Monoclonal antibodies, potentially powerful diagnostic and therapeutic reagents, are having a significant impact in basic and clinical research. Some persisting problems must be solved, however, in order to realize the potential of this technology. We review the basic biology of antibody molecules and the genes that encode them, and discuss how this knowledge can be applied to make more effective monoclonal antibodies.

The level of carcinoembryonic antigen (CEA) is often elevated in the serum of patients with cancer. This article reviews the clinical usefulness of this observation. Carcinoembryonic antigen is not useful for detecting asymptomatic cancer; its sensitivity and specificity are not high, particularly for early stages of disease, so in populations with low prevalence of disease there are many false-positive and false-negative results. Similarly, the antigen level cannot, by itself, provide enough diagnostic certainty to confirm or rule out suspected cancer. For some cancers, antigen levels at the time of diagnosis provide more precise prognosis than staging alone, but this information does not lead to more effective treatment. Serial measurement of CEA levels after surgery in patients with colorectal cancer can detect recurrences early, but few lives can be saved by this approach. Thus, CEA assays provide accurate information about some aspects of cancer but rarely lead to better outcomes for patients.

Although several risk factors for heart disease including high blood pressure, diabetes mellitus, and lipid and lipoprotein abnormalities are associated with overweight, overweight is not consistently associated with coronary heart disease risk. Some prospective studies of white men (life insurance cohorts, airline pilots, cancer study volunteers, and the Framingham population) have shown a positive linear relationship of weight to coronary heart disease. Other epidemiologic studies show a negative association, no association, a U-shaped relationship, or a threshold effect. The inconsistencies do not appear to be explained by differences in the definition or distribution of obesity, duration of follow-up, or risk factor distribution. Neither misclassification bias nor confounding by cigarette smoking or chronic disease appears to explain the inconsistencies. No known protective effect of obesity could explain these divergent findings. Inconsistent results with regard to the nature, strength, and linearity of the association between obesity and atherosclerosis do not support the hypothesis that obesity causes atherosclerosis, despite its biological plausibility.

Cardiopulmonary arrest is a test of the brain's tolerance to global ischemia. New insights into the pathophysiology of global ischemia have led to the potential use of early prophylactic anticonvulsants, hypothermia, barbiturate coma, glucose manipulations, calcium-blocking agents, and hemodilution. A wide spectrum of neurologic sequelae may follow global ischemia, ranging from brain death, vegetative states, and impairment of higher intellectual function to syndromes of amnesia and cortical blindness, post-anoxic myoclonus, delayed leukoencephalopathy, and spinal stroke. The distinctive features of these sequelae and their pathophysiologic aspects are discussed. Special attention is given to brain death and prognostication.

Male infertility is a common and distressing problem in which reproductive abnormalities frequently play an important role. Assessment requires an understanding of the control of spermatogenesis and factors responsible for normal sperm function. Standard tests for assessment of semen quality frequently fail to detect impaired function, but newer tests are now available to measure sperm movement and their ability to penetrate the ovum. Algorithmic approaches based on laboratory data can be used to characterize subgroups of infertile men, but many patients have subtle abnormalities. Treatment of male infertility is ideally directed to a specific pathogenic mechanism; nonspecific therapies have produced disappointing results. Surgery is indicated for certain types of ductal obstruction, but whether internal spermatic vein ligation should be used to treat varicocele remains uncertain.

Pentamidine isethionate, discovered to have antiprotozoal activity in 1938, has recently been approved in the United States for the treatment of Pneumocystis carinii pneumonia. Despite frequent adverse reactions, which are at times life-threatening, pentamidine remains an important alternative to trimethoprim-sulfamethoxazole for the treatment of P. carinii pneumonia in patients with a history of allergy to sulfonamides or who have severe reactions or a lack of response to treatment with trimethoprim-sulfamethoxazole. Although not approved for other indications, pentamidine has been shown to be effective when used prophylactically against Trypanosoma brucei gambiense, the cause of West African sleeping sickness, as well as for treatment of the early hemolymphatic stage of that disease, and for treatment of some forms of leishmaniasis.

Kaposi's sarcoma is a multifocal systemic neoplasm histologically characterized by proliferating fibroblastic and microvascular elements. Initial signs include macules, papules, or nodules on the skin or mucosal surface. Lesions are frequently found on the trunk, arms, and head and neck. In general, sites of involvement and tumor load do not correlate with prognosis. A general decrease in the functional capacities of T and B cells is found in most patients. Kaposi's sarcoma is reported as the initial manifestation of the acquired immunodeficiency syndrome (AIDS) in approximately 30% of cases. Most cases are in men, although it has been reported in all risk groups. Kaposi's sarcoma in AIDS is more frequent among whites and homosexuals than blacks and intravenous drug abusers. Overall mortality is approximately 41%, with over 60% of patients alive at 1 year and 50% at 22 months. Overall survival is 18 months; however, some patients who have had the disease for 3 to 4 years are still doing well.

The widespread use of coagulation factor concentrates prepared from the blood of numerous donors has doubled the life expectancy of persons with hemophilia, but parenteral exposure to alloantigens and infectious agents is not free of risk. The prevalence of the acquired immunodeficiency syndrome (AIDS) now approaches 1% in patients with hemophilia, and laboratory evidence of abnormal immunoregulation is found in at least 50% of treated patients with severe hemophilia. The immune defect is multifactorial. The attack rate of AIDS among patients with severe hemophilia appears to have reached a peak; further evidence suggests that only a minority of those infected with human T-lymphotropic virus type III will develop AIDS. The advent of improved donor screening methods and the application of heat treatment of coagulation factor concentrates should further reduce the risk of AIDS in persons with hemophilia.

Although effective therapies are available for many of the infections and tumors that occur in patients with the acquired immunodeficiency syndrome (AIDS), no therapy exists for the underlying immunodeficiency. Three approaches used to treat this immunodeficiency have included wholescale immune replacement through lymphocyte transfers, bone marrow transplantation, and thymic implantation; immunologic enhancement with biologic-response modifiers, such as gamma interferon, interleukin-2, and some drugs; and antiretroviral therapy. Because of the persistence of the etiologic virus, both immune replacement and enhancement will probably be ineffective unless effective strategies are developed against the virus. Agents that have shown antiviral activity in vitro which are currently in clinical trials include suramin, heteropolyanion-23 (HPA-23), ribavirin, and alpha interferon. Foscarnet and monoclonal antibodies have yet to enter clinical trials in the United States. It is still too early to tell if any of the antiviral agents will prove of value in the management of patients with AIDS.

Cell-mediated immune responses to cytomegalovirus infections were studied to define mechanisms for deficient effector T-cell responses in patients with the acquired immunodeficiency syndrome (AIDS). Progressive cytomegalovirus infection is common in such patients and is accompanied by a failure to develop HLA-restricted cytotoxic T-cell responses. The mechanism for the cytotoxic T-cell deficiency is presumably the basis for susceptibility to opportunistic infections. Precursors to these effector cells circulate in the peripheral blood of patients, but maturation of these cells into cytotoxic T cells is arrested during an interleukin-2-dependent phase. Production of interleukin-2 by lymphocytes from patients with AIDS is deficient because sera from these patients contain an inhibitor of interleukin-2 production. Excess suppressor cell activity does not appear to account for this deficient production. Studies of the source of the serum inhibitor should provide insights into the pathogenesis of AIDS and possible leads for effective treatment.

Many abnormalities of humoral and cellular immunity associated with the acquired immunodeficiency syndrome can be explained by the preferential infection of the T4 lymphocyte subset with the etiologic retrovirus. Severe alterations in specific T4 functions, such as inadequate immune responsiveness to specific antigen, result in devastating morbidity and mortality. On the basis of accumulated scientific knowledge, we outline the immunopathogenesis of this syndrome.

Antigens encoded by the gag and env genes of the human T-lymphotropic virus type III/lymphadenopathy associated virus (HTLV-III/LAV) include a p55 gag polyprotein that yields p24 as the major virus core protein, and an env gene polyprotein, gp 160, that produces gp 120, the most immunogenic protein in humans, at the amino terminus. Although its use is limited to research laboratories due to the cost and specialized procedures involved, the analysis of sera by radioimmunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis is the test providing the optimal balance of specificity and sensitivity. Because the gp 120 represents the external virus protein, it would be the most appropriate antigen for vaccine development. Also viruses serologically related to HTLV-III/LAV were detected recently in two species of Old World monkeys. Because about half the healthy African green monkeys appear to have been exposed to simian T-lymphotropic virus type III (STLV-III), a related agent of the species, a characterization of the STLV-III gp 120 and immune response of the host may provide additional information for vaccine development.

Peripheral mononuclear cells from more than 160 persons from groups at risk for the acquired immunodeficiency syndrome (AIDS) have yielded AIDS-associated retroviruses (ARV). Antibodies to ARV can also be found in these risk groups. Antibody-negative, virus-positive persons have been identified with early infection or possible viremia with immune complex formation. Established lines of human T and B cells, monocytes, and promyelocytes have been infected with ARV. Moreover, infectious virus has been recovered from macrophages cultured from the blood of some persons with AIDS. The cytopathic effects of ARV in T cells is associated with the accumulation of unintegrated viral forms in the infected cells. The ARV has also been isolated from plasma, serum, saliva, semen, urine, cerebrospinal fluid, and brain tissue. All these results reflect the wide host range of ARV and support its role in neurologic abnormalities seen in some patients. Molecular studies of independent ARV isolates indicate a polymorphism of nucleotide sequences, particularly in the viral envelope region. All these features place ARV in the lentivirus subfamily of human retroviruses.

Three human T-lymphotropic viruses have been isolated and characterized in the past 5 years. The ability to culture target cells with T-cell growth factor and sensitive detection systems for the virally encoded polymerase reverse transcriptase permitted isolation of HTLV-I, which is strongly linked to the cause of adult T-cell leukemia and associated with other lymphoid malignancies in endemic areas. The same techniques, using a permissive human tumor cell line, allowed the isolation and characterization of HTLV-III/lymphadenopathy-associated virus, which is implicated as the primary cause of the acquired immunodeficiency syndrome (AIDS). This virus shares some features with HTLV-I and HTLV-II, such as additional genes not found in most retroviruses. One gene codes for a transcriptional activator protein and may be a feature of a larger group of related retroviruses. The clear identification of the primary cause of AIDS has resulted in the development of specific immunologic reagents, preventive and therapeutic proposals, and comprehensive identification of the clinical diseases associated with this virus.

The discovery of human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) has opened a window to the understanding of the spectrum of the acquired immunodeficiency syndrome (AIDS) and related clinical syndromes. Analysis of risk factors for seropositivity has shown that HTLV-III is transmitted most efficiently via routes that involve close personal contact or parenteral exposure. Longitudinal studies have shown that HTLV-III infection has a long latent period. The prevalence of AIDS in different geographic areas and among different risk groups appears to depend in part on duration of exposure. Co-factors for AIDS outcome such as manner and route of exposure, underlying immune status, and host susceptibility are also likely to play a role in risk.

The incidence of the acquired immunodeficiency syndrome (AIDS) has continued to increase worldwide. From June 1981 to September 1985, 12 932 cases have been diagnosed and reported in the United States; this number is expected to double during the next year. The incubation period is long and few persons infected with human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) have AIDS diagnosed within 2 to 5 years of infection. The widespread use of HTLV-III/LAV serologic tests to screen donated blood and plasma, the continued deferral of donors from groups with an increased incidence of AIDS, and the use of heat-treated clotting factor concentrates should help prevent HTLV-III/LAV transmission through blood and blood products. Preventing transmission among sexual partners, among intravenous drug users, and from infected mothers to newborns will continue to be difficult without a vaccine, specific antiviral therapy, or both. Risk reduction strategies should involve community groups to provide accurate information and influence behaviors that lead to transmission of the virus.

Human T-lymphotropic virus type III is susceptible to attack at various sites during its replicative cycle. Inhibitors of reverse transcriptase activity, including suramin, antimoniotungstate (HPA-23), and trisodium phosphonoformate, have shown in-vitro activity against the virus in early clinical trials. Other significant antiviral agents are recombinant interferon alpha-A, ribavirin, and ansamycin. Double-blind, placebo-controlled clinical trials of interferon alpha, which inhibits viral replication at easily achievable serum levels, are underway. The development of optimal therapeutic regimens will require carefully controlled, multicenter collaborative trials with standardized criteria for evaluating responses. Prolonged treatment with combinations of antiviral and immunomodulating agents may be necessary for control of HTLV-III replication and for effective treatment of the acquired immunodeficiency syndrome.

The presence of antithyroid hormone autoantibodies in the sera of patients with thyroid and nonthyroid disorders is a well-known condition. When circulating thyroid hormones bind to the patients' immunoglobulins, serum levels of total and free thyroid hormones are often in discordance with clinical features. This problem occurs because the autoantibodies can interfere with radioimmunoassays. To avoid inappropriate treatment of such patients, it is clinically important to consider the presence of autoantibodies in patients with unexpectedly high or low total and free thyroid hormone values. We have reviewed the English and Japanese literature, both case reports and basic works, and summarize the incidence of antithyroid hormone autoantibodies, clinical features, effects on appropriate testing of the hypothalamic-pituitary-thyroid axis, diagnostic methods for confirming their presence of autoantibodies, treatment of patients with these disorders, and possible pathogenetic mechanisms.

Imipenem, the first of a new class of carbapenem antibiotics, has potent activity against most clinically important species of bacteria, including isolates resistant to other antibiotics. The drug is well distributed to most tissues and fluids after intravenous administration; however, levels in cerebrospinal fluid are modest. Most of the drug is eliminated in the urine, where it is metabolized by an enzyme on the brush border of the renal tubular cells; cilastatin is given simultaneously to inhibit this inactivation. Adverse effects include a syndrome of nausea and hypotension, especially after rapid intravenous infusion, and a predisposition to seizures in certain high-risk patients. Superinfections by resistant bacteria and fungi are infrequent. This new drug may be particularly useful in the treatment of infections caused by mixtures of bacteria for which a combination of antibiotics, often including an aminoglycoside, would otherwise be necessary. Examples include pulmonary, intra-abdominal, and soft-tissue infections.

Neuropathologic and neurochemical studies of older adults with Down's syndrome and those with Alzheimer's disease reveal striking similarities. Genetic studies indicate that near relatives of patients with Alzheimer's disease are at increased risk of developing Alzheimer's disease, and the risk appears to be age specific. These families with familial Alzheimer's disease have also been found to have a high incidence of Down's syndrome. Neurochemical data suggest that a cholinergic deficiency must be present for dementia to develop, and serial assessments of brain metabolic function with positron emission tomography in Alzheimer's disease have shown that the parietal lobe has reductions in metabolic function before the onset of neuropsychologic deficits in this brain region. Neuropsychologic testing indicates that patients with Down's syndrome over 35 years old have poorer cognitive skills than do younger patients. Brain metabolic function is excessively reduced in the demented adults with Down's syndrome.