Fistulas between the aorta and left atrium, invariably a complication of aortic valvular endocarditis, are rare and infrequently diagnosed premortem. We describe a patient who presented with this entity and review the reports of five other patients for whom a diagnosis was made premortem. A number of causative organisms have been identified. The clinical course is characteristically one of rapidly progressive heart failure. Notably, only half of these fistulas were detected by transthoracic echocardiography, whereas all were identified by transesophageal echocardiography when utilized. Once the diagnosis is made, prompt surgical repair is required to avert the high mortality from rapidly developing refractory congestive heart failure.

A number of general observations can be made from these recent studies. Lactate is a ubiquitous substance that is produced and removed from the body at all times, even at rest, both with and without the availability of oxygen. It is now recognized that lactate accumulates in the blood for several reasons, not just the fact that oxygen supply to the muscle is inadequate. Lactate production and removal is a continuous process; it is a change in the rate of one or the other that determines the blood lactate level. Rather than a specific threshold, there is most likely a period of time during which lactate production begins to exceed the body's capacity to remove it (through buffering or oxidation in other fibers). It may be appropriate to replace the term "anaerobic threshold" to a more functional description, since the muscles are never entirely anaerobic nor is there always a distinct threshold ("oxygen independent glycolysis" among others has been suggested) Lactate plays a major role as a metabolic substrate during exercise, is the preferred fuel for slow-twitch muscle fibers, and is a precursor for liver gluconeogenesis. The point at which lactate begins to accumulate in the blood, causing an increase in ventilation, is important to document clinically. Irrespective of the underlying mechanism or specific model that describes the process, the physiologic changes associated with lactate accumulation have significant import for cardiopulmonary performance. These include metabolic acidosis, impaired muscle contraction, hyperventilation, and altered oxygen kinetics, all of which contribute to an impaired capacity to perform work. Thus, any delay in the accumulation of blood lactate which can be attributed to an intervention (drug, exercise training, surgical, etc) may add important information concerning the efficacy of the intervention. A substantial body of evidence is available demonstrating that lactate accumulation occurs later (shifting to a higher percentage of Vo2max) after a period of endurance training. In athletes, the level of work that can be sustained prior to lactate accumulation, visually determined, is an accurate predictor of endurance performance. Presumably, these concepts have implications related to vocation/disability among patients with cardiovascular and pulmonary disease, but few such applied studies have been performed outside the laboratory. Blood lactate during exercise and its associated ventilatory changes maintain useful and interesting applications in both the clinical exercise laboratory and the sport sciences. However, the mechanism, interpretation, and application of these changes continue to rely more on tradition and convenience than science.

There is widespread acceptance that screening for lung cancer is not indicated, to our knowledge, because no randomized trial has demonstrated a reduction in mortality as a result of screening. The objectives of this work are to review prospective studies on lung cancer screening and to analyze the extent to which known biases may have influenced observed results.

Inhaled and systemic corticosteroids are commonly prescribed for the treatment of COPD. Despite their frequent use, there is insufficient evidence regarding efficacy of steroid therapy in COPD. While awaiting the results of more definitive prospective trials, the clinician must evaluate whether the benefits of such therapy outweigh the potential for adverse events. This is particularly pertinent in the population of patients with COPD who generally are older, less active, and have significant tobacco use histories, all of which may place them at greater risk for adverse effects. In this review, we examine the current scientific evidence supporting the many purported adverse systemic effects associated with the use of corticosteroids in the treatment of COPD.

This literature review compares the efficacy of the two most commonly recommended bedside tests for detecting aspiration in tube-fed patients: (1) adding dye to the formula and observing for its appearance in tracheobronchial secretions, and (2) using glucose oxidase reagent strips to test tracheobronchial secretions for glucose-containing enteral formula. The review also describes potential problems and cost associated with each test. Several studies indicate that the dye method is far less sensitive than the glucose reagent method; further, there are anecdotal reports of potential harm to patients when dye is added to tube feedings. Specificity of the glucose method has been challenged by several authors; also, cost is probably greater with this method.

Asthma correctly is characterized as a syndrome rather than a disease, because a single causative mechanism has not yet been defined. This lack of definition makes the search for a cure extremely complex. Until a common pathogenetic link is identified, the possibility of a cure is remote. The precise nature of the inflammatory response in asthma has not been defined, and current concepts of the pathogenesis of asthma represent, to some extent, a reductionistic approach to a process that has been seen variously as an allergic reaction, autonomic hyperresponsiveness, or both. Additional evidence of the polygenomic nature of the disease and the inability to define a specific pathogenetic process linked to a final common pathway suggest that gene therapies probably will not be feasible, at least for the near future. As expected, most approaches now being developed are directed toward improved therapies, and optimal treatment may obviate the need to develop complex therapies effecting a cure. Under any circumstance, the notion of a cure will have to await a more comprehensive understanding of the syndrome known as human asthma. This article is intended to provide provocative insights into the reasons why a cure remains elusive.

Pranlukast (SB 205312, ONO-1078) is an orally active, potent, selective blocker of peptidyl-leukotriene receptors. Pranlukast has been studied in a worldwide clinical development program and recently was approved in Japan for the treatment of asthma. This worldwide experience includes a pivotal safety and efficacy study conducted in Japan, a leukotriene D4 (LTD4) challenge study conducted in Europe, and two safety, tolerability, and clinical activity studies conducted in Europe and North America. The pivotal study was a randomized, double-blind, 8-week comparison of pranlukast, 225 mg bid, and azelastine, 2 mg bid. Improvements in asthma symptom scores, morning and evening peak expiratory flow rate (PEFR), and a decreased need for bronchodilators and corticosteroids in the pranlukast-treated group were statistically significant when compared with those in the azelastine-treated group. The most common adverse experiences were GI. The European challenge study evaluated the ability of 5-day therapy with pranlukast, 450 mg bid, to block the bronchoconstrictor effect of inhaled LTD4. A single dose of pranlukast resulted in a 10.6-fold increase in the concentration of LTD4 required to produce a 35% decrease in specific airways conduction; following 5 days of therapy, this increased to 25.9-fold. The two safety, tolerability, and clinical activity studies were randomized, double-blind, placebo-controlled, 4-week evaluations of pranlukast, 225 to 450 mg bid. Improvements in FEV1, PEFR, and asthma symptoms were noted. Ongoing studies will define further the role of pranlukast as a treatment for asthma and allergic rhinitis.

The leukotriene receptor antagonist pranlukast (SB 205312, ONO-1078) has demonstrated clinical activity as an antiasthma drug in traditional challenge models, including exercise-induced asthma and inhaled bronchoprovocations with sulpyrine (an aspirin analogue), antigen, methacholine, leukotriene C4, and leukotriene D4. This article reviews the results of a published sulpyrine-challenge study and two unpublished house dust mite antigen challenge studies. Statistically significant attenuation of the decrease in FEV1 induced by bronchoprovocation was observed with pranlukast compared with placebo or baseline control in all challenge studies. These challenge studies demonstrate that pranlukast significantly protects against aspirin-induced bronchoconstriction and significantly attenuates both the immediate (early) and late airway responses to inhaled allergen.

The cysteinyl leukotrienes (LTs) are chemical mediators that are thought to contribute to the pathophysiologic condition of asthma and other inflammatory diseases. The biological effects of the cysteinyl LTs in the lung are pleiotropic, including both bronchoconstrictor and a growing list of nonbronchoconstrictor activities that extend to inflammatory cell recruitment, vascular leakage, mucus production, neuronal dysfunction, and airways remodeling. This spectrum of effects of cysteinyl LTs is consistent with an expanded view of asthma that extends beyond simply bronchoconstriction and inflammation. Consequently, the clinical efficacy of cysteinyl LT receptor antagonists (LTRAs) in asthma may be related to antagonism of more than cysteinyl LT-induced bronchoconstriction. The relationship of antagonism of the multiple effects of cysteinyl LTs by cysteinyl LTRAs to their utility in the therapy of asthma is addressed, and the preclinical and clinical pharmacology of cysteinyl LTRAs is reviewed.

Asthma is a chronic inflammatory disease that is associated with widespread but variable airflow obstruction. The mechanisms that lead to airflow obstruction in asthma are bronchoconstriction, mucosal edema, increased secretion of mucus, and an inflammatory-cell infiltrate that is rich in eosinophils. Leukotrienes (LTs) B4, C4, D4, and E4 have been shown experimentally to play a role in each of these inflammatory mechanisms and to mimic the pathologic changes seen in asthma. Inhaled LTC4 and LTD4 are the most potent bronchoconstrictors yet studied in human subjects. LTC4 and LTD4 also may cause migration of inflammatory cells into the asthmatic airway. LTs are derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism, and increased production of LTs has been demonstrated in patients who have asthma. Leukotriene receptor antagonists and specific inhibitors of the 5-LO pathway hold great promise as new therapies to treat asthma. Because LTC4, LTD4, and LTE4 appear to interact with a common LTD4 receptor, selective LTD4 receptor antagonists (eg, pranlukast [SB205312/ONO-1078], zafirlukast [ICI 204,219], MK-571, and MK-679), as well as zileuton (A-64077, a direct inhibitor of 5-LO) have been developed as antiasthma agents. Clinical and experimental studies have demonstrated the efficacy of these compounds in reducing not only the symptoms of asthma, but use of beta 2-agonists and bronchoconstriction induced by exposure to allergens, exercise, aspirin, and cold air.

Effective treatments for asthma exist, but morbidity and mortality have continued to climb. Many attempts have been made to refine rather than change therapy over the past 20 years. Drugs currently used to treat asthma include beta 2-agonists, glucocorticoids, theophylline, cromones, and anticholinergic agents. For acute, severe asthma, the inhaled beta 2-agonists are the most effective bronchodilators. Short-acting forms give rapid relief; long-acting agents provide sustained relief and help nocturnal asthma; and serious adverse effects are rare when these drugs are used properly. First-line therapy for chronic asthma is inhaled glucocorticoids, the only currently available agents that reduce airway inflammation. Their side effects can be reduced by rinsing the mouth or by using large-volume spacers. Theophylline is a bronchodilator that is useful for severe and nocturnal asthma, but recent studies suggest that it may also have an immunomodulatory effect. Although theophylline is inexpensive, monitoring its plasma concentrations is both expensive and inconvenient. Cromones work best for patients who have mild asthma: they have few adverse effects, but their activity is brief, so they must be given four times daily. The anticholinergic bronchodilators are more useful for treating COPD than for chronic asthma. These drugs have virtually no side effects, and their onset is slower and their action longer than inhaled beta 2-agonists. The new direction in treating asthma will be orally administered medication that has few side effects and is targeted specifically to the pathogenesis of asthma.

The prevalence of asthma and allergic rhinitis is increasing in the general population, and a high proportion of new patients have coexisting upper and lower airway disease. Estimates show that 60 to 78% of patients who have asthma have coexisting allergic rhinitis. During the past decade, our understanding of asthma and allergic rhinitis has evolved. The historic perspective of these allergen-induced disorders as distinct and separate entities is being displaced by current thinking that they are described better as a continuum of inflammation involving one common airway. Therefore, traditional therapies originally indicated for allergic rhinitis and asthma are being reassessed to explore their potential utility in both upper and lower airway diseases. Recently, there has been a renewed interest in the role that histamines play in lower airway disease, and interest is increasing in the theory that leukotrienes, which are far more potent inflammatory mediators than histamines, play a role in upper airway disease. Given the pivotal role that leukotrienes play as potent inflammatory mediators in the pathophysiologic state of inflammation of both airways, leukotriene receptor antagonists recently have emerged as important therapeutic advances that have potential clinical utility in both asthma and allergic rhinitis.

The prevalence of asthma is increasing, despite better understanding of its pathogenesis and improved treatments. During the past 10 years, the perception of asthma has shifted from a disease primarily characterized by altered smooth muscle function to one mainly characterized by chronic inflammation. This article reviews the evidence supporting the relationship of inflammation in both the upper and lower airways, focusing on intermittent seasonal disease as well as on the more chronic and severe forms of asthma, including that associated with aspirin intolerance. It also presents evidence to support a pivotal role for the epithelial cell, together with the mast cell and the eosinophil, in initiating and maintaining inflammation in the upper and lower airways.

Cheyne-Stokes respiration (CSR) is a form of sleep-disordered breathing seen in approximately 40% of congestive heart failure patients with a left ventricular ejection fraction of < 40%. It is characterized by a crescendo-decrescendo alteration in tidal volume separated by periods of apnea or hypopnea. Sleep is generally disrupted, often with frequent nocturnal arousals. Clinical features include excessive daytime sleepiness, paroxysmal nocturnal dyspnea, insomnia, and snoring. Proposed mechanisms include the following: (1) an increased CNS sensitivity to changes in arterial PCO2 and PO2 (increased central controller gain); (2) a decrease in total body stores of CO2 and O2 with resulting instability in arterial blood gas tensions in response to changes in ventilation (underdamping); and (3) an increased circulatory time. In addition, hyperventilation induced hypocapnia seems to be an important determinant for the development of CSR. Mortality appears to be increased in patients with CSR compared to control subjects with a similar degree of left ventricular dysfunction. Therapeutic options include medically maximizing cardiac function, nocturnal oxygen therapy, and nasal continuous positive airway pressure. The role that other therapeutic modalities, such as inhaled CO2 and acetazolamide, might have in the treatment of CSR associated with congestive heart failure has yet to be determined.