Recent findings have led to a greater understanding of thyroid hormone action. The nuclear receptor for triiodothyronine is an integral component of a larger chromatin fragment. A stereospecific energy-dependent transport system appears responsible for translocation of triiodothyronine from cytosol to nucleus. In the liver, a multiplicative interaction between a signal from the triiodothyronine-nuclear receptor complex and a signal generated from carbohydrate metabolism results in the induction of specific mRNAs. Two-dimensional mRNA activity profiles suggest that approximately 8% of the visible mRNA sequences are differentially affected by alterations in thyroid states. Almost 30% to 40% of these changes are mediated by an increase in pituitary growth hormone induced by triiodothyronine. Sequential analyses of mRNA activity profiles have identified an mRNA sequence (mRNAs14) coding for a protein (S14) with Mr 17 010 and pI 4.9 which responds to triiodothyronine with a lag time of less than 20 minutes. The coordinate regulation of mRNAs14 by carbohydrate and triiodothyronine and its presence in lipogenic tissues (fat, liver, lactating mammary tissue) suggests that S14 is involved in some aspect of fatty acid synthesis degradation or storage.

Ovine and human corticotropin-releasing factors (CRF) have similar potencies in causing adrenocorticotropic hormone (ACTH) and cortisol secretion in normal humans. Using long-acting ovine CRF (1 microgram/kg body weight as an intravenous bolus), we tested patients with Cushing's syndrome, adrenal insufficiency, and psychiatric conditions with mild hypercortisolism. Over 95% of hypercortisolemic patients with a pituitary adenoma responded with increases in plasma ACTH and cortisol concentrations; patients with the ectopic ACTH syndrome had no ACTH or cortisol responses; patients with ACTH-independent hypercortisolism of adrenal origin had low or undetectable plasma ACTH concentrations before and after CRF without any cortisol response. The differences in responses of patients with adrenal insufficiency of primary, pituitary, or suprapituitary type likewise suggest value of the CFR test in their differential diagnosis. The responses in the psychiatric patients should permit differentiation between Cushing's syndrome and hypercortisolism of psychiatric origin.

Gonorrhea may be the most extensively studied infection of the past 20 years. The gonorrhea epidemic in the United States began in the early 1960s and peaked in 1975. Ironically, since 1976 the declining overall incidence has been offset by the advent of plasmid-mediated beta-lactamase production by Neisseria gonorrhoeae and by a growing problem with outbreaks due to strains with chromosomally mediated penicillin and tetracycline resistance. This new antimicrobial resistance, coupled with the frequency of concurrent chlamydial infection in developed countries and concurrent syphilis in some developing countries, has created a need for new approaches to gonorrhea therapy. With the introduction of certain new antimicrobial agents, highly effective forms of therapy are again available. New approaches to rapid diagnosis are also becoming available, but require critical appraisal. Unfortunately, in most of the world's population, gonorrhea remains epidemic, diagnosis of gonorrhea in women is extremely difficult, and highly effective antimicrobial agents are no longer affordable. Thus, vaccine development remains an extremely important goal. Although no candidate gonococcal vaccine currently holds high promise, the increasing understanding of the biology of the gonococcus and the pathogenesis of gonorrhea will serve to focus future research on vaccine development.

The incidence of cancer increases progressively with age. Rearrangements of genomes have been found to accompany cellular aging. These factors, in concert with age-dependent alterations in immune function and host defense, may help to explain the increased risk of malignant disease in aged persons. The clinical presentation and natural history of neoplasia are also affected by aging. This conference reviews recent developments in these areas, examines the effects of drug use in the elderly and implications for management, and discusses current information on how age may influence the response of cancer to therapy.

Methods now available for evaluating the pancreas include computed tomography, ultrasound, angiography, endoscopic retrograde cholangiopancreatography, and percutaneous fine-needle aspiration. Computed tomography is best for initial evaluation of the patient with suspected pancreatic disorders as it is technically adequate and provides detailed anatomic information. Ultrasound also provides detailed information and survey capabilities but examinations are often technically unsatisfactory. Angiography, endoscopic retrograde cholangiopancreatography, and fine-needle aspiration provide important diagnostic information but are more invasive and require considerable operator skill. These techniques are secondary tests not indicated for the initial evaluation of every patient. No single test will always provide all necessary diagnostic information, and the appropriate utilization of each method requires an understanding of its strengths and weaknesses.

Bronchoalveolar lavage has emerged as a useful technique for the study of pulmonary interstitial disorders. Several types of information are provided by the evaluation of lavage fluid. First, the identification of cellular constituents helps to separate inflammatory processes in which lymphocytes predominate (for example, sarcoidosis, hypersensitivity pneumonitis, and berylliosis) from those in which neutrophils or macrophages predominate (for example, idiopathic pulmonary fibrosis and histiocytosis X). Second, the cells removed during lavage can be studied for their immune properties and function; tested with specific antigens, in diseases such as berylliosis and hypersensitivity pneumonitis; and examined for the presence of unique surface antigens with monoclonal antibodies (for example, histiocytosis X). Third, in conjunction with scanning electron microscopy and electron probe analysis, lavage makes possible the identification of inorganic particles in alveolar macrophages of patients with pneumoconiotic lung disease. Finally, although lavage is still an investigative procedure for most pulmonary disorders, it has an established role in the diagnosis of opportunistic infections in the immunocompromised patient.

Cataract disrupts the crystalline lens, a transparent, elastic, avascular, biconvex structure composed of a capsule, lens epithelium, and lens fiber cells. Many factors contribute to the progression of lens opacity, but aging is most frequently associated with cataract. As aging-related cataract develops, many biochemical and biophysical changes occur, most notably a marked increase in the insolubilization of the crystallin and extensive oxidation damage to many of the lens constituents. Cataract management should include ophthalmologic history and examination, medical evaluation, optical correction, control of ocular and systemic disease that may contribute to cataract, discontinuation of cataractogenic drugs, and periodic reexamination. Surgery is indicated when cataract is associated with vision decrease interfering with activities important to the patient, intraocular inflammation or glaucoma, or interference with management of posterior segment disease. More than 600 000 cataract operations are done in the United States each year; in 1982 an estimated 496 000 cataract operations were combined with intraocular lens implantation.

Anorectal disorders include a diverse group of pathologic processes that are frequently encountered in general medical practice but are poorly understood. The optimal management of anal pain, itching, bleeding, and incontinence is based on sound anatomic and pathophysiologic principles. Advances have been made in understanding the pathogenesis and management of four anorectal disorders frequently encountered by internists: hemorrhoids, fissures, pruritus, and incontinence.

Using reasonable assumptions gathered from the published literature, we estimated that more than half of the decline in ischemic heart disease mortality between 1968 and 1976 was related to changes in lifestyle, specifically to reductions in serum cholesterol levels and cigarette smoking. In comparison, about 40% of the decline can be directly attributed to specific medical treatment of clinical ischemic heart disease and hypertension being the leading estimated contributors. Because many of these interventions have not yet been applied to their maximum potential, a continued decline in mortality rates might be anticipated in the coming decades. However, the relative costs of these medical interventions and lifestyle changes and the extent to which they interact with each other must be considered before an optimal national health strategy can be derived.

Computed tomography (CT) has emerged as a new imaging method for the diagnosis and evaluation of cardiovascular disease. With CT body scanners and contrast enhancement, evaluation of aortic dissections and aneurysms, coronary bypass graft patency, cardiovascular thrombus, cardiac tumors, and pericardial disease is possible. On occasion, this technique provides clinically useful information that is not available with other imaging methods. Electrocardiographic gating retrospectively or prospectively improves the image resolution of CT scans, but a new ultrafast CT scanner with a scan time of 30 to 50 milliseconds offers the greatest promise for expanding the application of the technology for cardiovascular diagnosis. Accurate measurement of cardiac chamber volume, mass, wall motion, and wall thickening will be feasible. Ultrafast CT scanning also shows great promise for the measurement of myocardial infarct size and regional myocardial blood flow.

Rheumatoid arthritis is a chronic inflammatory synovitis that primarily involves peripheral diarthrodial joints. Immunohistologic analysis of diseased synovium has shown a spectrum of abnormalities that resemble various stages of a cell-mediated, or delayed-type, immune reaction. The infiltrating mononuclear cells produce various factors that modulate adjacent tissues and appear to produce the characteristic destructive features of the disorder. Our understanding of the mechanisms of action of various therapeutic modes also indicates that the disease is primarily mediated by activated mononuclear cells. All effective therapies have been shown to affect either mononuclear cell function or the rates of production or elimination of these cells. The disorder likely represents the pathologic expression of a genetically controlled host immune response to an undefined causative stimulus. The stimulus could be an infectious agent(s), a product(s) derived from an infectious agent(s), a constituent(s) of synovial or connective tissue, or a combination of these.

Nonobstetric disease requiring surgery may complicate pregnancy and jeopardize maternal and fetal well-being. Surgery may be safely done if the physician is aware of anatomic and physiologic alterations during gestation that necessitate an altered approach to diagnosis and management. Fetal exposure to all diagnostic and therapeutic agents should be minimized, particularly during organogenesis. However, the risk to the fetus of diagnostic irradiation is justifiable when information essential to maternal health is likely to be obtained. Furthermore, the broad range of available antibiotic, analgesic, and anesthetic agents provide the physician with options for treatment that have an acceptable degree of risk to fetal health. Anesthesia and surgery are tolerated considerably better by the fetus than is maternal hypotension, hypoxia, or sepsis. When an operative procedure is urgently or emergently indicated, pregnancy should not delay timely intervention.

Cyclosporine, a cyclic endecapeptide of fungal origin, has recently been released for use in clinical transplantation. Trials in kidney, heart, liver and bone marrow recipients were encouraging: 1-year graft survival rates were 70% to 80% for kidney and heart recipients, and 60% to 65% for liver allograft recipients. Cyclosporine is also effective in treating bone marrow recipients with acute graft-versus-host disease. The drug selectively inhibits T-helper cell production of growth factors essential for B cell and cytotoxic T-cell differentiation and proliferation, while allowing expansion of suppressor T-cell populations. Drug absorption varies greatly, necessitating monitoring of drug level and individualization of therapy. Nephrotoxicity is the most frequent side effect of cyclosporine. An increased incidence of B-cell lymphomas seen when cyclosporine was used in conjunction with cytotoxic agents or anti-lymphocyte globulin has very rarely been observed when concomitant immunosuppression has been limited to low-dose corticosteroids. Lower initial doses of cyclosporine, followed by more rapid tapering may reduce the incidence of nephrotoxicity without compromising improved graft outcome.

In several bacterial diseases, the clinical, laboratory, and histologic findings result from the elaboration by the organism of a toxic product that binds to and may enter the host cell to alter its metabolism. In some cases, the intracellular mediators of toxin action are the cyclic nucleotides, cyclic adenosine 5'-monophosphate (cAMP) and cyclic guanosine 5'-monophosphate (cGMP), the ubiquitous second messengers through which numerous hormones, neurotransmitters, and drugs exert their effects. Certain toxins act by enhancing the activity of cellular enzymes that synthesize cAMP or cGMP; and others, by themselves catalyzing cAMP synthesis after entering the cell. Studies of the mechanism of action of these toxins have helped in deciphering the enzymatic components within animal cells that are responsible for cyclic nucleotide synthesis, degradation, and function as well as in understanding the pathogenesis of the diseases in which they are involved.

Glucose chemically attaches to proteins and nucleic acids without the aid of enzymes. Initially, chemically reversible Schiff base and Amadori product adducts form in proportion to glucose concentration. Equilibrium is reached after several weeks, however, and further accumulation of these early nonenzymatic glycosylation products does not continue beyond that time. Subsequent reactions of the Amadori product slowly give rise to nonequilibrium advanced glycosylation end-products which continue to accumulate indefinitely on longer-lived molecules. Excessive formation of both types of nonenzymatic glycosylation product appears to be the common biochemical link between chronic hyperglycemia and a number of pathophysiologic processes potentially involved in the development of long-term diabetic complications. The major biological effects of excessive nonenzymatic glycosylation include: inactivation of enzymes; inhibition of regulatory molecule binding; crosslinking of glycosylated proteins and trapping of soluble proteins by glycosylated extracellular matrix (both may progress in the absence of glucose); decreased susceptibility to proteolysis; abnormalities of nucleic acid function; altered macromolecular recognition and endocytosis; and increased immunogenicity.

The cause of multiple sclerosis is unknown but seems to be multifactorial. Susceptibility or resistance may be genetically determined; something in the environment interacts with the human host at the proper age to cause biochemical and structural lesions in the central nervous system. The systemic immune response and the response of the central nervous system become involved. Although multiple sclerosis cannot yet be cured, many clues are leading to an effective palliative therapy. Suppression or modulation of the immune responses may be the key to developing that treatment. If the environmental agent is one or several viruses, then antiviral regimens will be appropriate. Research must therefore continue at both basic science and clinical levels.

Sulfasalazine is metabolized by intestinal bacteria, resulting in the release of sulfapyridine and 5-aminosalicylate. The drug is useful in the treatment of active ulcerative colitis as well as in preventing relapses of the disease in remission. Although effective in active Crohn's disease as well, sulfasalazine appears to be of greater benefit to patients with colitis and ileocolitis than those with ileitis alone. 5-Aminosalicylate itself is efficacious when given in enema and suppository form; oral agents capable of delivering 5-aminosalicylate to distal disease sites are now under study. The drug's mechanism of action may relate to its effects on prostaglandin synthesis or interference with arachidonic acid metabolism by the lipoxygenase pathway. Common adverse reactions of sulfasalazine, including nausea, headache, and anorexia, as well as hemolysis, are associated with high serum sulfapyridine levels and often can be avoided by lowering the dose of sulfasalazine. Mild allergic reactions, such as rash and fever, may be overcome by gradual desensitization.

The incidence of congestive heart failure is increasing in the United States. This common syndrome is characterized not only by impaired ventricular function but also by an increase in some endogenous vasoconstrictor substances, including norepinephrine, angiotensin II, and arginine vasopressin. Although activation of the systems that release these substances is presumed to be compensatory (to maintain perfusion pressure during inadequate flow), the sympathetic nervous system, renin-angiotensin-aldosterone system, and arginine vasopressin may contribute to the pathogenesis of the syndrome. The excessive vasoconstriction present in heart failure likely produces a further burden on the failing myocardium. New strategies in therapy are being developed to counteract the activation of vasoconstrictor forces in congestive heart failure. Data indicate that selective blockade of the renin-angiotensin system is useful. Preliminary data suggest that inhibition of the sympathetic nervous system may be helpful, and inhibition of vasopressin in animals with heart failure is being studied. New and more selective therapy for heart failure may come from these studies.