Showing papers by "National Jewish Health published in 2005"

Daily versus As-Needed Corticosteroids for Mild Persistent Asthma

Abstract: Background Although guidelines recommend daily therapy for patients with mild persistent asthma, prescription patterns suggest that most such patients use these so-called controller therapies intermittently. In patients with mild persistent asthma, we evaluated the efficacy of intermittent short-course corticosteroid treatment guided by a symptom-based action plan alone or in addition to daily treatment with either inhaled budesonide or oral zafirlukast over a one-year period. Methods In a double-blind trial, 225 adults underwent randomization. The primary outcome was morning peak expiratory flow (PEF). Other outcomes included the forced expiratory volume in one second (FEV1) before and after bronchodilator treatment, the frequency of exacerbations, the degree of asthma control, the number of symptom-free days, and the quality of life. Results The three treatments produced similar increases in morning PEF (7.1 to 8.3 percent; approximately 32 liters per minute; P=0.90) and similar rates of asthma exacerbations (P=0.24), even though the intermittent-treatment group took budesonide, on average, for only 0.5 week of the year. As compared with intermittent therapy or daily zafirlukast therapy, daily budesonide therapy produced greater improvements in pre-bronchodilator FEV1 (P=0.005), bronchial reactivity (P Conclusions It may be possible to treat mild persistent asthma with short, intermittent courses of inhaled or oral corticosteroids taken when symptoms worsen. Further studies are required to determine whether this novel approach to treatment should be recommended.

ROS generated by pollen NADPH oxidase provide a signal that augments antigen-induced allergic airway inflammation

Abstract: Pollen exposure induces allergic airway inflammation in sensitized subjects. The role of antigenic pollen proteins in the induction of allergic airway inflammation is well characterized, but the contribution of other constituents in pollen grains to this process is unknown. Here we show that pollen grains and their extracts contain intrinsic NADPH oxidases. The pollen NADPH oxidases rapidly increased the levels of ROS in lung epithelium as well as the amount of oxidized glutathione (GSSG) and 4-hydroxynonenal (4-HNE) in airway-lining fluid. These oxidases, as well as products of oxidative stress (such as GSSG and 4-HNE) generated by these enzymes, induced neutrophil recruitment to the airways independent of the adaptive immune response. Removal of pollen NADPH oxidase activity from the challenge material reduced antigen-induced allergic airway inflammation, the number of mucin-containing cells in airway epithelium, and antigen-specific IgE levels in sensitized mice. Furthermore, challenge with Amb a 1, the major antigen in ragweed pollen extract that does not possess NADPH oxidase activity, induced low-grade allergic airway inflammation. Addition of GSSG or 4-HNE to Amb a 1 challenge material boosted allergic airway inflammation. We propose that oxidative stress generated by pollen NADPH oxidases (signal 1) augments allergic airway inflammation induced by pollen antigen (signal 2).

Ancestral antibiotic resistance in Mycobacterium tuberculosis.

Abstract: Chemotherapeutic options to treat tuberculosis are severely restricted by the intrinsic resistance of Mycobacterium tuberculosis to the majority of clinically applied antibiotics. Such resistance is partially provided by the low permeability of their unique cell envelope. Here we describe a complementary system that coordinates resistance to drugs that have penetrated the envelope, allowing mycobacteria to tolerate diverse classes of antibiotics that inhibit cytoplasmic targets. This system depends on whiB7, a gene that pathogenic Mycobacterium shares with Streptomyces, a phylogenetically related genus known as the source of diverse antibiotics. In M. tuberculosis, whiB7 is induced by subinhibitory concentrations of antibiotics (erythromycin, tetracycline, and streptomycin) and whiB7 null mutants (Streptomyces and Mycobacterium) are hypersusceptible to antibiotics in vitro. M. tuberculosis is also antibiotic sensitive within a monocyte model system. In addition to antibiotics, whiB7 is induced by exposure to fatty acids that pathogenic Mycobacterium species may accumulate internally or encounter within eukaryotic hosts during infection. Gene expression profiling analyses demonstrate that whiB7 transcription determines drug resistance by activating expression of a regulon including genes involved in ribosomal protection and antibiotic efflux. Components of the whiB7 system may serve as attractive targets for the identification of inhibitors that render M. tuberculosis or multidrug-resistant derivatives more antibiotic-sensitive.

Inhaled NO improves early pulmonary function and modifies lung growth and elastin deposition in a baboon model of neonatal chronic lung disease

Abstract: Nitric oxide (NO) serves multiple functions in the developing lung, and pulmonary NO production is decreased in a baboon model of chronic lung disease (CLD) after premature birth at 125 days (d) gestation (term = 185d). To determine whether postnatal NO administration alters the genesis of CLD, the effects of inhaled NO (iNO, 5 ppm) were assessed in the baboon model over 14d. iNO caused a decrease in pulmonary artery pressure in the first 2d and a greater rate of spontaneous closure of the ductus arteriosus, and lung compliance was greater and expiratory resistance was improved during the first week. With iNO, postmortem pressure-volume curves were shifted upward, lung DNA content and cell proliferation were increased, and lung growth was preserved to equal that which occurs during the same period in utero. In addition, the excessive elastin deposition characteristic of CLD was normalized by iNO, and there was evidence of stimulation of secondary crest development. Thus, in the baboon model of CLD, iNO improves early pulmonary function and alters lung growth and extracellular matrix deposition. As such, NO biosynthetic pathway dysfunction may contribute to the pathogenesis of CLD.

The Enhancement or Prevention of Airway Hyperresponsiveness during Reinfection with Respiratory Syncytial Virus Is Critically Dependent on the Age at First Infection and IL-13 Production

Abstract: Respiratory syncytial virus (RSV) infection in early life is suspected to play a role in the development of postbronchiolitis wheezing and asthma. Reinfection is common at all ages, but factors that determine the development of altered airway function after reinfection are not well understood. This study was conducted in a mouse model to define the role of age in determining the consequences on airway function after reinfection. Mice were infected shortly after birth or at weaning and were reinfected 5 wk later, followed by assessment of airway function, airway inflammation, and lung histopathology. Infection of mice at weaning elicited a protective airway response upon reinfection. In this age group, reinfection resulted in increased airway inflammation, but without development of airway hyperresponsiveness (AHR) or eosinophilia and decreased IL-13 levels. By contrast, neonatal infection failed to protect the airways and resulted in enhanced AHR after reinfection. This secondary response was associated with the development of airway eosinophilia, increased IL-13 levels, and mucus hyperproduction. Both CD4- and CD8-positive T cells were a source of IL-13 in the lung, and inhibition of IL-13 abolished AHR and mucus production in these mice. Inoculation of UV-inactivated virus failed to elicit these divergent responses to reinfection, emphasizing the requirement for active lung infection during initial exposure. Thus, neonatal RSV infection predisposes to the development of airway eosinophilia and enhanced AHR via an IL-13-dependent mechanism during reinfection, whereas infection at a later age protects against the development of these altered airway responses after reinfection.

Exhaled nitric oxide identifies the persistent eosinophilic phenotype in severe refractory asthma

Abstract: Background The fractional concentration of exhaled nitric oxide (FE NO ) is increased in asthma, correlates with eosinophilic inflammation, and decreases after steroid therapy. Objective We sought to examine whether persistent eosinophilia would be accompanied by an increased FE NO level despite steroid therapy in patients with severe refractory asthma (SRA) as manifestations of steroid resistance. Methods Subjects with SRA, subjects with mild-moderate asthma, and healthy control subjects had FE NO measured, followed by endobronchial biopsy and bronchoalveolar lavage. Tissue and bronchoalveolar lavage inflammatory cells were assessed for all subjects, and eosinophil status (EOS + /EOS − ) was determined for subjects with SRA. Results Twenty-four subjects with SRA, 15 subjects with moderate-mild asthma, and 17 healthy control subjects were studied. Subjects with EOS + SRA had significantly higher median FE NO levels compared with levels in subjects with EOS − SRA ( P = .0084) and all other groups. In subjects with SRA, FE NO levels correlated with tissue eosinophils ( r s = 0.54, P = .007), lymphocytes ( r s = 0.40, P = .003), and mast cells ( r s = 0.44, P = .05). FE NO levels of greater than 72.9 ppb were associated with a sensitivity of 0.56 and a specificity of 1.0 for EOS + status in subjects with SRA. Conclusion FE NO measurement identified the subgroup of subjects with SRA with persistent eosinophilia despite steroid therapy. Further studies are needed on the use of FE NO to monitor response to therapy over time in subjects with SRA.

Leukotriene B4 Receptor-1 Is Essential for Allergen-Mediated Recruitment of CD8 + T Cells and Airway Hyperresponsiveness

Abstract: Recent studies in both human and rodents have indicated that in addition to CD4+ T cells, CD8+ T cells play an important role in allergic inflammation. We previously demonstrated that allergen-sensitized and -challenged CD8-deficient (CD8-/-) mice develop significantly lower airway hyperresponsiveness (AHR), eosinophilic inflammation, and IL-13 levels in bronchoalveolar lavage fluid compared with wild-type mice, and that all these responses were restored by adoptive transfer of in vivo-primed CD8+ T cells or in vitro-generated effector CD8+ T cells (T(EFF)). Recently, leukotriene B4 and its high affinity receptor, BLT1, have been shown to mediate in vitro-generated T(EFF) recruitment into inflamed tissues. In this study we investigated whether BLT1 is essential for the development of CD8+ T cell-mediated allergic AHR and inflammation. Adoptive transfer of in vivo-primed BLT1+/+, but not BLT1-/-, CD8+ T cells into sensitized and challenged CD8-/- mice restored AHR, eosinophilic inflammation, and IL-13 levels. Moreover, when adoptively transferred into sensitized CD8-/- mice, in vitro-generated BLT1+/+, but not BLT1-/-, T(EFF) accumulated in the lung and mediated these altered airway responses to allergen challenge. These data are the first to show both a functional and an essential role for BLT1 in allergen-mediated CD8+ T(EFF) recruitment into the lung and development of AHR and airway inflammation.

Radiologic and pathologic features of bronchiolitis.

Abstract: OBJECTIVE. The purpose of this article is to describe and illustrate the clinical, pathologic, and imaging features of the inflammatory and fibrotic forms of bronchiolitis. The CT features presented in this article represent the typical features associated with each entity.CONCLUSION. Direct signs of bronchiolitis include centrilobular nodules and tree-in-bud pattern. Indirect signs include mosaic attenuation and air trapping. Although classic examples of each entity exist, there can be substantial overlap in the appearances, and distinguishing among these entities is not always possible. When high-resolution CT features overlap, clinical details will usually help to narrow the differential diagnosis.

Requirement for leukotriene B4 receptor 1 in allergen-induced airway hyperresponsiveness.

Abstract: Rationale: Leukotriene B4 (LTB4) is a rapidly synthesized, early leukocyte chemoattractant that signals via its cell surface receptor, leukotriene B4 receptor 1 (BLT1), to attract and activate leukocytes during inflammation. A role for the LTB4–BLT1 pathway in allergen-induced airway hyperresponsiveness and inflammation is not well defined. Objectives: To define the role of the LTB4 receptor (BLT1) in the development of airway inflammation and altered airway function. Methods: BLT1-deficient (BLT1−/−) mice and wild-type mice were sensitized to ovalbumin by intraperitoneal injection and then challenged with ovalbumin via the airways. Airway responsiveness to inhaled methacholine, bronchoalveolar lavage fluid cell composition and cytokine levels, and lung inflammation and goblet cell hyperplasia were assessed. Results: Compared with wild-type mice, BLT1−/− mice developed significantly lower airway responsiveness to inhaled methacholine, lower goblet cell hyperplasia in the airways, and decreased interleukin...

Genome-wide search for sarcoidosis susceptibility genes in African Americans.

Abstract: Sarcoidosis, a systemic granulomatous disease of unknown etiology, likely results from an environmental insult in a genetically susceptible host. In the US, African Americans are more commonly affected with sarcoidosis and suffer greater morbidity than Caucasians. We searched for sarcoidosis susceptibility loci by conducting a genome-wide, sib pair multipoint linkage analysis in 229 African-American families ascertained through two or more sibs with a history of sarcoidosis. Using the Haseman–Elston regression technique, linkage peaks with P-values less than 0.05 were identified on chromosomes 1p22, 2p25, 5p15-13, 5q11, 5q35, 9q34, 11p15 and 20q13 with the most prominent peak at D5S2500 on chromosome 5q11 (P=0.0005). We found agreement for linkage with the previously reported genome scan of a German population at chromosomes 1p and 9q. Based on the multiple suggestive regions for linkage found in our study population, it is likely that more than one gene influences sarcoidosis susceptibility in African Americans. Fine mapping of the linked regions, particularly on chromosome 5q, should help to refine linkage signals and guide further sarcoidosis candidate gene investigation.

Downregulation of Peroxisome Proliferator–Activated Receptor-α Gene Expression in a Mouse Model of Ischemic Cardiomyopathy Is Dependent on Reactive Oxygen Species and Prevents Lipotoxicity

Abstract: Background— The peroxisome proliferators–activated receptor-α (PPARα), a transcription factor that modulates fatty acid metabolism, regulates substrate preference in the heart. Although in acute ischemia there is a switch in substrate preference from fatty acids to glucose, metabolic gene expression in repetitive ischemia is not well described. In a mouse model of ischemic cardiomyopathy induced by repetitive ischemia/reperfusion (I/R), we postulated that downregulation of PPARα is regulated by reactive oxygen species and is necessary for maintaining contractile function in the heart. Methods and Results— Repetitive closed-chest I/R (15 minutes) was performed daily in C57/BL6 mice, mice overexpressing extracellular superoxide dismutase, and mice treated with the PPARα agonist-WY-14,643. Echocardiography, histology, and candidate gene expression were measured at 3, 5, 7, and 28 days of repetitive I/R and 15 and 30 days after discontinuation of I/R. Repetitive I/R was associated with a downregulation of PPA...

Job and industry classifications associated with sarcoidosis in A Case-Control Etiologic Study of Sarcoidosis (ACCESS).

Abstract: Objectives:Objective: To determine whether specific occupations and industries may be associated with sarcoidosis.Methods:A Case Control Etiologic Study of Sarcoidosis (ACCESS) obtained occupational and environmental histories on 706 newly diagnosed sarcoidosis cases and matched controls. We

Host cell lipids control cholesteryl ester synthesis and storage in intracellular Toxoplasma

Abstract: The intracellular protozoan Toxoplasma gondii lacks a de novo mechanism for cholesterol synthesis and therefore must scavenge this essential lipid from the host environment. In this study, we demonstrated that T. gondii diverts cholesterol from low-density lipoproteins for cholesteryl ester synthesis and storage in lipid bodies. We identified and characterized two isoforms of acyl-CoA:cholesterol acyltransferase (ACAT)-related enzymes, designated TgACAT1alpha and TgACAT1beta in T. gondii. Both proteins are coexpressed in the parasite, localized to the endoplasmic reticulum and participate in cholesteryl ester synthesis. In contrast to mammalian ACAT, TgACAT1alpha and TgACAT1beta preferentially incorporate palmitate into cholesteryl esters and present a broad sterol substrate affinity. Mammalian ACAT-deficient cells transfected with either TgACAT1alpha or TgACAT1beta are restored in their capability of cholesterol esterification. TgACAT1alpha produces steryl esters and forms lipid bodies after transformation in a Saccharomyces cerevisiae mutant strain lacking neutral lipids. In addition to their role as ACAT substrates, host fatty acids and low-density lipoproteins directly serve as Toxoplasma ACAT activators by stimulating cholesteryl ester synthesis and lipid droplet biogenesis. Free fatty acids significantly increase TgACAT1alpha mRNA levels. Selected cholesterol esterification inhibitors impair parasite growth by rapid disruption of plasma membrane. Altogether, these studies indicate that host lipids govern neutral lipid synthesis in Toxoplasma and that interference with mechanisms of host lipid storage is detrimental to parasite survival in mammalian cells.

The use of cystatin C to inhibit epithelial–mesenchymal transition and morphological transformation stimulated by transforming growth factor-β

Abstract: Transforming growth factor-β (TGF-β) is a potent suppressor of mammary epithelial cell (MEC) proliferation and is thus an inhibitor of mammary tumor formation. Malignant MECs typically evolve resistance to TGF-β-mediated growth arrest, enhancing their proliferation, invasion, and metastasis when stimulated by TGF-β. Recent findings suggest that therapeutics designed to antagonize TGF-β signaling may alleviate breast cancer progression, thereby improving the prognosis and treatment of breast cancer patients. We identified the cysteine protease inhibitor cystatin C (CystC) as a novel TGF-β type II receptor antagonist that inhibits TGF-β binding and signaling in normal and cancer cells. We hypothesized that the oncogenic activities of TGF-β, particularly its stimulation of mammary epithelial–mesenchymal transition (EMT), can be prevented by CystC. Retroviral infection was used to constitutively express CystC or a CystC mutant impaired in its ability to inhibit cathepsin protease activity (namely Δ14CystC) in murine NMuMG MECs and in normal rat kidney (NRK) fibroblasts. The effect of recombinant CystC administration or CystC expression on TGF-β stimulation of NMuMG cell EMT in vitro was determined with immunofluorescence to monitor rearrangements of actin cytoskeletal architecture and E-cadherin expression. Soft-agar growth assays were performed to determine the effectiveness of CystC in preventing TGF-β stimulation of morphological transformation and anchorage-independent growth in NRK fibroblasts. Matrigel invasion assays were performed to determine the ability of CystC to inhibit NMuMG and NRK motility stimulated by TGF-β. CystC and Δ14CystC both inhibited NMuMG cell EMT and invasion stimulated by TGF-β by preventing actin cytoskeletal rearrangements and E-cadherin downregulation. Moreover, both CystC molecules completely antagonized TGF-β-mediated morphological transformation and anchorage-independent growth of NRK cells, and inhibited their invasion through synthetic basement membranes. Both CystC and Δ14CystC also inhibited TGF-β signaling in two tumorigenic human breast cancer cell lines. Our findings show that TGF-β stimulation of initiating metastatic events, including decreased cell polarization, reduced cell–cell contact, and elevated cell invasion and migration, are prevented by CystC treatment. Our findings also suggest that the future development of CystC or its peptide mimetics hold the potential to improve the therapeutic response of human breast cancers regulated by TGF-β.

Pulmonary and psychosocial findings at enrollment in the ACCESS study.

Abstract: Aim To assess lung involvement and the association of demographic and psychosocial factors with respiratory health in 736 persons with sarcoidosis at enrollment in A Case Control Etiologic Study of Sarcoidosis (ACCESS). Methods 736 patients with biopsy diagnosis of sarcoidosis within 6 months of enrollment were studied at 10 US centers. Lung involvement was evaluated by chest radiography, spirometry and dyspnea questionnaire. Demographics, number of involved extrathoracic organ systems, comorbidities, and health-related quality of life (HRQL) were assessed. Results 95% of patients had lung involvement. 8% were Scadding Stage 0, 40% I, 37% II, 10% III, and 5% IV 51% reported dyspnea. Increasing radiographic lung stage was associated with decreasing Forced Vital Capacity (FVC) (p or = 40, African-American race, body mass index > or = 30kg/m2, and CES-D scores > 9 were associated with decreased FVC and greater dyspnea. Impaired spirometry and greater dyspnea were associated with poorer quality of life. Conclusion A "global" approach to the sarcoidosis patient, including careful assessment of dyspnea and health related quality of life, as well as of lung function and radiographic changes, and any extrathoracic involvement, is important, not only in management of the individual patient, but should also prove beneficial in assessing outcomes in clinical trials in the future.

The Clinical Pharmacokinetics of Rifampin and Ethambutol in HIV-Infected Persons with Tuberculosis

Abstract: BACKGROUND The pharmacokinetics of rifampin and ethambutol in HIV-infected patients with tuberculosis (TB) are incompletely characterized. We examined the pharmacokinetics of rifampin and ethambutol in a cohort of patients with HIV-related TB who were treated in the United States. METHODS Serum drug concentrations were determined 2, 6, and 10 h after dosing in 36 HIV-infected patients with TB who were taking rifampin and in 49 who were taking ethambutol. Observed serum concentrations were compared with published normal ranges and published data. RESULTS With daily dosing of rifampin (600 mg), 26 (77%) of 34 patients (95% confidence interval [CI], 59%-89%]) had a low maximum concentration of rifampin (<8 microg/mL), and 12 (35%; 95% CI, 20%-54%) had a very low maximum concentration (<4 microg/mL). With intermittent rifampin dosing (600 mg), 13 (68%) of 19 patients (95% CI, 44%-85%) had a low maximum concentration of rifampin, and 5 (26%; 95% CI, 11%-50%) had a very low maximum concentration. With daily ethambutol dosing (20 mg/kg), 33 (69%) of 48 patients (95% CI, 55%-81%) had a low maximum concentration of ethambutol (<2 microg/mL), and 18 (38%; 95% CI, 24%-53%) had a very low maximum concentration (<1 microg/mL). With intermittent ethambutol dosing (50 mg/kg twice weekly or 30 mg/kg thrice weekly), 13 (72%) of 18 patients (95% CI, 47%-88%) had a low maximum concentration of ethambutol (<4 microg/mL), and 5 (28%; 95% CI, 12%-54%]) had a very low maximum concentration (<2 microg/mL). CONCLUSIONS In HIV-infected patients with TB who are receiving rifampin and ethambutol, low maximum concentrations of rifampin and ethambutol were common. For patients with HIV-related TB, therapeutic monitoring of rifampin and ethambutol levels may help clinicians achieve target serum concentrations.

Ozone Exposure in Vivo and Formation of Biologically Active Oxysterols in the Lung

Abstract: Ozone toxicity in the lung is thought to be mediated by products derived from the reaction of ozone with components of the lung epithelial lining fluid. Cholesterol is an abundant component of this epithelial lining fluid, and it is susceptible to ozonolysis, yielding several stable products including 3β-hydroxy-5-oxo-5,6-secocholestan-6-al and 5β,6β-epoxycholesterol. Both 5β,6β-epoxycholesterol and its metabolite, cholestan-6-oxo-3,5-diol, have been shown to cause cytotoxicity in vitro, suggesting that they may be potential mediators of ozone toxicity in vivo. An ozone-sensitive mouse strain, C57BL/6J, was exposed to varying concentrations of ozone (0.5-3.0 ppm), and subsequently the levels of these cholesterol ozonolysis products were quantitated by electrospray ionization mass spectrometry in bronchoalveolar lavage fluid, lavaged cells, and lung homogenate. An ozone dose-dependent formation of these biologically active oxysterols was observed in vivo, supporting a role for these compounds in ozone toxicity. Since the 5β,6β-epoxycholesterol metabolite, cholestan-6-oxo-3,5-diol, was isobaric with other cholesterol ozonolysis products, 3β-hydroxy-5-oxo-5,6-secocholestan-6-al and its aldol condensation product, 3β-hydroxy-5β-hydroxy-B-norcholestan-6β-carboxaldehyde, detailed mass spectral analysis using electron impact ionization was utilized to differentiate these isobaric cholesterol ozonolysis products. The specific detection of cholestan-6-oxo-3,5-diol in lung homogenate after ozone exposure established formation of 5β,6β-epoxycholesterol within the lung after exposure to 0.5 ppm ozone.

Inhibition of factor b, the alternative complement pathway and methods related thereto

Abstract: Disclosed are novel inhibitors of the alternative complement pathway and particularly, novel anti-factor B antibodies. Also disclosed is the use of such inhibitors to reduce or prevent airway hyperresponsiveness and/or airway inflammation by selectively inhibiting the alternative complement pathway, thereby treating diseases in which such conditions play a role. Also disclosed is the use of such inhibitors to reduce or prevent other diseases and conditions, including ischemia-reperfusion injury, by inhibition of the alternative complement pathway.

Alteration of airway neuropeptide expression and development of airway hyperresponsiveness following respiratory syncytial virus infection.

Abstract: The mechanisms by which respiratory syncytial virus (RSV) infection causes airway hyperresponsiveness (AHR) are not fully established. We hypothesized that RSV infection may alter the expression of...

Fibulin-5 function during tumorigenesis.

Abstract: Tumorigenesis is the process by which normal cells evolve the capacity to evade and overcome the constraints normally placed upon their growth and survival. During cancer progression, indolent tumors experience an array of genetic and epigenetic events that ultimately coordinate the development of tumor metastasis, which is the most lethal facet of cancer and the leading cause of cancer-related death. The therapeutic necessity to combat tumor metastasis continues to drive investigations aimed at identifying novel regulators of this deadly process. Fibulin-5 is a newly described extracellular matrix protein that is important for normal embryonic development and organogenesis. Fibulin-5 expression may also be associated with the suppression of tumor formation through its control of cell proliferation, motility and angiogenic sprouting. Here, the tumor suppressing activities of fibulin-5 are reviewed, and the potential use and targeting of fibulin-5 to combat growth and metastasis of human malignancies is di...

A sarcoidosis genetic linkage consortium: the sarcoidosis genetic analysis (SAGA) study.

Abstract: Background Sarcoidosis, a systemic granulomatous disease of unknown etiology, likely results from an environmental insult in a genetically susceptible host. In the United States of America, African Americans have a higher sarcoidosis incidence and suffer greater morbidity than Caucasians. Methods A sarcoidosis genetic linkage study consortium was established to recruit African-American affected sib pair (ASP) families to identify chromosomal regions that may harbor sarcoidosis susceptibility genes and to determine if environmental factors modify any genetic effects. Results We successfully met our goal of enrolling 359 ASPs using a multifaceted recruitment approach. In the total 559 sib pairs that were enrolled, genetic analyses revealed incorrectly specified relationships that required reclassification or removal from the analysis dataset of 10.4% of reported full and 1.4% of reported half sib pairs. The final study sample comprised 415 full and 104 half sib pairs with complete data. This included 338 ASPs. Within sib pairs, affection status was not associated with sex. Only 15 per cent of the 229 families had three or more affected sibs, but they contributed 42 per cent of the ASP total. Conclusions The SAGA study experience should provide useful lessons and information to serve others in conducting genetic studies of complex diseases in African-American families.

Human insulin-like growth factor-IA expression in transgenic mice promotes adenomatous hyperplasia but not pulmonary fibrosis

Abstract: Insulin-like growth factor-I (IGF-I) has been implicated in postnatal alveolar development, pulmonary fibrosis, and non-small cell lung cancer. To further investigate the role of IGF-I, we created ...

The protooncogene MYC can break B cell tolerance.

Abstract: The protooncogene MYC has been implicated in both the proliferation and programmed cell death of lymphoid cells, and in the genesis of lymphoid tumors. Here, we report that overexpression of MYC, as found in many lymphomas, can break immune tolerance. Mice that would otherwise be tolerant to a transgenic autoantigen mounted an immune response to the antigen if MYC was vigorously expressed in the B cell lineage. The responsive B cells converted to an activated phenotype and produced copious amounts of autoantibody that engendered immune complex disease of the kidney. MYC was required to both establish and maintain the breach of tolerance. These effects may be due to the ability of MYC to serve as a surrogate for cytokines. We found that the gene could mimic the effects of cytokines on both B cell proliferation and survival and, indeed, was required for those effects. These findings demonstrate a critical role for MYC in the response of B cells to antigen and expand the potential contributions of MYC to the genesis of lymphomas.

Aerosolized sodium hypochlorite inhibits viability and allergenicity of mold on building materials

Abstract: Background Commercial and residential buildings can become contaminated with molds, which may trigger allergic disorders. Mold remediation efforts may require costly replacement of mold-contaminated building materials. Disinfectants that contain dilute sodium hypochlorite can kill mold and are practical to use. Whether they also inhibit mold allergy symptoms is unknown. Objective We tested the hypothesis that sodium hypochlorite–containing spray products kill Aspergillus fumigatus and inhibit A fumigatus allergens. Methods A fumigatus was grown on 3 common building construction materials, as well as in solution by conventional laboratory methods. Two sodium hypochlorite–containing household products (diluted bleach and Tilex) were sprayed on the mold-contaminated materials or added to mold in solution and compared with untreated controls. Surface mold and associated debris were mechanically removed from treated and untreated boards. Conidia in the extracted board materials were quantified by light microscopy, examined for morphologic changes by scanning electron microscopy, and cultured for viable mold. Extracts were tested for A fumigatus antigen by ELISA, and for A fumigatus allergen by skin prick testing using extracts prepared from both the boards and the cultured solutions. Results Both sodium hypochlorite disinfectants killed A fumigatus in solution and on mold-contaminated building materials. Light microscopy and scanning electron microscopy demonstrated changes to the conidial surface. Both dilute bleach and Tilex inhibited A fumigatus recognition by ELISA. Skin testing supported the results of the ELISAs and demonstrated loss of skin test reactivity to the sodium hypochlorite–treated mold solutions in most of the subjects. Of the 4 individuals who had a positive skin test result to mold grown on oriented strand board building material, 3 no longer reacted to extracts from bleach-treated boards. Conclusion Spray application of sodium hypochlorite–containing disinfectants onto mold-contaminated building material kills A fumigatus , modifies the surface characteristics of A fumigatus conidia, reduces recognition of A fumigatus mold by ELISA, and results in loss of skin test reactivity to the treated mold in individuals allergic to A fumigatus .

S-carboxymethylcysteine normalises airway responsiveness in sensitised and challenged mice

Abstract: S -carboxymethylcysteine ( S -CMC) has been used as a mucoregulator in respiratory diseases. However, the mechanism of action of S -CMC on allergic airway inflammation has not yet been defined. In the present study, BALB/c mice were initially sensitised and challenged to ovalbumin (OVA) and, weeks later, re-challenged with OVA (secondary challenge). S -CMC (5–100 mg·kg −1 ) was administered from 2 days before the secondary challenge through to the day of assay. Mice developed airway hyperresponsiveness (AHR) 6 h after the secondary challenge and increased numbers of neutrophils were present in the bronchoalveolar lavage (BAL) fluid. At 72 h after secondary challenge, mice again developed AHR, but the BAL fluid contained large numbers of eosinophils. S -CMC treatment was found to reduce AHR and neutrophilia at 6 h, as well as eosinophilia and AHR at 72 h. These effects appeared to be dose dependent. Goblet cell hyperplasia, observed at 72 h, was reduced by S -CMC. In BAL fluid, increased levels of interferon-γ, interleukin (IL)-12 and IL-10 and decreased levels of IL-5 and IL-13 were detected. In conclusion, the data indicate that S -carboxymethylcysteine is effective in reducing airway hyperresponsiveness and airway inflammation at two distinct phases of the response to the secondary allergen challenge in sensitised mice.

Airway Hyperresponsiveness in the Absence of CD4+ T Cells after Primary but Not Secondary Challenge

Abstract: CD4+ T cells have been shown to play a role in the development of airway hyperresponsivness (AHR) and airway eosinophilia in mice using ablation as well as adoptive transfer experiments. However, as other T cell subsets (CD8, NKT) may play a role in these models, we examined the responses of sensitized CD4-deficient mice after either primary or secondary airway allergen challenge. After sensitization, CD4-deficiency in mice was not associated with airway eosinophilia, allergen-specific IgE, or elevated levels of interleukin (IL)-4 or IL-13. Increases in lung CD8 T cells and IL-5 were observed and shown to be essential for AHR as demonstrated after CD8 T cell depletion or anti-IL-5 treatment. In contrast to the response of sensitized CD4-deficient mice to primary allergen challenge, they failed to develop AHR after secondary allergen challenge. Although the importance of this CD4+ T cell-independent pathway in normal mice is unclear at this time, these studies identify the diversity of the cellular pathway, which may contribute to the development of AHR after primary allergen exposure of sensitized mice.

Human vitreous distribution of linezolid after a single oral dose.

Abstract: PURPOSE To evaluate the relationship between vitreous linezolid concentrations versus both time and serum concentrations after a single 600 mg oral dose. METHODS Two groups of six subjects undergoing a pars plana vitrectomy indicated by macular pucker or full thickness macular hole were given a single tablet of linezolid before surgery. The early group underwent vitrectomy at random times before the time of maximum serum linezolid concentration (i.e., 77 minutes) and the late group underwent vitrectomy at random times afterward. Each patient had a serum sample drawn shortly before and after vitrectomy and the vitreous specimen was sampled at the initiation of surgery. RESULTS The early group and late group had mean vitreous linezolid concentrations of 0.06 mcg/mL and 1.25 mcg/mL, respectively. The vitreous linezolid concentration showed a strong correlation to the interpolated serum concentration (R2 = 0.74, P < 0.01) at the time of vitrectomy. CONCLUSION The study demonstrates that linezolid penetrates the blood-retina barrier in noninflamed eyes. Because the vitreous concentrations appeared to exponentially trend upward with time and 33% of the late group achieved sufficient MIC90 levels for the common pathogens found in postoperative endophthalmitis, adequate concentrations might be achieved with an altered dosing regimen to achieve higher serum steady state levels. Further study is warranted.

A middle-aged woman with recurrent respiratory infections.

Abstract: aDepartment of Medicine, bProgram in Cell Biology, National Jewish Medical and Research Center, cDivision of Pulmonary Sciences and Critical Care Medicine, dDivision of Infectious Diseases, University of Colorado Health Sciences Center, eDenver Veterans Administration Medical Center, Denver, Colo., and fDepartment of Medicine, University of North Carolina, Chapel Hill, N.C., USA Received: January 19, 2004 Accepted after revision: May 18, 2004