The alveolitis of pulmonary sarcoidosis is characterized by an intense, mononuclear cell infiltrate that probably precedes granuloma formation. Pathogenic mechanisms underlying pulmonary sarcoidosis can be shown by study of the mononuclear cells composing the alveolitis. Bronchoalveolar lavage has shown that the sarcoid lung is characterized by increased numbers of "activated" T-lymphocytes within the alveolar structures. In contrast to normal control cells, the lung T-lymphocytes of patients with sarcoid release the mediator, monocyte chemotactic factor, that probably contributes to the pathogenesis of sarcoidosis by recruiting blood monocytes to the lung, thus providing cellular building blocks for granuloma formation. Conventional monitors of the activity of pulmonary sarcoidosis, such as blood studies, pulmonary function testing, and chest roentgenograms, show little assessed by bronchoalveolar lavage or by histopathologic studies. In contrast, quantification of lavage T-lymphocyte populations and 67Ga scintigraphy of the chest provide a sensitive and specific means of assessing the activity of the alveolitis in pulmonary sarcoidosis and may provide a rational basis for therapy.

Hypersensitivity reactions from cytotoxic agents have not been accorded much attention. Certain drugs (L-asparaginase, cisplatin, intravenous melphalan, topical mechlorethamine, zinostatin, and teniposide) produce reactions often enough to be a clinical problem. Others (cyclophosphamide, doxorubicin, daunorubicin, methotrexate, and procarbazine) do so only occasionally. Bleomycin uniquely produces an occasional hyperpyrexic reaction with clinical findings similar to anaphylaxis. Some cytotoxic agents have never been known to produce hypersensitivity reactions. This paper reviews the frequency and clinical information about such reactions, factors augmenting or decreasing the frequency, and, where possible, the etiologic mechanisms.

Platelets form a plug and promote thrombin generation at sites of vascular injury. These processes are initiated by interaction of the platelet plasma membrane with various substances within or accumulating at the injured vessel. Thus, platelet adhesion to exposed subendothelium requires the binding of von Willebrand factor to platelets. Agonists such as thrombin bind to membrane receptors, thereby stimulating the binding of fibrinogen to platelets and resulting in the aggregation of platelets onto those already adherent to the vessel wall. Agonists also stimulate transfer of membrane=bound calcium into the cytoplasm. This triggers the secretion of granule substances and results in the recruitment of additional platelets to the hemostatic plug. Concomitant with secretion, the platelet surface supports several reactions leading to thrombin generation. Thus, hemostasis requires a series of coordinated responses involving platelet membranes. A defect in any of these responses can lead to a bleeding diathesis.

Minoxidil is an orally active vasodilator for treatment of severe hypertension. In combination with diuretics and beta-adrenergic blocking agents, it is effective treatment for more than 80% of patients whose blood pressure has been inadequately controlled with combinations of other been inadequately controlled with combinations of other antihypertensive drugs. Major adverse reactions include reflex activation of the adrenergic nervous system, renal sodium retention, and hypertrichosis. Despite the possibility of adverse reactions, minoxidil is indicated in patients whose blood pressure cannot be controlled with conventional therapy, in persons with major adverse reactions to other drugs, and in patients who are candidates for bilateral nephrectomy for control of hypertension.

The calcium channel blocking agents have multiple hemodynamic effects that make them potentially valuable in treating many cardiovascular disorders. They are potent dilators of coronary and peripheral arteries and in isolated tissue preparations exert potent negative inotropic, chronotropic, and dromotropic effects. In intact animals the peripheral arterial vasodilatation induces reflex-mediated adrenergic activity, which opposes the direct negative inotropic, chronotropic, dromotropic, and hypotensive effects. The individual calcium channel blockers have different relative potencies on various cardiovascular functions. The net hemodynamic and electrophysiologic effect of each agent, therefore, results from a complex interplay of direct and reflex phenomena. The clinical efficacy of these agents in classic angina pectoris relates to their ability to decrease afterload, myocardial contractility, and heart rate and increase coronary blood flow. The agents have been used to prevent coronary spasm in Prinzmetal's variant angina. The negative inotropic effects of verapamil are valuable in improving the symptoms and hemodynamic disturbances of hypertrophic cardiomyopathy. The role of these agents in treating arterial hypertension, unstable angina pectoris, acute myocardial infarction, and ischemia during cardiopulmonary bypass needs to be determined.

Asthma is not an uncommon medical problem during pregnancy. Various physiologic alterations of pregnancy may theoretically affect asthma. Fetal oxygenation is affected more by maternal alkalosis than by hypoxemia, both of which can occur during uncontrolled asthma. Clinical studies suggest a variable effect of pregnancy on asthma and increased maternal and fetal morbidity and mortality associated with severe asthma. Most antiasthmatic drugs are safe to use during pregnancy. Medications used during delivery by the obstetrician may affect asthma, and some antiasthmatic medications may alter labor. We review here a rational approach to the management of steroid preparation for delivery in steroid-dependent asthmatic patients. Asthmatic mothers may breast-feed with minimal risk of adverse drug effects on the infant.

Calcium ions play an important role in the cardiovascular system. They are involved in electrophysiologic processes, link excitation to muscular contraction, control energy storage and utilization, and constrict vascular smooth muscle in coronary and systemic arteries. A new group of pharmacologic agents that block the passage of calcium ions across cell membranes has been developed. These agents act during the slow inward current of cellular depolarization. The most extensive clinical experience has been obtained with four of these agents: verapamil, nifedipine, perhexiline, and diltiazem. Verapamil, which has profound electrophysiologic effects on the slow inward current, is emerging as a valuable antiarrhythmic agent. Re-entrant supraventricular arrhythmias, such as paroxysmal supraventricular tachycardia, are particularly amenable to treatment with intravenous verapamil. Preliminary trials of long-term therapy with oral verapamil for control of atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia suggest that this agent is effective for therapy of these arrhythmias.

Many of the complications experienced by patients undergoing hemodialysis can be attributed to their altered host defenses. Increased cutaneous staphylococcal carriage along with repeated intravascular cannulation and defective mucocutaneous barriers lead to frequent invasion by infectious agents. Pathogens encounter granulocytes with subnormal locomotion, phagocytosis, and intracellular killing. Depressed cell-mediated immunity may be explained by shortened lymphocyte survival, lymphopenia, inhibition of lymphocyte transformation, and suppressor T-cell activity. This is manifested by cutaneous anergy, prolonged graft survival, altered tumor surveillance, and abnormal responses to hepatitis B and tuberculosis. Host interaction with the hemodialysis membrane leads to cellular disruption, which may induce autoantibodies. Activation of the alternate complement pathway during hemodialysis leads to granulocyte sequestration in small vessels, specifically within the lungs. These hemodialysis-induced alterations along with the manifestations of underlying chronic renal insufficiency may obscure clinical evaluation of these patients.

Since the original description by Dessertenne, predominantly European literature has reported the features of the unusual ventricular arrhythmia "les torsades de pointes." Named because of the way the polarity of the QRS complexes seems to spiral around the baseline of the ECG, this arrhythmia is virtually always associated with prolongation of the Q-T interval. Its importance lies not in its unusual structure but in the potentially fatal outcome if conventional treatment is administered. Antiarrhythmic drugs that further prolong the Q-T interval frequently aggravate the arrhythmia and are contraindicated. Overdrive pacing, preferably atrial, is the treatment of choice with attention to any correctable causes of associated Q-T prolongation. Electrophysiologic studies so far favor a re-entrant cause for the arrhythmia, but the exact mechanism and its true relation to both conventional ventricular tachycardia and ventricular fibrillation remain to be defined.

Tremor, the commonest of the involuntary movement disorders, is characterized by rhythmical oscillatory movement that occurs at rest or during activity; all tremors cease during sleep. Physiologic tremor is present in normal persons and is asymptomatic. Tremor is considered pathologic when it impairs a patient's function. Clinically, the pathologic tremors may be classified as accentuated physiologic, parkinsonian, essential, and cerebellar. We review here the basic mechanisms and clinical features of various tremors and emphasize recent advances in pathophysiology and management.

The products of oxygen reduction (superoxide anion, hydrogen peroxide, hydroxyl radicals) and excitation (singlet oxygen) have been implicated in the toxic properties of phagocytes (neutrophils, eosinophils, and mononuclear phagocytes). Enzymes that potentiate (such as peroxidase) or limit (such as catalase, superoxide dismutase) the toxicity of these agents contribute to the complexity of the oxygen-dependent antimicrobial systems of phagocytes. These toxic systems are dormant when the phagocyte is at rest but are activated when the need arises and directed to the destruction of invading microorganisms and other foreign cells. Occasionally, the toxic systems are directed against normal host cells and in this way contribute to the pathogenesis of disease.

Human gene mapping is concerned with the assignment of individual genes to specific parts of chromosomes. The rapid progress in this field has shown the importance of genetics to human biology and to clinical medicine. Several approaches are available for expanding the human gene map. The gene dosage approach was used in the mapping of the esterase D and retinoblastoma locus on the long arm of chromosome 13. The principles behind kindred linkage analysis and the application of somatic cell hybridization techniques are examined in relation to human gene mapping. Recent data on the steroid sulfatase gene suggest that not all X-linked genes are susceptible to inactivation. Several clinical applications of human gene mapping and linkage information are presented. With the application of current molecular techniques, the human gene map may be substantially completed by the end of the century.

Important insights have recently been derived from studies of inborn human defects of sulfur metabolism. Metabolic lesions responsible for homocystinuria have been elucidated, with possible implications for understanding atherogenesis in the general population. The cause of cystinosis remains enigmatic, but important information has been gained on the origin of some stored cystine from degraded protein. Cysteamine and ascorbic acid deplete the cystine content of cystinotic fibroblasts in vitro, and clinical trials with these agents have been undertaken. Studies of patients with glutathione synthetase deficiency have provided new understanding of the roles of glutathione as in antioxidant and as a modulator of microtubule-related processes. Studies of patients with this disorder and glucose-6-phosphate dehydrogenase deficiency, in which the capacity to maintain glutathione in the reduced state is compromised, indicate that pharmacologic doses of vitamin E can correct certain functional consequences of an inadequate supply of reduced glutathione both in erythrocytes and polymorphonuclear leukocytes. Much remains to be learned about the mechanisms of membrane damage in these states of enhanced oxidative susceptibility.

Data are presented in tabular form that provide guidelines for drug use in adult patients with renal insufficiency. The data are derived from the current medical literature. If specific information about a drug is unavailable or conflicting, emphasis is given to normal pharmacokinetic variables in arriving at recommendations for therapy. Nephrotoxicity or adverse effects in patients with renal disease are noted and adjustments for dialysis suggested.

Since the introduction of antineoplastic chemotherapy, lasting clinical remissions have been obtained for many patients with acute lymphoblastic leukemia, Hodgkin's disease, gestational trophoblastic tumors, and other malignancies. With this therapeutic success there have been concerns about persistent or delayed toxicities of cancer chemotherapy that may become clinically significant for long-term survivors. Gonadal toxicity and infertility occur in many men, women, and children treated with antineoplastic drugs. In this paper we review the clinical syndromes of chemotherapy-related gonadal toxicity and discuss how particular drug classes, doses, or combinations correlate with the degree of gonadal injury and with the potential for recovery of function. Further, we examine how drug effects on germ cell production and endocrine function vary with the age of the patient at the time of treatment. Finally, we comment on the need for long-term prospective studies of fertility, teratogenesis, and mutagenesis in patients receiving cancer chemotherapy.

The term mucormycosis encompasses a distinctive group of infections caused by fungi belonging to genera within the taxonomic order Mucorales, usually Rhizopus, Absidia, Mortierella, and Mucor. These fungi are widespread in nature, subsisting on decaying vegetation and diverse organic materials. Although the fungi and spores of Mucorales show minimal intrinsic pathogenicity toward normal persons, they can initiate aggressive and fulminant infections under certain clinical conditions. Ketoacidotic diabetics are predisposed to rhinocerebral mucormycosis, whereas patients with leukemia or lymphoma are susceptible to pulmonary or disseminated infections. These infections, which often result in devastating long-term sequelae for surviving patients, pose difficult diagnostic and therapeutic challenges.

The major determinants of cancer risk are environmental carcinogens and predisposing host factors. Interactions between these determinants are now being studied by clinical-laboratory investigations. An individual may be predisposed to cancer by both genetic and acquired conditions. Genes related to malignancy and to carcinogenesis have been mapped to individual chromosomes in several species, including humans. Because most environmental chemical carcinogens require enzymatic activitation and a wide variation in carcinogen metabolism among people has been found, the ratio of metabolic activation to deactivation of carcinogens may ascertain, in part, a person's cancer risk. Additionally, cancer risk of chemical and physical agents can be qualitatively predicted by carcinogenicity tests in experimental animals. The emerging field of cancer ecogenetics is aiding efforts to prevent human cancer.

In addition to gonorrhea and syphilis, both of which may develop primarily at anorectal or pharyngeal sites, a number of conditions, including Neisseria meningitidis urethritis, nonspecific urethritis, anorectal herpes, condyloma acuminatum, amebiasis, giardiasis, shigellosis, typhoid fever, enterobiasis, and hepatitis A and B, have been identified as being transmitted by male homosexual contact. Proctologic complications of anal intercourse include allergic reactions to anal lubricants, prolapsed hemorrhoids, and fistulas, and fissures. Rectosigmoid tears may result from fist, forearm, and foreign body penetration of the bowel. Physicians can best help their homosexual patients by accepting them and their relationships nonjudgmentally and by understanding their special health needs.

Deficiencies of two enzymes that catalyze sequential reactions in the purine catabolic pathway have been causally associated with immunodeficiency states. Adenosine deaminase (ADA) deficiency results in severe combined immunodeficiency disease, while purine nucleoside phosphorylase (PNP) deficiency results in an isolated T-cell defect. Recent work in this area has provided major new insights into the molecular pathology of these syndromes. Deoxyadenosine and deoxyguanosine, substrates that accumulate in ADA and deoxyguanosine, substrates that accumulate in ADA and PNP deficiency, respectively, appear to be selectively phosphorylated by lymphoid cells to the corresponding deoxynucleoside triphosphate, resulting in inhibition of DNA synthesis in these cells. Both deoxynucleosides are far more toxic to cultured T lymphoblasts than to B lymphoblasts. Adenosine and deoxyadenosine may have additional lymphotoxic effects mediated by inhibition of essential methylation reactions. These observations help to explain the immunologic manifestations of ADA and PNP deficiency. Perhaps more important, they lay the foundation for the use of deoxynucleosides or enzyme inhibitors, or both, as selective immunosuppressive and chemotherapeutic agents.

A number of chemotherapeutic agents show moderate promise for the palliative treatment of metastatic prostatic carcinoma. Although patterns of metastatic disease make classic response rates difficult to obtain and interpret, doxorubicin, cyclophosphamide, dacarbazine (DTIC), and cisplatin have activity in patients who have failed conventional hormonal treatment. In most studies, a survival advantage is seen for responders to these and other chemotherapeutic agents, but no survival advantage has been seen for the treatment cohorts when compared to groups not receiving chemotherapy. Therefore, estimates of the usefulness of these agents must be considered tentative. Multiple drug therapy has not yet shown definite superiority to single agent treatment. The uses and limitations of acid phosphatase as a tumor marker, as well as particular difficulties in measuring tumor response in the disease, are detailed herein.