The best available data support the hypothesis that there are at least two types of vagal nerves responsible for initiating coughing reflexes. One type of nerve conducts action potentials in the A-range and is characterized by rapidly adapting responses to mechanical probing or acidification of the large airway epithelium. Stimulation of these nerves can evoke cough in unconscious experimental animals and humans. These nerves are important in immediate cough evoked by aspiration and as such perform a critical role in airway defense. The other type of primary afferent nerve involved in cough is the vagal C-fiber. Inhalation of selective C-fiber stimulants leads to cough only in conscious animals. In clinical studies, inhalation of a low concentration of a C-fiber stimulant causes an irritating, itchy urge-to-cough sensation that mimics the urge-to-cough sensations associated with respiratory tract infection, post-infection, gastroesophageal reflux disorders, and inflammatory airway diseases. Here we discuss the recent advances in sensory neurobiology that allow for the targeting of vagal C-fibers for novel antitussive therapy. No attempts are made to be all-inclusive with respect to the numerous possible molecular targets being considered to accomplish this goal. Rather, two general strategies are discussed: decreasing generator potential amplitude and decreasing the efficiency by which a generator potential evokes action-potential discharge. For the first category we focus on two targets, transient receptor potential vanilloid 1 and transient receptor potential A1. For the latter category we focus on recent advances in voltage-gated sodium (Na(V)) channel biology.

Test accuracy of interferon-gamma release assays (IGRAs) for diagnosing TB differs when using older or precommercial tools and inconsistent diagnostic criteria. This metaanalysis critically appraises studies investigating sensitivity and specificity of the commercial T-Spot.TB and the QuantiFERON-TB Gold In-Tube Assay (QFT-IT) among definitely confirmed TB cases. We searched Medline, EMBASE, and Cochrane bibliographies of relevant articles. Sensitivities, specificities, and indeterminate rates were pooled using a fixed effect model. Sensitivity of the tuberculin skin test (TST) was evaluated in the context of IGRA studies. In addition, the rates of indeterminates of both IGRAs were assessed. The pooled sensitivity of TST was 70% (95% CI, 0.67-0.72) compared with 81% (95% CI, 0.78-0.83) for the QFT-IT and 88% (95% CI, 0.85-0.90) for the T-Spot.TB. Sensitivity increased to 84% (95%CI, 0.81-0.87) and 89% (95% CI, 0.86-0.91) for the QFT-IT and T-Spot.TB, respectively, when restricted to performance in developed countries. In contrast, specificity of the QFT-IT was 99% (95% CI, 0.98-1.00) vs 86% for the T-Spot.TB (95% CI, 0.81-0.90). The pooled rate of indeterminate results was low, 2.1% (95% CI, 0.02-0.023) for the QFT-IT and 3.8% (95% CI, 0.035-0.042) for the T-Spot.TB, increasing to 4.4% (95% CI, 0.039-0.05) and 6.1% (95% CI, 0.052-0.071), respectively, among immunosuppressed hosts. The newest commercial IGRAs are superior, in comparison with the TST, for detecting confirmed active TB disease, especially when performed in developed countries.

Following publication of the Leuven Intensive Insulin Therapy Trial in 2001, tight glycemic control became the standard of care in ICUs around the world. Recent studies suggest that this approach may be flawed. The goal of this systematic review was to determine the benefits and risks of tight glycemic control in ICU patients and to explain the differences in outcomes among reported trials.

Obstructive sleep apnea (OSA) and stroke are frequent, multifactorial entities that share risk factors, and for which case-control and cross-sectional studies have shown a strong association. Stroke of respiratory centers can lead to apnea. Snoring preceding stroke, documentation of apneas immediately prior to transient ischemic attacks, the results of autonomic studies, and the circadian pattern of stroke, suggest that untreated OSA can contribute to stroke. Although cohort studies indicate that OSA is a stroke risk factor, controversy surrounds the cost-effectiveness of the screening for and treatment of OSA once stroke has occurred.

Massive transfusion (MT) is used for the treatment of uncontrolled hemorrhage. Earlier definitive control of life-threatening hemorrhage has significantly improved patient outcomes, but MT is still required. A number of recent advances in the area of MT have emerged, including the use of "hypotensive" or "delayed" resuscitation for victims of penetrating trauma before hemorrhage is controlled and "hemostatic resuscitation" with increased use of plasma and platelet transfusions in an attempt to maintain coagulation. These advances include the earlier use of hemostatic blood products (plasma, platelets, and cryoprecipitate), recombinant factor VIIa as an adjunct to the treatment of dilutional and consumptive coagulopathy, and a reduction in the use of isotonic crystalloid resuscitation. MT protocols have been developed to simplify and standardize transfusion practices. The authors of recent studies have advocated a 1:1:1 ratio of packed RBCs to fresh frozen plasma to platelet transfusions in patients requiring MT to avoid dilutional and consumptive coagulopathy and thrombocytopenia, and this has been associated with decreased mortality in recent reports from combat and civilian trauma. Earlier assessment of the exact nature of abnormalities in hemostasis has also been advocated to direct specific component and pharmacologic therapy to restore hemostasis, particularly in the determination of ongoing fibrinolysis.

Abnormalities of platelet number and function are the most common coagulation disorders seen among ICU patients. This article reviews the most frequent causes of thrombocytopenia by providing an overview of the following most common mechanisms: impaired production; sequestration; dilution; and destruction. Guidelines for treating thrombocytopenia and platelet dysfunction are also provided.

Navigational bronchoscopy provides a three-dimensional virtual "roadmap" that enables a physician to maneuver through multiple branches of the bronchial tree to reach targeted lesions in distal regions of the lung. It is designed to be used with a standard bronchoscope to facilitate obtaining tissue samples and for placing radiosurgical or dye markers. This article overviews this technology and the Current Procedural Terminology codes that have been created for its use.

Since it was first widely recognized at the end of the 19th century, acute pancreatitis has proven a formidable clinical challenge, frequently resulting in management within critical care settings. Because the early assessment of severity is difficult, the recognition of severe acute pancreatitis (SAP) and the implementation of critical care treatment precepts often are delayed. Although different management strategies for life-threatening features of SAP have been debated for decades, there has been little recent reduction in mortality rates, which can be as high as 30%. This article discusses severity designation at the time of diagnosis, reviews the pathophysiologic mechanisms so well characterized by the noxious combination of severe systemic inflammation and hypoperfusion, and provides a management algorithm that parallels current critical care strategies.

Interstitial lung disease (ILD) is a frequent extraarticular manifestation of rheumatoid arthritis (RA). While the nonspecific interstitial pneumonia pattern predominates in most forms of connective tissue-associated ILD, studies in patients with RA-associated ILD (RA-ILD) suggest that the usual interstitial pneumonia (UIP) pattern is more common in this patient population. High-resolution CT (HRCT) scans appear accurate in identifying UIP pattern in many patients with RA-ILD. Although the data are limited, UIP pattern appears to predict worse survival in RA-ILD patients. Larger, prospective, multicenter studies are needed to confirm this finding. We propose that the evaluation of patients with RA-ILD should focus on identifying those with UIP pattern on HRCT scans, as these patients are likely to carry a worse prognosis. In patients in whom the underlying pattern cannot be determined by HRCT scanning, surgical lung biopsy should be considered.

Long work hours, overnight call duty, and rotating shifts are implicit features of hospital medical practice. Rigorous schedules have been deemed necessary to fulfill the professional obligation of patient beneficence, to optimize trainee learning, and to respond to economic realities. However, the resultant disruption and restriction of physicians' sleep produce demonstrable neurobehavioral impairments that may threaten other fundamental professional mandates, such as that of primum non nocere ("first, do no harm"). This article provides a basic overview of sleep/wake regulatory processes, examines the impact of physician schedules on sleep/wake homeostasis, summarizes the laboratory-demonstrated effects of sleep loss on humans, highlights recent literature on the personal and professional effects of sleep loss on physicians, and, finally, discusses the specific countermeasure of work-hour limits applicable to resident physicians but not attending physicians.

Despite medical advances, pneumonia remains a leading cause of morbidity and mortality among patients in developed countries. It is therefore not surprising that much research has been devoted to improving outcomes associated with this condition. Traditionally thought of as lipid-lowering agents, the 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors (hereafter referred to as statins) have "pleiotropic" effects of clinical relevance. Several studies have reported an association between statin use and improved health outcomes, including those associated with pneumonia. While many of these are limited by their retrospective or observational methodology, the finding that statin use may improve pneumonia outcomes is tantalizing and worthy of further exploration. Our review of the literature found several potential mechanisms by which statins could influence the course of bacterial pneumonia. For instance, statins directly attenuate inflammation and inflammatory markers, are antioxidative and immunomodulatory, and exert in vitro antibacterial effects on microbial pathogens. On the other hand, statin use is also thought to be a surrogate marker for better health and may simply be a confounding variable when it comes to pneumonia. This article explores some of the potential mechanisms by which statin therapy may impact the course of pneumonia. In addition, we review the clinical studies both supporting and arguing against such an effect.

Sarcoidosis is a common disease and affects the respiratory system in > 90% of cases, most commonly the intrathoracic lymph nodes and the respiratory parenchyma. Less commonly, the airways are involved, and the disease is manifested as mucosal erythema, edema, granularity and cobblestoning, plaques, nodules, and bronchial stenosis, airway distortion, traction bronchiectasis, and bronchiolitis. Airway involvement may lead to airflow limitation. Involvement of oral, nasal, and pharyngeal mucosa may cause hoarseness, dysphagia, laryngeal paralysis, and upper airway obstruction. Airway symptoms are important indicators of airway involvement in sarcoidosis. Pulmonary function testing, radiologic imaging, and bronchoscopy occupy a significant role in the diagnosis and management of airway involvement in patients with sarcoidosis.

The understanding of the pathogenesis of pulmonary fibrosis continues to evolve. The initial hypothetical model suggested chronic inflammation as the cause of pulmonary fibrosis, whereas a subsequent hypothesis posited epithelial injury and impaired wound repair as the etiology of fibrosis without preceding inflammation. Over the past decade, several concepts have led to refinement of these hypotheses. These include the following: (1) the importance of the integrity of the alveolar-capillary barrier basement membrane (BM) to conserving the architecture of the injured lung; (2) conversely, that the failure of reepithelialization and reendothelialization of this BM results in pathologic fibrosis; (3) transforming growth factor-beta is necessary but not sufficient to the pathologic fibrosis of the lungs; (4) the role of persistent antigens in the pathogenesis of usual interstitial pneumonia; and (5) the contribution of epithelial-to-mesenchymal transformation and bone marrow-derived progenitor cells in the pathogenesis of lung fibrosis. In this review, we will discuss these evolving conceptual mechanisms for the pathogenesis of pulmonary fibrosis relevant to idiopathic pulmonary fibrosis.

The risks and benefits of anticoagulation for stroke prevention with atrial fibrillation is clearly delineated in the general population. Little evidence exists for patients with end-stage renal disease (ESRD) about whether the extrapolation of these guidelines is appropriate. In patients with ESRD who are undergoing hemodialysis, the rates for both stroke and bleeding are 3 to 10 times higher than that for the general population. Furthermore, the proportion of hemorrhagic to ischemic strokes has increased, making the decision of whether to initiate anticoagulation problematic. In this commentary, we discuss the existing literature for stroke in atrial fibrillation, stroke type, risk reduction with anticoagulation, and bleeding risks in the hemodialysis population. We comment on validated risk stratification models of stroke prevention and bleeding and their applicability to patients undergoing hemodialysis. Finally, we recommend treatment strategies that are based on the existing state of knowledge.

Antimicrobial therapy is the mainstay of management for community-acquired pneumonia (CAP). Accordingly, the choices of treatment are influenced by the likely etiologies, local resistance patterns of the pathogens, as well as patient factors. As the leading cause of acute CAP, the susceptibility patterns of Streptococcus pneumoniae have greatly influenced antimicrobial agents and dosage recommended for empirical treatment of this condition. The worldwide emergence of community-acquired methicillin-resistant Staphylococcus aureus has also led to discussion of this pathogen in recent revisions of the international CAP guidelines. This pathogen is important because of its resistance to antibiotics commonly recommended for the empirical treatment of CAP and the association with a rapidly fatal form of pneumonia characterized by tissue necrosis, pulmonary hemorrhage, and rapid progression to respiratory failure. In tropical regions of Australia and Asia, CAP due to Acinetobacter baumannii is also increasingly recognized. This review discusses their recent epidemiology, microbiology, clinical features, and treatment of CAP caused by these antimicrobial-resistant pathogens.

Over the past 5 to 10 years, we have reached a treatment plateau using standard platinum-based doublets in an unselected population of patients with advanced non-small cell lung cancer (NSCLC). Recent studies have focused on improving patient outcomes with new chemotherapeutic or targeted agents, as well as on individualizing therapy on the basis of patient characteristics such as tumor histology and biomarker analysis. This article summarizes recent data on histologic response determinants to chemotherapy and targeted therapy, with particular attention to the importance of standardized tissue collection, handling, storage, and analysis techniques, in order to best apply the results of tumor analysis to patient-care decisions. Such decisions are related to both improving patient safety and optimizing efficacy with standard chemotherapy as well as newer targeted therapy agents. This entails a change from a generalized approach in treating patients with NSCLC to an individualized strategy based on tumor histology.

Vasculitides associated with serum positivity for antineutrophil cytoplasmic antibodies (ANCAs) are a well-established subgroup affecting small- to medium-sized vessels that are commonly recognized as ANCA-associated vasculitis, which includes necrotizing granulomatous vasculitis (NGV) [formerly Wegener granulomatosis], microscopic polyangiitis (MPA), and Churg-Strauss syndrome. NGV usually starts as a granulomatous disease of the respiratory tract and progresses to systemic disease with proteinase 3 (PR3)-ANCA-associated vasculitis, suggesting an aberrant cell-mediated immune response to exogenous or endogenous antigens in the respiratory tract and resulting in granuloma formation. In NGV, granulomata may represent lymphoid structures ultimately responsible for PR3-ANCA production. In both NGV and MPA, necrotizing glomerulonephritis and necrotizing pulmonary capillaritis may well result from an injury orchestrated by ANCA. Untreated NGV and MPA normally are rapidly progressive and fatal. Pulmonary capillaritis with alveolar hemorrhage is a severe complication in patients with MPA and NGV. Because plasma exchange removes circulating ANCAs and other proteins from the blood, its use has been advocated in critical situations of severe renal and pulmonary involvement. However, no studies of plasma exchange in ANCA-associated vasculitis focused on pulmonary involvement have been reported. Dissecting the mechanisms of inflammation may identify molecular targets for future therapies in ANCA-associated vasculitis. Thus, biological agents are emerging as potential therapies in refractory cases. Notably, rituximab and infliximab have been trialed with apparent initial clinical success.

The treatment of asthma relies on the use of the following two major drug classes: beta(2)-agonists, both short acting and long acting; and corticosteroids (CSs). Although the properties of each drug class are well described, their use in combination delivered either separately or through one device has provided some clear and important clinical advantages. The mechanisms underlying these interactions have emerged as novel and provocative. beta(2)-Agonists can stimulate the glucocorticoid receptor (GR) and promote its translocation to the nucleus, resulting in increased CS-mediated gene transcription. In structural airway cells, such as fibroblasts and smooth muscle, this gene transcription is associated with the formation of a complex between the GR and another transcription factor, CCAAT enhancer-binding protein (C/EBP)-alpha. Airway smooth muscle cells from persons with asthma are deficient in C/EBP-alpha, which may explain the finding that CSs do not inhibit the proliferation of these cells in vitro. Whether this deficiency can explain the increased bulk of muscle in the asthmatic airway remains to be established. beta(2)-Agonists can inhibit mast cell mediator release, but this response is susceptible to desensitization, a process that CSs can inhibit. CSs also can increase the transcription of the beta(2)-receptor gene in the lung and the nasal mucosa. These effects of CSs mitigate against the reduced transcription of beta(2)-receptors, which occurs as a consequence of long-term beta(2)-agonist administration. Delineation of the exact mechanisms underlying these effects will ensure rational, direct therapy.

Experimental and clinical evidence has demonstrated a strong cause-and-effect relationship between persistence vs reduction in systemic inflammation and progression (unresolving) vs resolution (resolving) of ARDS. In this review, the cellular mechanisms involved in activating and regulating inflammation are contrasted between patients with resolving and unresolving ARDS. At the cellular level, patients with unresolving ARDS have deficient glucocorticoid (GC)-mediated down-regulation of inflammatory cytokine and chemokine transcription despite elevated levels of circulating cortisol, a condition defined as systemic inflammation-associated acquired GC resistance. These patients, contrary to those with resolving ARDS, have persistent elevation in levels of both systemic and BAL fluid inflammatory cytokines and chemokines, markers of alveolar-capillary membrane permeability and fibrogenesis. At the tissue level, the continued production of inflammatory mediators leads to tissue injury, intravascular and extravascular coagulation, and the proliferation of mesenchymal cells, all resulting in maladaptive lung repair and progression of extrapulmonary organ dysfunction. In ARDS, down-regulation of systemic inflammation is essential to restoring homeostasis, decreasing morbidity, and improving survival. Prolonged low-to-moderate dose GC therapy promotes the down-regulation of inflammatory cytokine transcription at the cellular level. Eight controlled studies have consistently reported a significant reduction in markers of systemic inflammation, pulmonary and extrapulmonary organ dysfunction scores, duration of mechanical ventilation, and ICU length of stay. In the aggregate (n = 628), reduction in mortality was substantial for all patients (relative risk [RR], 0.75; 95% CI, 0.63 to 0.89; p < 0.001; I(2), 43%) and for those treated before day 14 (RR, 0.71; 95% CI, 0.59 to 0.85; p < 0.001; I(2), 40%).

Inhaled corticosteroids (ICS) have been shown to decrease the occurrence of COPD exacerbations. However, the relationship of baseline lung function and reduction of exacerbations with the use of ICS remains unknown. Herein, we perform a metaregression to evaluate the efficacy of ICS in preventing COPD exacerbations.