of physiologic abnormalities seen in patients. The use of endoscopy has enabled more reliable evaluation of new treatments. Histamine H2-receptor antagonists are the dominant mode of treatment, but increasing attention is being given to agents that enhance the resistance of the mucosa to injury, such as prostaglandins. Because of the lower frequency of side effects, proximal gastric vagotomy is gradually replacing truncal vagotomy with drainage. The possibility that endoscopic treatments, such as laser coagulation, may reduce mortality from bleeding ulcers is being investigated.

Nerve conduction and stimulation studies and needle electromyography are useful in objectively verifying the presence of disease of nerve and muscle. How pathologic alterations in muscle and nerve produce the electrical abnormalities detected by these combined techniques is explored to guide the clinician in distinguishing whether a neuromuscular disorder involves the motor neuron, peripheral nerve axon or myelin, neuromuscular synapse, or muscle; whether the problem is focal or generalized; and whether there is evidence of ongoing disease or repair.

The mechanisms of flushing reactions are pharmacologically and physiologically heterogeneous. Flushing may result from agents acting directly on the vascular smooth muscle or may be mediated by vasomotor nerves. Vasomotor nerves may lead to flushing as a result of events at both peripheral and central sites. In susceptible persons, frequent, intense flushing leads to a cluster of physical signs (rosacea). Flushing provoked by alcohol has been associated with ethnic sensitivity, a possible predisposition to alcoholism, various disulfiramlike agents, one type of diabetes mellitus, and the carcinoid syndrome and other types of neoplasia. Flushing reactions also occur during the menopause, after glutamate ingestion, and in response to oral thermal challenges.

Aplastic anemia is characterized by decreased bone marrow function with inadequate production of erythrocytes, granulocytes, and platelets. Marrow failure may be caused by absence of or defects in hematopoietic stem cells, abnormalities of the bone marrow microenvironment, ineffective cell-to-cell interactions, or immune disorders. Although most patients with aplastic anemia have normal immunity, some have abnormalities of T- and B-lymphocytes. Rare patients have an immune cause of marrow failure. Treatment of aplastic anemia involves blood transfusions and withdrawal of potential causal factors. Efforts to stimulate hematopoiesis with androgens, corticosteroids, and other drugs have been largely unsuccessful. Some patients may recover after treatment with antithymocyte globulin or other immunosuppressive agents. Bone marrow transplantation is the preferred treatment for patients with severe aplastic anemia who have a human-leukocyte-antigen-identical related donor. Transplants of hematopoietic stem cells obtained from alternative sources, such as fetal liver cells or stem cells from long-term, in-vitro cultures, also may be useful.

Nausea and vomiting are frequent and serious toxicities of cancer chemotherapy that have been largely ignored in the past. Recently there has been renewed interest in this significant problem, with important advances in understanding the physiology of vomiting and a burgeoning number of clinical trials that use newer classes of antiemetics. At present phenothiazines are the only class of antiemetics that have shown both efficacy and safety in large numbers of cancer patients, but they are inadequate against strongly emetic agents such as cisplatin. New agents and new approaches have shown promise but need additional testing before they can be recommended for routine use.

Recent studies have provided major new insights into the syndromes of inappropriate secretion of thyroid-stimulating hormone (TSH), a heterogeneous group of disorders in which patients show inappropriately elevated levels of serum immunoactive TSH in the presence of elevated free thyroid hormone levels. Certain of these patients appear to have a non-neoplastic disorder associated with variable degrees of pituitary and peripheral resistance to the action of thyroid hormone, whereas others harbor a tumor of pituitary thyrotropic cells. Measurement of free serum alpha subunit has proved valuable in differentiating these disorders, showing normal alpha concentration and alpha-to-TSH ratios in the non-neoplastic and highly elevated values in the neoplastic disorders. All these syndromes appear unrelated to Graves' disease because thyroid-binding and thyroid-stimulating antibodies are usually absent. Some of these patients also have abnormal metabolism of thyroid hormones. Although the pathogenesis of these syndromes remains to be elucidated, increased recognition and study of these patients should provide fundamental insights into the regulation of TSH secretion as well as the action of thyroid hormone.

The literature on the fluorescent antinuclear antibody (FANA) test, commonly used in diagnosing systemic lupus erythematosus, was analyzed. The specificity of the test reported in early descriptive studies is much greater than the value obtained when the test is used in clinical practice. The probability of systemic lupus erythematosus in a specific patient was determined when different numbers of the classification criteria developed by the American Rheumatism Association are present. The predictive value of a positive or negative FANA test result was calculated using different pretest probabilities based on clinical criteria. The marginal benefit of the FANA test was determined as minimal at points of very large and very small pretest probability of systemic lupus erythematosus, and as maximal when five clinical criteria are present.

A double-masked study was conducted to determine the efficacy and safety of randomly allocated chenodiol (chenodeoxycholic acid, 750 mg/d or 350 mg/d) or placebo administered for 2 years to 916 patients for dissolution of radiolucent gallstones. There was confirmed complete dissolution in 13.5% of patients (750 mg/d), 5.2% (375 mg/d), and 0.8% (placebo), p less than 0.0001. Partial (over 50%) or complete dissolution (by validated roentgenographic metrology) occurred in 40.8% (750 mg/d), 23.6% (375 mg/d), and 11.0% (placebo), p less than 0.0001. Dissolution occurred more frequently in women, thin patients, or patients with small or floating gallstones or serum cholesterol greater than or equal to 227 mg/dL. Clinically significant hepatotoxicity occurred in 3% of patients (750 mg/d), 0.4% (375 mg/d), and 0.4% (placebo), p less than 0.007, and always was reversible biochemically. Elevations of 10% or more of serum cholesterol, mostly low-density lipoproteins, occurred in 85.2% of patients (750 mg/d), 82.8% (375 mg/d), and 67.0% (placebo), p less than 0.001. Chenodiol, 750 mg/d for up to 2 years, is appropriate therapy for dissolution of gallstones in selected patients who are informed of the risks and benefits.

Serious ventricular arrhythmias, a common complication of coronary artery disease, frequently respond to medical management. When pharmacologic and pacemaker therapy fail to control them, however, surgical therapy must be considered. In this review we assess the efficacy of surgical treatment of these arrhythmias. Coronary revascularization fails to reduce the frequency and complexity of ventricular ectopic activity and may exacerbate them. Recurrent ventricular fibrillation due to acute, reversible ischemic events may respond favorably to coronary revascularization. Recurrent ventricular fibrillation associated with recent myocardial infarction when unresponsive to medical therapy can be managed with coronary revascularization and infarctectomy with comparatively good results. Recurrent sustained ventricular tachycardia is not optimally treated with coronary artery bypass grafting and myocardial resection. Operations guided by activation mapping that isolate or destroy the site of origin of the ventricular tachycardia show promise.

The principal function of erythrocytes is the transport of oxygen. Erythropoiesis proceeds at a rate consistent with the demand for oxygen-carrying capacity, and the major regulator of erythrocyte production is erythropoietin. Erythropoietin is produced primarily by the kidney under control of a tissue oxygenation sensor. The recently developed erythropoietin radioimmunoassay should provide a clinically useful tool. Erythrocytosis is a pathologic state characterized by an elevated erythrocyte mass, which may result from increased proliferation of erythroid progenitors due to an intrinsic cellular defect or in response to extrinsic signals. Secondary erythrocytosis results from either physiologically appropriate compensation for inadequate tissue oxygenation or from inappropriate stimulation of erythropoiesis. Erythrocytosis increases oxygen-carrying capacity of the blood, but at high hematocrit levels increased blood viscosity may result in decreased tissue oxygen delivery. Polycythemia vera is a hematopoietic stem cell disease of clonal origin. Initial results from the Polycythemia Rubra Study Group suggest that therapy with chlorambucil is associated with an unacceptably high risk for development of acute leukemia, and 32P is preferred for situations in which phlebotomy alone is insufficient.

Tardive dyskinesia is one of the most prevalent and disabling of the iatrogenic disorders. Characterized by involuntary movements of the orofacial-cervical musculature that develop after prolonged use of neuroleptic drugs, it is sometimes confused with other involuntary movements involving predominantly the head and neck region. In this review the differential diagnosis of the orofacial-cervical dyskinesias is discussed. A therapeutic approach is presented in view of our recent understanding of the possible biochemical mechanisms of tardive dyskinesia.

Whether triggered activity plays a role in the genesis of cardiac arrhythmias is considered in this review. The characteristics of triggered activity are compared with those of automaticity and re-entry at the cellular electrophysiologic level, and these observations then are related to cardiac arrhythmias. We stress, however, that the relation between triggered activity and clinical arrhythmias still is largely speculative and that further experimental and clinical study is needed before the presence (or absence) of a role for triggered activity is verified.

Strict case definitions were applied to 123 clinically diagnosed cases of infective endocarditis. Cases were categorized as definite (19), probable (44), or possible (41) endocarditis or were rejected (19). Compared to other published studies, our patients had an advanced mean age (57), high incidence of underlying valvular disease (66%), short mean duration of symptoms (27 days), and 15% mortality, the lowest reported for a large series. Most cases were caused by viridans streptococci, Staphylococcus aureus, or enterococci; Enterobacteriacae were absent, and negative cultures infrequent (5%). Subgroups included nosocomial endocarditis (13%), usually with underlying valvular disease and invasive procedures; prosthesis endocarditis (12%); and cases requiring cardiac surgery (18%). Deaths were caused by heart failure, neurologic events, or superinfection. Strict definitions are useful in managing suspect cases, and are essential in comparing clinical studies. Early recognition and treatment should be the focus of efforts to reduce mortality from endocarditis.

The clinical and physiologic features of anorexia nervosa seem to be consequences of a complex interaction among psychologic abnormalities, endocrine disturbances, and malnutrition. Although a spectrum of psychologic disorders has been observed, distortion of body image, weight phobia, disordered perception of hunger and satiety, and a sense of ineffectiveness are encountered most frequently. The impaired secretion of luteinizing hormone-releasing factor, release of gonadotropins, and production of estrogens reflect a defect in the hypothalamic-anterior pituitary-gonadal axis. Because most of the endocrine abnormalities are reversible with improved nutrition, they are probably secondary to malnutrition rather than to hypothalamic dysfunction. Hypercarotenemia observed in 16 of 21 patients studied recently seems useful in differentiating anorexia nervosa from other forms of malnutrition and weight loss. A combined medical and psychiatric approach has been successful in drastically reducing the mortality of this disorder.

Sinemet (a combination of levodopa with carbidopa, a dopa-decarboxylase inhibitor) has replaced levodopa for early treatment of parkinsonism. The blocking of the systemic uptake of dopamine has eliminated the previous complications of nausea, vomiting, and cardiac and respiratory arrhythmias; pyridoxine need not now be avoided. However, the earlier appearance of abnormal involuntary movements, hallucinations, occasional psychosis, and a dopa-resistant state limits treatment efficacy. In all-over experience the combination drug offers the best relief for rigidity and akinesia. It has improved the quality of life and reduced mortality by one half. The greatest benefits appear in the first 3 years; then complications set in. The relation of complications to dosage is now better understood, and the ratio of dopa-decarboxylase inhibitor to levodopa inhibitor to levodopa of 1:4 is better than the previous 1:10. Levodopa with or without dopa decarboxylase is not a cure for parkinsonism. Some agonist drugs (bromocryptine, lisuride) are showing promise in the testing stage. The evolving knowledge about neurotransmitters and peptide messengers offers hope for the growing number of patients with parkinsonism.

Recent observations and discoveries necessitate reassessing the pathophysiology of acute myocardial infarction. Platelet aggregability has been shown to be increased in patients with an acute myocardial infarction, and coronary arterial spasm has been documented by arteriography done just before and during the onset of infarction. These clinical observations have been complemented by the recent discovery of two potent substances; thromboxane A2 and prostacyclin, which affect platelet aggregability and coronary arterial tone. These recent observations and discoveries are blended with older pathologic information to attain a more comprehensive understanding of the pathophysiology of acute myocardial infarction. A dynamic interaction among damaged intima, platelet aggregates, and spasm is postulated to occur as a prelude to thrombosis in acute transmural myocardial infarction. Spasm appears to initiate the infarction process in some instances, but the exact sequence of events has not been established.

Epidemiologic studies show that non-Hodgkin's lymphomas tend to develop after prolonged antigenic stimulation, after loss of normal regulation of lymphoid proliferation, or especially after both processes. Study of these tumors in vitro has greatly increased understanding of their pathophysiology and has provided a conceptual framework for their morphologic diversity. Lymphomas are now understood to be expanded clones of their normal counterparts. The anatomic location, phenotypic characteristics, proliferative capacity, and functional capabilities of the neoplasm often reflect those of the equivalent normal cells. If neoplastic transformation can occur at any stage of lymphoid differentiation, then it is theoretically possible that neoplastic lymphocytes may respond, or could be induced, to normal regulatory influences. Further study of selective cytotoxicity may reveal exploitable differences among lymphocytic subpopulations and permit more rational choices of therapy. Of major aid to future clinical trials should be the recent consensus on nomenclature by an international panel of experts.

The histiocytoses are a diverse group of disorders involving cells of the mononuclear phagocyte series. These diseases are usually characterized by proliferation and activation of macrophages caused either by external stimuli or by an intrinsic cellular abnormality. We propose that these conditions be classified as reactive histiocytosis (inciting agent known or unknown), lipid storage disorder, and mononuclear phagocyte neoplasia based on apparent cause and natural history. Recent knowledge of monocyte-macrophage development and function allows for construction of pathophysiologic models of diseases formerly approached in a descriptive fashion. Macrophage activation appears to mediate many clinical features of th histiocytic disorders, such as hemophagocytosis, fever, and osteolysis. Further understanding of the pathogenesis of the histiocytic disorders should lead to improved therapy.