Alcohol withdrawal syndrome is characterized by signs of overactivity of the sympathetic nervous system. Biochemical studies indicate that increased release of norepinephrine is associated with certain symptoms of alcohol withdrawal, and the severity of the withdrawal symptoms correlates positively with the amount of norepinephrine released. In the rat, the brain epinephrine concentration is reduced by alcohol, a phenomenon probably associated with both the intoxicating and rewarding effects of alcohol intake. Furthermore, intoxicating effects of alcohol can be reversed by inhibiting epinephrine synthesis in the rat brain. In this species, alcohol withdrawal is associated with profound depletion of epinephrine in the hypothalamus. When clonidine, a norepinephrine alpha-2-receptor agonist, was infused in alcoholics, these receptors were found to be subsensitive during alcohol withdrawal, and this subsensitivity may contribute to the syndrome. Repeated withdrawals may lead to "kindling" and thus further enhancement of noradrenergic overactivity. Pituitary responsiveness to corticotropin-releasing hormone, which is a central regulator of stress responses and increases the firing rate of brain noradrenergic neurons, is altered during alcohol withdrawal.

The marriage of cytogenetics and molecular biology has resulted in major advances in our understanding of acute nonlymphocytic leukemia. These technologies reveal a number of clearly recognizable syndromes of acute nonlymphocytic leukemia. This review describes the salient features of several of these syndromes: acute myelomonocytic leukemia with abnormal eosinophils; acute nonlymphocytic leukemia with 11q abnormalities [biphenotypic leukemia with t(4;11); and acute monocytic leukemia with t(9;11)]; acute nonlymphocytic leukemia with t(8;21); acute promyelocytic leukemia; acute nonlymphocytic leukemia with normal or elevated platelet counts and rearranged 3q21 and 3q26; and acute nonlymphocytic leukemia with increased basophils and t(6;9). The pathogenesis of therapy-related leukemias is discussed also.

Judges and juries are increasingly being asked to settle questions about disease caused by hazardous products. With the growth of litigation on toxic substances and unsafe products, more and more courts must wrestle with the complicated scientific proof of the relation between exposure and disease or injury. This proof frequently involves the use of probabilistic evidence in the form of statistical tests and epidemiologic studies. Anglo-American law relies on deductive notions of causation and is suspicious of probabilistic evidence of causation. As a result, court decisions of hazardous substance cases are sometimes based on a confused understanding of the critical causal connection. Physicians who testify in such cases, either as the treating doctor or as expert witnesses, must be aware of the court's difficulty with probabilistic evidence. In addition, physicians must state clearly the role of such evidence in the identification of a hazardous substance as the cause of a disease or injury.

Conventional implantable dual-chamber cardiac pacemakers adjust heart rate and maintain normal atrial and ventricular contraction by tracking "native" atrial electrical activity and pacing the ventricles after a predetermined programmable atrioventricular delay. However, in patients with symptomatic bradyarrhythmias, optimal function of "atrial-tracking" devices may be limited by concomitant sinoatrial disease. Provision of chronotropic response during physical exertion or emotional stress may be achieved by using physiologic sensors to alter pacing rate independently of atrial activity. Additional systems using sensor technologies are being developed. Future pacing systems will have dual-chamber pacing capability and may use several sensors coupled synergistically in order to take advantage of particular strengths of each. Physiologic sensor technology may be of diagnostic value in both antitachycardia devices and implantable cardioverter and defibrillator systems.

Toxic oxygen free radicals have been implicated as important pathologic mediators in many clinical disorders. We discuss the chemistry of oxygen radical production and the roles of iron and of various antioxidants as well as the diseases that have received active attention in oxy-radical research. Particular attention is focused on cigarette smoke oxidants, ischemia-reperfusion-induced radical production, carcinogenesis, and aging. Such research may well provide a firm foundation for therapeutic breakthroughs.

Diabetic peripheral neuropathies are a group of heterogeneous syndromes with considerable morbidity. At least 50% of diabetic patients develop one or several of these neuropathies within 25 years after the diagnosis. In recent years several pathogenetic mechanisms have been proposed, with the newest findings suggesting a link between several of these hypotheses. The hypoxic hypothesis has revived the role of vascular factors in the pathogenesis of diabetic peripheral neuropathies. Although the exact role of hyperglycemia in the development of peripheral neuropathy is not known, the balance of evidence indicates that attainment and maintenance of normal blood glucose remains the cornerstone of treatment of diabetes and diabetic neuropathies. There is no convincing evidence that any of the treatments devised to correct the metabolic derangements in nerve are of sufficient value or safety to be recommended for routine use.

Intravenous immunoglobulins are stable monomeric pooled human IgG preparations for therapeutic use. Three intravenous immunoglobulins licensed in the United States are generally therapeutically equivalent. Intravenous immunoglobulin is the preferred agent for replacement therapy for most patients with primary or secondary antibody immunodeficiency because of the rapidity and ease of giving large quantities of IgG, even by self-administration. Disadvantages of intravenous immunoglobulins include frequent (approximately 10%) but usually not serious side effects, the need for venous access (often difficult in infants and young children), and high cost. Intravenous immunoglobulins are also beneficial in the prevention of certain viral infections, such as cytomegalovirus pneumonia and varicella; they may also have a synergistic effect with antibiotics in certain bacterial diseases. Intravenous immunoglobulin has also been used successfully in the management of idiopathic thrombocytopenia purpura, Kawasaki disease, and certain autoimmune diseases. Intravenous immunoglobulin may also be of use in certain high-risk and premature newborns.

Evidence on the safety and efficacy of methotrexate as a second- or third-line agent for treating patients with rheumatoid arthritis is reviewed. Four placebo-controlled clinical trials have documented short-term benefit from methotrexate; although true remission is rare, patients receiving methotrexate showed a 26% (95% confidence interval [CI], 17% to 35%) greater improvement in their inflamed joint count and a 39% (95% CI, 26% to 51.5%) greater improvement in pain than did controls receiving nonsteroidal anti-inflammatory agents with or without prednisone. With respect to long-term benefit, improvement usually occurs within 1 month, reaching a maximum at 6 and then leveling off for the duration of treatment; in some patients, the benefit may wane after an initial satisfactory response in the first 4 to 6 months. In one third of those given methotrexate, treatment had to be discontinued because of adverse effects, less than 1% of which were life threatening. Careful baseline and follow-up monitoring is recommended until more data on the safety of methotrexate are available.

Subacute encephalitis caused by infection of the central nervous system by the human immunodeficiency virus (HIV) is the most frequent cause of neurologic dysfunction in patients with the acquired immunodeficiency syndrome (AIDS). This disorder results in progressive cognitive, motor, and behavioral abnormalities in at least two thirds of patients with AIDS. Pathologic evidence of subacute encephalitis is found in 90% of these patients at autopsy. Human immunodeficiency virus is also the etiologic agent of aseptic meningitis, a disease that can occur at the time of seroconversion. Other neurologic disorders frequently associated with HIV include peripheral neuropathies and vacuolar myelopathy. Thus, HIV is neurotropic and may enter the central nervous system early in the course of infection. Neurologic disease may be the only clinical manifestation of HIV infection. Although mechanisms of pathogenesis are unclear, cells of monocyte-macrophage lineage may be important in viral spread to and within the central nervous system. Effective antiviral therapy will probably require penetration of drugs across the blood-brain barrier.

Recent advances in the understanding of the pathogenesis of infection with human immunodeficiency virus (HIV) stems from the demonstration that the membrane glycoprotein, CD4, is the cellular receptor for HIV. This glycoprotein is found mainly on the surface of a major subpopulation of T lymphocytes and also on macrophages, natural killer cells, some B lymphocytes, and neuronal cells. Cells infected with HIV may be destroyed or have their normal function impaired. Host immune responses to HIV are poor and are not sustained. Neutralizing antibody often is not produced, or HIV may escape from normal immunosuppressive mechanisms through the process of rapid antigenic variation. Factors and markers that may be important in the outcome or that may predict progression of HIV infection are genetic (Gc type), environmental (nutritional status or intercurrent sexually transmitted diseases sustained by the host), and immunologic (rate of decline in number and impairment of function of CD4 lymphocytes and of decline in antibody titers to HIV core protein, p24). A recombinant vaccine will probably be developed for testing in future clinical trials.

Meta-analysis is the process of combining study results that can be used to draw conclusions about therapeutic effectiveness or to plan new studies. We review important design and statistical issues of this process. The design issues include protocol development, objectives, literature search, publication bias, measures of study outcomes, and quality of the data. The statistical issues include consistency (homogeneity) of study outcomes, and techniques for pooling results from several studies. Guidelines are provided to assess the quality of meta-analyses based on our discussion of the design and statistical issues. Limitations and areas for further development of this approach are discussed; researchers should come to a general agreement on how to conduct meta-analysis. As an explicit strategy for summarizing results, meta-analysis may help clinicians and researchers better understand the findings of clinical studies.

Allergic reactions to the beta-lactam antibiotics (penicillins, cephalosporins, carbapenems, and monobactams) are a major factor limiting their use. Immediate hypersensitivity reactions to penicillins depend on the presence of preformed allergic (IgE) antibodies to several penicillin determinants. These materials can be used in in-vivo skin testing to exclude those patients at risk for immediate or accelerated allergic reactions. The cephalosporins have not had their relevant determinants defined as related to allergic reactions. The results of in-vivo challenges of patients with IgE to penicillin suggest the incidence of reactivity of cephalosporins in patients allergic to penicillin is less than generally appreciated. The monocyclic beta-lactam antibiotic, aztreonam (a monobactam), failed to show cross-reactivity with penicillin antibodies, because immune reactivity toward the monobactam was directed against side chain rather than nuclear determinants. On the other hand, the new bicyclic carbapenem beta-lactam drugs, represented by imipenem, showed extensive in-vivo cross-reactivity with penicillins.

We used a meta-analysis protocol to evaluate the results of 18 controlled trials that measured the effectiveness of perioperative total parenteral nutrition. The pooled results of 11 trials that were randomized or quasi-randomized showed trends suggesting that total parenteral nutrition reduced the risk for complications from major surgery (p = 0.21) and fatalities (p = 0.21). Consideration of these pooled estimates of the effectiveness of this intervention must be offset by the poor quality of the trials' methodologies and the iatrogenic complications (pneumothorax, septicemia) that occurred at a pooled rate of 0.067. Alternately, other design flaws, such as the failure to exclude patients who were not malnourished from the trials, may have limited the ability of these trials to show the effectiveness of total parenteral nutrition. The evidence available up to August 1986 shows that the routine use of perioperative total parenteral nutrition in unselected patients having major surgery is not justified; however, this intervention may be helpful in subgroups of these patients who are at high risk.

Progressive multifocal leukoencephalopathy, a common complication of infections with human immunodeficiency virus (HIV), occurs in as many as 3.8% of patients with the acquired immunodeficiency syndrome (AIDS). We report 16 cases and review 12 previously reported cases of progressive multifocal leukoencephalopathy associated with HIV infection. This illness was the presenting manifestation of HIV infection in 8 cases. Limb weakness, gait abnormalities, visual loss, aand altered mental status were the commonest initial complaints. Computed tomography of the brain frequently showed hypodense, nonenhancing white matter lesions. Magnetic resonance imaging was more sensitive than computed tomography in detecting lesions. Cerebrospinal fluid analysis and electroencephalography were nondiagnostic. Impaired cell-mediated immunity was typically noted, even in the absence of other immunodeficiency-associated illnesses. Death occurred within 10 days to 18 months of the onset of symptoms in 22 patients. However, 4 patients remain alive at 3 to 23 months; of these 4, 2 have had significant improvement without treatment. Various therapies were unsuccessful.

The syndrome of bulimia is a common disorder and can be associated with serious psychological and physical morbidity. Unfortunately, many patients are reluctant to discuss their symptoms with their physicians and few clues can be found on physical examination to aid in the diagnosis. Possible physical signs include ulceration or scarring of the dorsum of the hand, salivary gland hypertrophy, and dental enamel erosion. In laboratory testing it is fairly common for patients with active bulimia to have fluid and electrolyte abnormalities, particularly hypokalemic alkalosis, and some also have elevated serum amylase levels. Rare complications include myopathies from misuse of ipecac, ruptured esophagus and pneumomediastinum associated with vomiting, and subtle abnormalities in neuroendocrine regulatory systems. Medical management including monitoring of fluid and electrolyte balance is essential during treatment.

Advances in diagnostic imaging methods during the last decade have facilitated the identification of focal or diffuse parathyroid abnormalities. Major advances have included improvements in computed tomography and high-resolution ultrasonography, and the introduction of thallium-201-technetium-99m parathyroid subtraction scintigraphy. The more invasive methods of venous sampling and selective angiography have also been refined, but they have not been used as extensively because of the need for highly skilled personnel. The role of these diagnostic tools before surgery in the routine evaluation of patients with suspected primary hyperparathyroidism is unclear because a skilled surgeon should be able to achieve cures in 90% of these patients during exploratory surgery. However, most physicians would agree that, in those patients whose abnormalities go undetected during exploratory surgery of the neck, diagnostic imaging methods should be used before additional surgery is planned. Further prospective studies are needed to determine if routine localization before surgery is cost effective.

During the past 5 years, clinical trials in hairy cell leukemia have shown dramatic activity for alpha-interferon and 2'-deoxycoformycin (pentostatin). Responses can be induced in more than 80% of patients using either agent, although a greater number of complete pathologic remissions may be achieved with deoxycoformycin. Despite interesting preliminary data, the optimal dose, schedule, treatment duration, and impact of therapy on survival are unknown. Clinical trials comparing efficacy and toxicity of alpha-interferon and deoxycoformycin, the extent of cross-resistance, and relationship of activity to previous splenectomy are in progress. Additional studies are testing combinations of these agents. Although interferon is commercially available for treating hairy cell leukemia, considering such therapy routine is counterproductive. Long-term clinical trials of interferon and deoxycoformycin are essential to advance our biologic knowledge of this rare disease, and to ensure optimal therapy for a potentially curable malignancy.

The intestine is a unique immunologic organ that comprises an afferent and efferent compartment and provides the host with the ability to respond through several different effector mechanisms against environmental factors. We discuss mechanisms in three intestinal diseases in this overview of the mucosal immune system. Genetic and immunologic factors are important in the pathogenesis of celiac disease, which is characterized by damage to the mucosa of the small intestine with resultant malabsorption. Pathogenic microbes are important environmental agents that interact with the intestinal mucosa and initiate local immune responses. Advances in the understanding of the mucosal immune response to these pathogenic microbes have produced a clear picture of the way in which this specialized immune system works in concert with systemic immunity. As to the autoimmune nature of inflammatory bowel disease, no specific antigen has been shown to incite the inflammatory reactions and neither the target cells nor the effector mechanism involved have been identified. Several factors exist, however, to suggest an autoimmune mechanism and the role of mucosal immunologic factors in this disease.

Kidney transplantation using either kidneys from living or nonliving donors is now generally regarded as the primary therapy for most patients with end-stage kidney failure. In 1984, 32% of all kidney transplantations done in the United States involved living donors. Reasons justifying the use of kidneys from living donors are the higher success rate and the inadequate supply of cadaveric kidneys. In addition, with a living donor, it is easier to arrange for kidney transplantation before dialysis therapy needs to be started. An analysis of 2495 donor nephrectomies reported in the literature, and 5698 donor nephrectomies reported from the 12 largest centers that do kidney transplantation with living donors, indicates an approximate incidence of 1 donor death per 1600 nephrectomies. Although long-term follow-up in kidney donors has shown only that mild, nonprogressive proteinuria develops in about 33% and that the frequency of hypertension may increase, we advise that the kidney donor have a careful long-term follow-up and avoid a high protein intake because of its potential to lead to progressive glomerular damage.