To propose a new classification for the primary immunodeficiency disorders and to review potential therapeutic applications of biologic response modifiers in these disorders.

To determine whether there is sufficient information in the medical literature to guide appropriate treatment of hypertensive women.

As the need to set limits in health care becomes more generally accepted, physicians and policymakers need to consider who can best decide how to allocate medical resources among patients. This commentary focuses on the two obvious candidates: payers and physicians. Although payer-based allocation has the advantage of allowing physicians to act strictly on behalf of their patients, it lacks precision and flexibility. Physician-based allocation places allocation decisions in the hands of individuals better positioned and better equipped to make choices that maximize health outputs. To preserve clinical freedom and minimize micromanagement of individual patients, physicians should expand their advocacy role beyond individual patients and recognize their responsibility to populations. In doing so, physicians would acknowledge that societal and patient interests differ and that health care is just one of many important social goods. For physicians willing to make these choices, five general guidelines are offered. Finally, mechanisms to encourage physician-based allocation are considered.

We present a practical set of guidelines for assessing competency in patients with cognitive deficits due to neurologic disorders such as stroke, head injury, Alzheimer disease, and multi-infarct dementia. Our focus is the evaluation of cognitive processes underlying the ability to make competent decisions, with an emphasis on the identification of areas of preserved function that may be used to bypass intellectual deficits. The assessment of the cognitive processes underlying competency involves a series of steps designed to evaluate attention, language, memory, and frontal lobe function. The examiner must first show that the patient has an adequate level of attention for participation in the further testing of specific cognitive functions; second, that the patient is able to comprehend relevant instructions, retain information long enough to evaluate it in relation to relevant recent and remote experiences, and express his or her wishes; and finally, that the patient has sufficiently intact judgment and awareness. The examiner must determine whether the patient's preserved cognitive abilities are sufficient for him or her to make an adequate judgment in relation to the specific question being asked. If cognitive function is found to be significantly impaired, the examiner should do a detailed assessment for the presence of compensatory abilities that can be used to bypass the deficits. For example, the examiner should assess whether patients who cannot speak are still able to express their wishes by pointing, using gesture, or even by drawing pictures. Unless such an assessment has been done, patients should not be considered incompetent.

Lipoprotein(a) [Lp(a)], a lipoprotein variant, was relegated for almost 25 years to the study of a few specialists. During the past 3 to 4 years, however, there has been a tremendous upsurge of interest in Lp(a), primarily because of multidisciplinary efforts in structural and molecular biology. Findings emerging from these efforts include the following: Lp(a) represents a cholesteryl-ester, low-density-lipoprotein (LDL)-like particle with apolipoprotein (apo) B-100 linked to apo(a); apo(a) is a glycoprotein coded by a single gene locus on the long arm of chromosome 6, which has several alleles, accounting for its remarkable size polymorphism (300 to 800 kD); apo(a) size polymorphism relates to plasma levels and density distribution of Lp(a); apo(a) is strikingly similar to plasminogen; and in vitro, Lp(a), in appropriate levels, competes for some physiologic functions of plasminogen in the coagulation and fibrinolytic cascade and may thus be thrombogenic. The LDL-like properties of Lp(a) may also confer atherogenic potential, but the mechanisms underlying this atherogenicity remain to be defined. In epidemiologic studies, high plasma Lp(a) levels have been associated with an increased incidence of atherosclerotic cardiovascular disease, especially in patients less than 60 years of age. Moreover, Lp(a) has been found as an intact particle in the arterial intima, particularly in association with atherosclerotic plaque. This finding suggests that Lp(a) can transverse the endothelium, possibly by a non-receptor-mediated process, and, at the intimal level, acquire thrombogenic and atherogenic potentials. Current information justifies the need to determine plasma Lp(a) levels in patients with a history of atherosclerotic cardiovascular disease. Unfortunately, the available techniques need to be standardized. Apolipoprotein(a) exists in isoforms of different sizes, and the importance of determining apo(a) phenotypes in clinical practice remains to be established.

Pharmaceutical manufacturers commonly contract with clinical investigators for pre-market testing of new products. The per-patient reimbursement offered to the investigator generally exceeds the per-patient costs incurred by the investigator. This excess represents a windfall that can be used to pay for travel, equipment, or supplies, or to fund research for which the investigator cannot obtain funding through peer-reviewed granting channels. This excess raises a potential conflict of interest, because it may lead the investigator to propose experimental treatment for a patient when the patient might be better served by conventional treatment or by no treatment at all. Not only does this situation pose a conflict of interest, it also is a conflict of which few patients are aware and fewer are informed. We propose that all experimental subjects be informed of the source, amount, and mechanism of funding for the experimental treatments they undergo. Further, we propose that payments from pharmaceutical manufacturers for pre-market testing of drugs go to the medical school dean rather than to the individual investigator. With this money, the dean can defray the direct as well as the indirect costs of the clinical study; the remainder, which would otherwise go directly to the investigator, should be placed in a funding pool for which the entire medical school could compete. This solution largely eliminates conflict of interest, addresses informed consent, and reasonably balances the interests of the experimental subject, the clinical investigator, the pharmaceutical manufacturer, and the academic institution.

This conference focuses on the controversies about managing thyroid cancer, emphasizing the possibility that the treatment of patients with potentially fatal thyroid cancer may be improved. Although the mortality rate from thyroid cancer is low, it is the highest among cancers affecting the endocrine glands (excluding the ovary). Exposure to radiation during childhood in the 1930s and 1940s increased the incidence of but not the mortality from thyroid cancer, because these tumors are mainly papillary cancers developing in young adults. These rates may change as the exposed cohort ages. Risk factors that increase mortality include older patient age and the growth characteristics of the tumor at diagnosis, the presence of distant metastases, and cell type (for example, the tall-cell variants of papillary cancer, follicular cancer [to be distinguished from the more benign follicular variant of papillary cancer], medullary cancer, and anaplastic cancer). Local metastases in lymph nodes do not seem to increase the risk for death from papillary cancer, but they do increase the risk for death from follicular and medullary cancer. In the latter, mortality is decreased by the early detection and treatment of patients with the familial multiple endocrine neoplasia syndrome 2a. There are excellent tumor markers for differentiated cancer of the parafollicular and of the follicular cells (serum calcitonin and serum thyroglobulin levels, respectively). Measuring the calcitonin level allows early diagnosis of familial medullary cancer, whereas measuring the thyroglobulin level, although useful only after total thyroidectomy, allows early recognition of recurrence or metastases of papillary or follicular cancer. Initial surgery, protocols for follow-up, and the use of radioiodine for the ablation of any residual thyroid and the treatment of metastatic cancer are discussed. Because these tumors resist currently available chemotherapy regimens, possible ways to increase the effectiveness of radioiodine therapy are considered as are new approaches to treatment.

To examine, from the perspective of primary care physicians, the value of mental status findings and ancillary tests in diagnosing dementia or its causes.

To review the recent literature on the efficacy of combined insulin and sulfonylurea therapy in patients with type 2 diabetes.

To discuss adjunctive pharmacologic agents for acute myocardial infarction, to critique their initial effects in clinical trials, and to review their potential for improving the clinical conditions of patients with acute myocardial infarction.

The variable mortality risk associated with chronic stable angina calls for careful selection of patients for coronary artery bypass grafting (CABG) if the aim of management is to prolong life. The randomized and observational studies done in the last 20 years have identified the variables relevant to patient selection and thus have provided a rational basis for such clinical decisions. These studies showed that the sicker the patient, as gauged by relevant measures of coronary disease and cardiovascular morbidity, the more likely it is that CABG will prolong life. A CABG-related improvement in survival is therefore more likely to occur the worse the left ventricular function; the greater the number of diseased vessels; the more proximal the location of coronary lesions (more muscle is threatened by such lesions); the greater the severity of the lesions as determined by angiography; the more severe the angina; the more easily provocable the ischemia or the more extreme the measures of ischemia; and, within limits, the older the patient. Greater survival gain after CABG also occurs in patients with peripheral vascular disease, in patients with baseline electrocardiographic ST-segment and T-wave changes, and probably in women. Thus, patients are likely to live longer after CABG if they have left main disease; three-vessel disease with left ventricular dysfunction (ejection fraction less than 50%), class III or IV angina, provocable ischemia, or disease in the proximal left anterior descending coronary artery; two-vessel disease with proximal left anterior descending artery involvement; and two-vessel disease with class III or IV angina as well as either severe left ventricular dysfunction alone or moderate left ventricular dysfunction together with at least one proximal lesion. When the decision of whether to do CABG is less clear-cut, the presence of peripheral vascular disease, female sex, baseline electrocardiographic ST-segment and T-wave changes, or older age (over 60 but under 80 years) should weigh in favor of doing CABG. In general, patients with single-vessel disease do not seem to derive survival benefit from CABG.

To review the incidence, risk factors, pharmacology, and management of central nervous system reactions to histamine-2 receptor (H2) blockers.

Considerable progress has been made in recent years in our understanding of atherogenesis and, in particular, of how it relates to lipoprotein metabolism. In this conference, we attempt to re-evaluate the data on the relation between alcohol intake and coronary heart disease, emphasizing the effects of alcohol on lipoprotein metabolism. Epidemiologic data generally show an inverse correlation between coronary heart disease risk and moderate alcohol intake (variously defined but generally corresponding to 2 to 4 drinks per day). The potentially drastic effects of excessive alcohol intake on health, however, preclude any recommendation that patients increase their alcohol consumption. Equally, there may be no basis for prescribing moderate alcohol intake but, even here, the data are far from complete. The mechanism by which moderate alcohol intake "protects" remains unclear. Perhaps the best available hypothesis relates to the increased concentration of high-density lipoprotein (HDL) cholesterol associated with moderate alcohol intake. However, it should be stressed that we are still uncertain about the mechanisms linking a high HDL level to protection against coronary heart disease. If a high HDL level is only a marker (and not directly protective), raising HDL levels need not confer protection. Alcoholism, on the other hand, is associated with marked elevation of triglyceride-rich lipoproteins and is among the most common causes of hypertriglyceridemia. Moreover, once hepatic damage occurs, plasma HDL levels may actually be lower than normal. The determining point is that high alcohol intakes are associated with increased overall mortality. Until we know more about the metabolic and behavioral effects of alcohol and about its linkage to atherosclerosis, we have no basis for recommending either that patients increase their alcohol intake or that they start to drink if they do not already.

To examine the evidence for a relation between advancing patient age and the risk for adverse drug reactions.

In a landmark decision, the U.S. Supreme Court affirmed a Missouri ruling that sharply limited family decisions about life-sustaining treatment for incompetent patients. The Court held that the Constitution protects the refusal of life-sustaining treatment by competent patients. For incompetent patients, states may require "clear and convincing" evidence of refusal, specifically for the withdrawal of tube feedings, if such a person were in a persistent vegetative state. The ruling left many clinical questions unanswered, such as whether life-sustaining treatment must be given to terminally ill incompetent patients, whether patients may refuse artificial feedings, and what constitutes clear and convincing evidence of refusal. The decision also has potentially harmful consequences. It may undermine family decision making, encourage cynicism and disregard of the law, and promote defensive medicine. Physicians can minimize such consequences by encouraging patients to provide advance directives, such as the durable power of attorney for health care, by urging legislative action, and by setting national practice standards for decisions regarding incompetent patients.

Diuretic drugs usually improve edema when used judiciously. Some patients, however, become resistant to their effects. Diuretic resistance may result from dietary indiscretion, poor compliance, impaired bioavailability, imparied diuretic secretion into the lumen of the renal tubule, or because other drugs interfere with diuretic activity. When easily treatable causes of diuretic resistance have been excluded, resistance often reflects the intensity of the stimuli to sodium retention. Recent experimental work has indicated ways in which the kidney adapts to chronic diuretic treatment and has indicated how these adaptations may limit diuretic effectiveness. First, nephron segments downstream from the site of diuretic action increase sodium-chloride (NaCl) reabsorption because the delivered NaCl load increases. Second, diuretic-induced contraction of the extracellular fluid volume stimulates kidney tubules to retain NaCl until the next dose of diuretic is administered. Third, kidney tubules themselves may become hypertrophic because they are chronically stimulated by diuretic-induced increases in NaCl delivery. These adaptations all increase the rate of NaCl reabsorption and blunt the effectiveness of diuretic therapy. When diuretic resistance is present, using a second diuretic drug that acts in a different nephron segment is often effective. Recent experimental results suggest that a second class of drug may act synergistically with the first by blocking the adaptive processes that limit diuretic effectiveness. On the basis of an understanding of the mechanisms of diuretic adaptation and resistance, treatment regimens can be designed to block specific adaptive mechanisms and to improve diuretic therapy.

To review the status of emergency, urgent, routine, and selective angiography after intravenous thrombolytic therapy.

Ventricular arrhythmias remain the leading cause of death from coronary artery disease. This review summarizes current thinking in several areas relating to the pathophysiology, prognosis, and therapy of ventricular arrhythmias associated with acute and chronic coronary artery disease syndromes. The experimental basis of arrhythmias in the setting of acute myocardial ischemia and chronic myocardial infarction is described, stressing the important pathophysiologic differences between these two conditions. The effects of the autonomic nervous system as a key modulator of ischemic arrhythmogenesis are discussed. Insights, derived from endocardial mapping studies, into the nature of ventricular tachycardia in humans with chronic myocardial infarction are described, including implications for risk stratification and therapy to prevent arrhythmia recurrence. Current therapeutic principles are discussed in the management of ventricular arrhythmias associated with coronary artery disease, including pharmacologic approaches, surgical and catheter ablation, and automatic implantable cardioverting and defibrillating devices.

Clinicians increasingly are urged to integrate preventive services into their clinical practices. To facilitate this process, several groups have developed practice guidelines for preventing disease in asymptomatic patients. In this paper, we compare and contrast preventive guidelines from the American College of Physicians (ACP), the Canadian Task Force on the Periodic Health Examination (CTF), the United States Preventive Services Task Force (USPSTF), and other well-known authorities. We chose these groups because they based their recommendations on explicit methods that include critical appraisal of the pertinent literature. Recommendations from these authorities usually are consistent with each other. Moreover, the ACP, CTF, and USPSTF all favor a shift away from the relatively simple classification of patients by age and sex for general preventive interventions to the more complex stratification of patients by additional risk factors and the formulation of a selective prevention strategy that is specific to each risk profile. Some guidelines, particularly the criteria used to define patients who are at increased risk for preventable disease and who should have more intensive surveillance, are difficult to interpret. Further research is needed to address some areas of disagreement and ambiguity. In addition, new tools must be developed to help physicians apply preventive guidelines, particularly those that require noting many patient-specific characteristics.