The etiology of atopy is unknown. Its family distribution suggests transmissibility. Populations moving from countries with a low incidence to those with a high incidence increase to the higher rate. African and New Guinea village groups developed asthma with return of individuals who have acquired atopy in the city. Protection (and possibly immunity) develops with early exposure to child care or to affected older siblings. T helper (Th) type 2 clones driving specific allergies remain active even without further allergen exposure. Other IgE responses remain normal. Once boosted to completeness, the patterns of skin test results remain quite stable, possibly by the localization of abnormality maintained by immunity. An example of a virus causing the immortality of Th2 cells is herpes simplex virus type 1. It infects mouse or human Th2 cells and, although it does not multiply, causes immortality by increasing FAS-mediated apoptosis of T cells directed against the infected cells. Human T-cell leukemia virus 1 and probably others use similar ploys. Abnormal levels of FAS receptors and resistance to FAS apoptosis in nasal polyp lymphocytes and abnormal Th2 clones of atopy are interesting in this regard. The localizing role of a staphylococcal superantigen in atopic dermatitis, and possibly in autoimmunity in nonatopic eczema and intrinsic asthma, encourage the consideration of roles for microorganisms in localization and etiology. The epidemiology and characteristics of atopic disease support the plausibility of a viral hypothesis.

Patients with obstructive sleep apnea (OSA) are at increased risk for coronary artery and cerebrovascular diseases. Numerous studies suggest that a hypercoagulable state is prospectively related to atherothrombotic events. This review explores whether changes in hemostasis may constitute one biological link between OSA and vascular disease.

The air medical transport of cardiac patients is a rapidly expanding practice. For various medical, social, and economic indications, patients are being flown longer distances at commercial altitudes, including international and intercontinental flights. There are data supporting the use of short-distance helicopter flights early in the course of a cardiac event for patients needing emergent transfer for percutaneous coronary intervention or aortocoronary bypass. When considering elective long-distance air medical transport of cardiac patients for social or economic reasons, it is necessary to weigh the benefits against the potential risks of flight. A few recent studies suggest that long-distance air medical transport is safe under certain circumstances. Current guidelines for air travel after myocardial infarction do not address the use of medical escorts or air ambulances equipped with intensive care facilities. Further research using larger prospective studies is needed to better define criteria for safe long-distance air medical transport of cardiac patients.

The assessment of the structure and function of the subvalvular apparatus (SVA) in patients with rheumatic mitral stenosis (MS) is complex, yet is of major importance prior to therapeutic decision making. Currently available methods of assessment are neither sufficiently accurate nor feasible. We review anatomic and functional aspects of the SVA and define SVA involvement in rheumatic MS. The role of various noninvasive and invasive methods for evaluating the integrity and function of SVA in rheumatic MS, as well as clinical implications and pitfalls in assessment of SVA are also discussed.

In addition to its primary role in hemostasis and blood coagulation, thrombin is a potent mitogen capable of inducing cellular functions. Therefore, it should come as no surprise that thrombin has proved to be of importance in the behavior of cancer. In this review, we focus on the ability of tissue factor (TF) and thrombin to influence tumor angiogenesis. Both exert their influence on angiogenesis through clotting-dependent and clotting-independent mechanisms: (1). directly affecting signaling pathways that mediate cell functions, and (2). mediating clot formation, thereby providing a growth media for tumor cells. Therefore, anticoagulant drugs may prove efficacious in cancer treatment due to their ability to reduce the characteristic hypercoagulability of cancer and alter the fundamental biology of cancer.

The exploration of coagulation led to identifying inflammation as a major factor in arterial disease throughout life. "Integrative molecular physiology" reflects our emerging understanding of how coagulation and inflammation integrate with one another, in both normal physiology and in pathophysiology. Our own responses to environmental challenge provide much of the damage that cumulatively results in chronic cardiovascular disease. Only by intervening in exquisitely precise ways can we hope to effectively and safely modify the course of lifelong chronic diseases, such as atherosclerosis.

Venous thromboembolism (VTE) is a common and potentially lethal disease that recurs frequently and is associated with long-term impairment and suffering. Despite a great deal of effort, the incidence of VTE has not changed substantially in the last 20 years. Independent risk factors include hospitalization (either for surgery or for acute medical illness), trauma, malignant neoplasm, central venous catheters or transvenous pacemakers, superficial vein thrombosis, and extremity paresis. Of these, hospitalization accounts for almost 60% of all VTE occurring in the community. Thus, universal effective prophylaxis of hospitalized patients would significantly reduce the incidence of VTE. Parenteral direct thrombin inhibitors are safe and effective for both prevention and treatment of acute VTE, and do not require laboratory monitoring or dose adjustment. Oral direct thrombin inhibitors may also be safe and effective, and offer enhanced convenience without diet or drug-drug interactions.

When the activities of the coagulation and fibrinolytic cascades are properly regulated, so that fibrin (FN) deposition and removal are properly balanced, the vascular system is protected from catastrophic blood loss at the site of an injury, while its fluidity is ensured elsewhere. When these activities are not properly regulated, however, the organism is subjected to either excessive bleeding or thrombosis. Thrombomodulin on the endothelial cell is very important in this regulation because it converts thrombin to an anticoagulant enzyme by directing it toward the activation of protein C. It also converts thrombin to an antifibrinolytic enzyme by directing it toward the activation of thrombin-activatable fibrinolysis inhibitor (TAFI). By doing so, it creates a direct molecular connection between the coagulation and fibrinolytic cascades, such that activation of the former suppresses the activity of the latter. Recent studies indicate that the TAFI pathway functions in vivo and is likely relevant in maintaining the proper balance between FN deposition and removal. Whether it will be a target for pharmaceutical manipulation of this balance remains to be determined.

The protein C anticoagulant pathway serves as a major system for controlling thrombosis, limiting inflammatory responses, and potentially decreasing endothelial cell apoptosis in response to inflammatory cytokines and ischemia. The essential components of the pathway involve thrombin, thrombomodulin, the endothelial cell protein C receptor (EPCR), protein C, and protein S. Thrombomodulin binds thrombin, directly inhibiting its clotting and cell activation potential while at the same time augmenting protein C (and thrombin activatable fibrinolysis inhibitor [TAFI]) activation. Furthermore, thrombin bound to thrombomodulin is inactivated by plasma protease inhibitors > 20 times faster than free thrombin, resulting in increased clearance of thrombin from the circulation. The inhibited thrombin rapidly dissociates from thrombomodulin, regenerating the anticoagulant surface. Thrombomodulin also has direct anti-inflammatory activity, minimizing cytokine formation in the endothelium and decreasing leukocyte-endothelial cell adhesion. EPCR augments protein C activation approximately 20-fold in vivo by binding protein C and presenting it to the thrombin-thrombomodulin activation complex. Activated protein C (APC) retains its ability to bind EPCR, and this complex appears to be involved in some of the cellular signaling mechanisms that down-regulate inflammatory cytokine formation (tumor necrosis factor, interleukin-6). Once APC dissociates from EPCR, it binds to protein S on appropriate cell surfaces where it inactivates factors Va and VIIIa, thereby inhibiting further thrombin generation. Clinical studies reveal that deficiencies of protein C lead to microvascular thrombosis (purpura fulminans). During severe sepsis, a combination of protein C consumption, protein S inactivation, and reduction in activity of the activation complex by oxidation, cytokine-mediated down-regulation, and proteolytic release of the activation components sets in motion conditions that would favor an acquired defect in the protein C pathway, which in turn favors microvascular thrombosis, increased leukocyte adhesion, and increased cytokine formation. APC has been shown clinically to protect patients with severe sepsis. Protein C and thrombomodulin are in early stage clinical trials for this disease, and each has distinct potential advantages and disadvantages relative to APC.

The accumulation of thrombin at sites of vascular injury provides one of the chief means for recruiting platelets into a growing hemostatic plug. Studies completed over the past 10 years show that platelet responses to thrombin are mediated by a subset of G protein-coupled receptors known as protease-activated receptors. These receptors are activated on cleavage by thrombin, initiating the intracellular signaling events needed to transform mobile, nonadhesive platelets into cells that can participate in the growth of an immobile hemostatic plug. How this is accomplished is the subject of this review.

After generation from prothrombin, thrombin plays multiple roles in the blood coagulation cascade that are mediated by interaction with a number of physiologic substrates, effectors, and inhibitors. Structural and mutagenesis studies have helped unravel the molecular basis of thrombin interactions in the context of both well-established and emerging new roles of the enzyme. The functional versatility of thrombin owes much to its evolutionary origin and results from structural determinants and mechanisms that can be exploited by pharmacologic intervention.

The generation of the enzyme thrombin from its precursor prothrombin is the central event of the blood coagulation process, which is essential to hemostasis and the culprit in thrombosis. Thrombin is produced by a complex series of proteolytic events that are initiated when cryptic tissue factor interacts with plasma factor VIIa to initiate the complex series of events leading to the formation of the blood coagulation enzyme complexes that lead to the efficient generation of the enzyme. During these processes, thrombin contributes to both the generation of the catalysts involved in its ultimate production and to the catalysts that lead to attenuation of its production. Thrombin-catalyzed events both enhance and diminish the process of thrombin generation, which is down-regulated by stoichiometric and dynamic inhibitory processes. The combinations of intensities of activation and inhibition processes provide tight regulation of the hemostatic process, establishing reaction thresholds, essentially leading to an "on/off" switch. This review provides a brief summary of the evolution of knowledge with respect to present-day concepts of thrombin generation via the tissue factor pathway and its regulation.

Asbestosis can cause significant impairment and even death. It is also a well-recognized risk factor for the development of lung cancer. However, asbestosis is usually diagnosed on clinical grounds without the aid of pathology. Many physicians and researchers believe that in asbestos-exposed individuals with adequate latency, chest radiographic findings that are compatible with asbestosis are sufficient for the diagnosis. In order to determine whether this approach is reasonable, the positive predictive value of the chest radiograph for the diagnosis of pathologic asbestosis must be determined. This requires information about the prevalence of asbestosis, and the sensitivity and specificity of the chest radiograph in its diagnosis. In this article, the sensitivity and specificity of the chest radiograph in diagnosing asbestosis is determined from a literature analysis. The prevalence of asbestosis among present-day cohorts, such as construction workers and petrochemical workers, is assessed based on the relative risk of lung cancer in patients with asbestosis and the overall relative risk of lung cancer in these occupationally asbestos-exposed cohorts. The results indicate a positive predictive value for abnormal chest radiograph findings alone to be significantly < 50%. Therefore, the chest radiograph is inadequate as the sole clinical tool to be used to diagnose asbestosis in these cohorts. However, when rales and a low diffusing capacity of the lung for carbon monoxide are also present, the diagnosis of asbestosis on clinical grounds can be made with reasonable confidence.

Chronic heart failure (CHF) increases the resistance to gas transfer across the alveolar-capillary interface. Recent reports highlight the pathophysiologic relevance of changes in the lung leading to impaired fluid and gas exchange in the distal airway spaces. Under experimental conditions, an acute pressure or volume overload can injure the alveolar blood-gas barrier. This may disrupt its anatomic configuration, cause the loss of regulation of fluid-flux, and thereby affect alveolar gas conductance properties. These ultrastructural changes have been identified under the term of stress failure of the alveolar-capillary membrane. In the short term, these alterations are reversible due to the reparative properties of the alveolar surface. However, when the alveolar-capillary membrane is chronically challenged, for instance in patients with CHF, by noxious stimuli, such as humoral, cytotoxic, and genetic factors other than by mechanical trauma, remodeling of pathophysiologic and clinical importance may take place. These changes in some respects resemble the remodeling process in the heart. Emerging findings support the view that, in patients with CHF, alveolar-capillary membrane dysfunction may contribute to symptom exacerbation and exercise intolerance, and may be an independent prognosticator of clinical course. Angiotensin-converting enzyme inhibitors ameliorate the alveolar membrane gas conductance abnormality, reflecting improvement in the remodeling process. This article reviews the putative mechanisms involved in the impairment in gas diffusion in CHF patients and provides a link between physiologic changes and clinical findings.

Transesophageal echocardiography (TEE) is a growing technology that is frequently utilized in the critical care setting by intensivists, surgeons, anesthesiologists as well as specialists in cardiovascular diseases. The clinical application of TEE continues to emerge, and the indications and diagnostic utility of this technology as currently available are summarized in this review.