Chronic obstructive pulmonary disease and vascular disease delay timeliness of early stage lung cancer resectional surgery.

INTRODUCTION: Lung cancer remains the leading cause of cancer death in the United States and worldwide. Timeliness to diagnosis and referral for resectional surgery is key to successful management for early stage disease. METHODS: We investigated the contribution of medical co-morbidities in the timeliness to resectional surgery for non-small cell lung cancer (NSCLC). A retrospective record review of NSCLC surgery cases at Naval Medical Center San Diego (NMCSD) from 2004 to 2009 from the tumor registry was conducted. RESULTS: More than 75% of NSCLC patients exhibited at least one co-morbidity. Of the 84 patients, 26% of patients had diabetes, patients with different vascular co-morbidities accounted for 39%, whereas 33% of subjects had COPD. Patients with sleep apnea or liver disease each accounted for 6%. Vascular disease co-morbidity and COPD in NSCLC patients significantly delayed time from initial cardiothoracic surgery evaluation to thoracotomy (p = 0.01-0.02 and p < 0.05 respectively). CONCLUSION: Although significances of different co-morbities in the development NSCLC cannot be extrapolated, theses data show that COPD and vascular diseases are significant risk factors that delay surgical treatment of early stage lung cancer.

Diagnosis of right ventricular cardiac sarcoidosis with cardiac magnetic resonance in a patient presenting with ventricular tachycardia.

Sarcoidosis patients often have myocardial involvement, however, very few have clinically significant cardiac disease and ventricular tachycardia as the initial presentation is exceedingly rare. We report the case of a middle-aged male with symptomatic but clinically stable ventricular tachycardia. Chest radiograph, computed tomography, and positron emission tomography demonstrated pulmonary and mediastinal abnormalities but no definitive etiology for his arrhythmia. Transthoracic echocardiogram revealed the nonspecific cardiac abnormalities of right ventricular dilation and septal flattening. Cardiac magnetic resonance demonstrated delayed enhancement and akinesia of the right ventricular free and inferior walls--virtually diagnostic of an infiltrative myocardial disease. The diagnosis was then verified with transbronchial biopsy showing noncaseating granulomas consistent with sarcoidosis. In conclusion, this case illustrates an unusual presentation of sarcoidosis and demonstrates how the diagnosis can be made using cardiac magnetic resonance alongside transbronchial biopsy.

Population characterization, histological evaluation, and timeliness of care of surgical nonsmall cell lung cancer patients in a military academic medical center.

UNLABELLED: Lung cancer remains a major medical impediment in which early diagnosis and timely treatment are key factors in its management. This study evaluated nonsmall cell lung cancer (NSCLC) patients in a large military medical center to determine the timeliness to diagnosis and curative surgery in comparison with published guidelines. A retrospective record review of tumor registry NSCLC surgery cases at Navy Medical Center San Diego (NMCSD) from 2004 to 2009 was conducted. Of the 84 patients, 49% were women, the median age was 63, 58% were Caucasian, and 71% represented ex- or active smokers. A significant number of women were Asian (30%) and nonsmokers (77%). The predominant histology was adenocarcinoma (86%) with positron emission tomography-computed tomography (PET-CT) nonavid (57%). Median time for pulmonologist evaluation was 8 days, median time for PET-CT was 13 days, median time for cardiothoracic surgery evaluation to thoracotomy was 25 days, and median time from pulmonologist evaluation to thoractomy was 59 days. CONCLUSIONS: Except for the pulmonary specialist referral time (8 vs. 7 days), timeliness of diagnosis and curative surgery for NSCLC patients at NMCSD was within international guideline recommendations. Additional proposals have been made to improve the evaluation and treatment of lung cancer patients.

The bone marrow lesion in osteoarthritis.

Osteoarthritis (OA) is considered a multifactorial disease whose development and progression may include several structural abnormalities aside from cartilage destruction. Bone marrow lesions (BMLs) have been reported to be associated with OA pathology, and several studies have advocated its close connection to the severity of joint structural alterations and pain, the main OA clinical manifestation. Hence, BMLs may not only affect subchondral bone and its neuronal and vascular structures but also negatively influence the adjacent tissues. Here, we analyze the pathophysiology and natural history of OA-associated BMLs and their potential relevance to the radiographic progression and severity of the disease. The notion that BMLs may be a precursor to additional articular abnormalities, can be a potential risk factor for development of OA, and may serve as an additional diagnostic tool and a therapeutic target are further discussed.

Recognizing asthma mimics and asthma complications.

Asthma is a chronic inflammatory disorder of the airways characterized by airflow obstruction, bronchial hyperreactivity, and underlying inflammation. Two common reasons asthmatics fail standard therapy are incorrect diagnosis and failure to recognize underlying contributing factors. A correct diagnosis of asthma is of great importance to military practitioners since misdiagnosis or uncontrolled asthma affects an individual's operational readiness or determines whether one can receive a medical waiver to enlist in military service. This article presents four cases of patients with dyspnea that have conditions which mimic asthma or complicate asthma management: vocal cord dysfunction misdiagnosed as asthma, respiratory bronchiolitis interstitial lung disease mistaken as asthma, difficult-to-control asthma because of bronchiectasis and allergic bronchopulmonary aspergillosis, and difficult and fatal asthma. Asthma is contrasted to other respiratory disorders, and an outlined approach to asthma diagnosis and management is presented using the Global Initiative for Asthma guidelines.

Prevention of lipopolysaccharide-induced microangiopathy by gp49B1: evidence for an important role for gp49B1 expression on neutrophils.

gp49B1 is expressed on mast cells and inhibits immunoglobulin E-dependent activation and inflammation in vivo. We now show that gp49B1 is expressed on neutrophils and prevents neutrophil-dependent vascular injury in response to lipopolysaccharide (LPS). The intradermal (i.d.) injection of LPS into gp49B1-null (gp49B-/-) but not gp49B1-sufficient (gp49B+/+) mice elicited macroscopic hemorrhages by 24 h, which were preceded on microscopic analyses by significantly more intravascular thrombi (consisting of neutrophils, platelets, and fibrin) that occluded venules and by more tissue neutrophils than in gp49B+/+ mice. However, there were no differences in the number of intact (nondegranulating) mast cells or the tissue levels of mediators that promote neutrophil recruitment. Hemorrhage was prevented by depleting neutrophils, blocking beta2 integrin-intercellular adhesion molecule 1 interactions, or inhibiting coagulation. These characteristics indicate that gp49B-/- mice are exquisitely sensitive to a local Shwartzman reaction (LSR) after a single i.d. injection of LPS, whereas in the classic LSR, a second exposure is required for increased beta2 integrin function, intravascular neutrophil aggregation, formation of occlusive thrombi, and hemorrhage. Moreover, LPS increased gp49B1 expression on neutrophils in vivo. The results suggest that gp49B1 suppresses the LPS-induced increase in intravascular neutrophil adhesion, thereby providing critical innate protection against a pathologic response to a bacterial component.

Therapeutic inhibition of matrix metalloproteinases for the treatment of chronic obstructive pulmonary disease (COPD).

BACKGROUND: The incidence of chronic obstructive pulmonary disease (COPD) is increasing worldwide and is ranked as the fourth most common cause of death in the United States. COPD is caused by long-term exposure to cigarette smoke, toxic gases, and particulate matter, leading to airway flow limitation and pulmonary failure. The disease is characterized by an excess of extracellular matrix deposition, increased thickness of airway walls, and destruction of alveolar septae, resulting in reduced functional lung parenchyma and reduced elastic tethering forces to maintain airway patency. Matrix metalloproteinases (MMPs) have been suggested as the major proteolytic enzymes involved in the pathogeneses of COPD because these proteins are a unique family of metalloenzymes that, once activated, can destroy connective tissue. Although several MMP inhibitors have been developed, in vivo specificity and selectivity have slowed the progress. SCOPE: This review discusses the structural features of MMPs, their pulmonary cellular sources during the course of the disease, past anti-MMP therapies, and future approaches to inhibiting these proteins for treating COPD patients. Literature searches of PubMed, BioMed, and Medline formed the basis of this analysis and our current understanding of pulmonary changes associated with COPD and the capacity of MMPs to induce a variety of these changes of current biomedical and clinical interest.

Molecular characterization of antigen-induced lung inflammation in a murine model of asthma.

Asthma is one of the foremost contributors to morbidity and mortality in industrialized countries. Our objective was to characterize the acute response to allergen and to identify potentially novel molecular targets for pharmacological intervention in asthma. We therefore designed a study to identify genes whose regulation was altered following ovalbumin (OVA) challenge in the presence and absence of treatment with glucocorticoids in BALB/c mice. RNA was isolated from lungs for gene profiling from 8-week-old sensitized mice, 3 and 18 hours post OVA challenge on days 1, 4, and 7 of aerosol challenge. Taqman (real time RT-PCR) analysis of marker genes indicative of Th2 (IL-4, IL-13), eosinophil (RANTES, eotaxin), Th1/macrophage (IFNgamma) and epithelial cell (MUC5AC) phenotypes were used to characterize responses to allergen challenge. Histological evaluation of lungs from additional challenged animals revealed inflammatory infiltrates on days 4 and 7, but not on day 1 post challenge. We postulate that expression of IL-4, IL-13 and other genes by OVA at day 1 probably reflects activation of resident cells, whereas the fivefold increase in the number of regulated genes at day 7 reflects the contribution of recruited cells. Of the regulated genes, only a subset was counter-regulated by dexamethasone treatment. Although regulated genes included genes in many protein families, herein we report regulation of two proteases whose role in response to OVA challenge has not been characterized. This model will be used to generate disease hypotheses for which may play an important role in initiating disease pathology in this model.

Plasmapheresis in the management of severe hypertriglyceridemia.

Plasmapheresis can benefit a variety of critically ill patients. A woman with diabetic ketoacidosis and severe hypertriglyceridemia was treated with plasmapheresis when conventional treatments did not markedly reduce her triglyceridemia. The patient was admitted to a medical intensive care unit because of diabetic ketoacidosis with severe lipemia. The lipemia-associated interference in laboratory studies made treatment of electrolyte abnormalities extremely difficult. The hypertriglyceridemia was initially treated with insulin, antilipidemic medications, and heparin, but the levels of triglycerides remained elevated, delaying results of needed laboratory studies for hours. After plasmapheresis, the serum level of triglycerides decreased by 77% in less than 24 hours. Severe lipemia interferes with photometric laboratory studies, yielding an underestimation of serum levels of electrolytes. Plasmapheresis is safe, rapid, and effective for emergent management of severe hypertriglyceridemia in critically ill patients. The impact of the procedure on critical care nursing is growing as nurses become involved in the treatment and follow-up care of patients who have plasmapheresis.

The immune response and its therapeutic modulation in bronchiectasis.

Bronchiectasis (BC) is a chronic pulmonary disease with tremendous morbidity and significant mortality. As pathogen infection has been advocated as a triggering insult in the development of BC, a central role for the immune response in this process seems obvious. Inflammatory cells are present in both the airways as well as the lung parenchyma, and multiple mediators of immune cells including proteases and cytokines or their humoral products are increased locally or in the periphery. Interestingly, a defect in the immune system or suppression of immune response during conditions such as immunodeficiency may well predispose one to the devastating effects of BC. Thus, the outcome of an active immune response as detrimental or protective in the pathogenesis of BC may be dependent on the state of the patient's immunity, the severity of infection, and the magnitude of immune response. Here we reassess the function of the innate and acquired immunity in BC, the major sites of immune response, and the nature of the bioactive mediators. Furthermore, the potential link(s) between an ongoing immune response and structural alterations accompanying the disease and the success of therapies that can modulate the nature and extent of immune response in BC are elaborated upon.

The interleukin 1beta pathway in the pathogenesis of osteoarthritis.

Osteoarthritis (OA) is a major disabling disease and is ranked as a major cause of chronic pain in adults. The pathology of the illness is characterized by a loss of articular cartilage leading to narrowing of joint space, increased joint friction, potential structural remodeling, persistent pain, and functional impairment. The proinflammatory cytokine interleukin 1beta (IL-1beta) has several chemical and bioactive characteristics allowing this catabolic protein to be involved in initiation and progression of OA. We review the current understanding of the pathogenesis of OA, and how upregulation of IL-1beta initiates a cascade of intracellular events that can culminate in activation of proteinases, creation of a pro-destructive articular milieu, suppression of anabolic pathways, and a decrease in the synthesis of cartilage extracellular matrix. Therapeutic approaches to block the action of IL-1beta and overcome its signal transduction to curtail disease progression are discussed.

The gp49B1 inhibitory receptor regulates the IFN-gamma responses of T cells and NK cells.

The magnitude and diversity of Ag-specific T cell effector activity have been proposed to be controlled by an integration of positive signals transduced by the TCR and negative signals originating from inhibitory cell surface molecules. Although the lectin family of NK cell-associated inhibitory receptors has been reported to regulate the function of murine CTLs, gp49B1, the Ig superfamily member is not known to be expressed on T cells. Moreover, the consequences of the lack of an endogenously expressed NK cell-associated inhibitory receptor on T cell functions are not known. We report that gp49B1 is expressed by nearly all activated CD8 and CD4 T cells in addition to NK cells during an immune response to viral, bacterial, or tumor challenge. Kinetics of gp49B1 expression parallel functional capability and subside in the memory phase. Following vaccinia viral infection, IFN-gamma production by both subsets of T cells and NK cells is enhanced in gp49B1-deficient mice compared with gp49B1(+/+) mice. The stimulation threshold for IFN-gamma production is also lower in gp49B1-deficient T cells. In contrast, no significant differences were observed in the cytotoxic responses. We conclude that gp49B1 is a unique inhibitory receptor that is induced in multiple lineages of innate and adaptive immune cells during an infection and controls their IFN-gamma, but not cytotoxic responses.

Bax is crucial for IFN-gamma-induced resolution of allergen-induced mucus cell metaplasia.

Allergic airway responses cause proliferation of epithelial cells and mucus cell metaplasia (MCM), and the resolution of MCM involves reduction of cell numbers. The role of inflammation and apoptosis on this process was investigated in P-selectin +/+ and -/- mice sensitized and challenged with OVA by analyzing the expression and the role of regulators of apoptosis in metaplastic mucus cells. No differences were observed in MCM at 5 days of allergen exposure between +/+ and -/- mice, despite reduced IL-13 levels in -/- mice. Although IL-4 levels were similar in both -/- and +/+ mice, IL-13 and IL-5 levels had decreased and IFN-gamma levels were increased earlier in -/- compared with +/+ mice. MCM levels were decreased 4-fold at 7 days of allergen exposure in -/- mice and at 15 days in +/+ mice. The percentage of Bax-expressing mucus cells increased significantly at 7 days in -/- mice and at 10 days in +/+ mice. The Bax-positive mucus cells exhibited caspase-specific cleavage of cytokeratin 18. IFN-gamma caused Bax expression in IL-13-induced MCM in microdissected airway cultures. MCM remained significantly elevated in Bax -/- mice following 15 days of allergen exposure compared with +/+ mice, while the number of eosinophils was reduced in both Bax +/+ and -/- mice at 15 days. Together, these data demonstrate that reduced IL-13 levels were sufficient to elicit maximum MCM, that IFN-gamma induces Bax in metaplastic mucus cells, and that Bax plays a critical role in the resolution of MCM, but not in the resolution of eosinophils.

gp49B1 suppresses stem cell factor-induced mast cell activation-secretion and attendant inflammation in vivo.

We report that gp49B1, a mast cell membrane receptor with two immunoreceptor tyrosine-based inhibitory motifs (ITIM), constitutively inhibits mast cell activation-secretion induced by stem cell factor (SCF), a tissue-derived cytokine that also regulates mast cell development. The intradermal injection of SCF into the ears of gp49B1 null (gp49B(-/-)) mice elicited approximately 4- and 2.5-fold more degranulating mast cells and tissue swelling caused by edema, respectively, than in gp49B(+/+) mice. SCF did not induce tissue swelling in mast cell-deficient mice, and the responsiveness of gp49B(-/-) mice to mast cell-associated amine and lipid mediators was unaltered. When gp49B(+/+) and gp49B(-/-) mice were pretreated with antagonists of the amines, SCF-induced tissue swelling was reduced by >90% and 60%, respectively, and it was reduced by >90% in both genotypes when a cysteinyl leukotriene receptor antagonist was also provided. Hence, the dominant contribution of secretory granule amines to SCF-induced tissue swelling is the result of gp49B1-mediated inhibition of the production of cysteinyl leukotrienes by mast cells. Our findings also provide the first example of an ITIM-bearing receptor that constitutively suppresses inflammation generated in vivo independently of the adaptive immune response by a receptor that signals through intrinsic tyrosine kinase activity rather than immunoreceptor tyrosine-based activation motifs.