Showing papers by "National Jewish Health published in 2003"

A Tyrosine Kinase Created by Fusion of the PDGFRA and FIP1L1 Genes as a Therapeutic Target of Imatinib in Idiopathic Hypereosinophilic Syndrome

Abstract: Background Idiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction. It is of unknown cause. Recent reports of responses to imatinib in patients with the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause. Methods We treated 11 patients with the hypereosinophilic syndrome with imatinib and identified the molecular basis for the response. Results Nine of the 11 patients treated with imatinib had responses lasting more than three months in which the eosinophil count returned to normal. One such patient had a complex chromosomal abnormality, leading to the identification of a fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRα (PDGFRA) gene generated by an interstitial deletion on chromosome 4q12. FIP1L1-PDGFRα is a constitutively activated tyrosine kinase that transforms hematopoietic cells and is inhibited by imatinib (50 perce...

Development of Human Protein Reference Database as an Initial Platform for Approaching Systems Biology in Humans

Abstract: Human Protein Reference Database (HPRD) is an object database that integrates a wealth of information relevant to the function of human proteins in health and disease. Data pertaining to thousands of protein-protein interactions, posttranslational modifications, enzyme/substrate relationships, disease associations, tissue expression, and subcellular localization were extracted from the literature for a nonredundant set of 2750 human proteins. Almost all the information was obtained manually by biologists who read and interpreted >300,000 published articles during the annotation process. This database, which has an intuitive query interface allowing easy access to all the features of proteins, was built by using open source technologies and will be freely available at http://www.hprd.org to the academic community. This unified bioinformatics platform will be useful in cataloging and mining the large number of proteomic interactions and alterations that will be discovered in the postgenomic era.

Effect of Anti-IgE Therapy in Patients with Peanut Allergy

Abstract: background Peanut-induced anaphylaxis is an IgE-mediated condition that is estimated to affect 1.5 million people and cause 50 to 100 deaths per year in the United States. TNX-901 is a humanized IgG1 monoclonal antibody against IgE that recognizes and masks an epitope in the CH3 region of IgE responsible for binding to the high-affinity Fc e receptor on mast cells and basophils. methods We conducted a double-blind, randomized, dose-ranging trial in 84 patients with a history of immediate hypersensitivity to peanut. Hypersensitivity was confirmed and the threshold dose of encapsulated peanut flour established by a double-blind, placebo-controlled oral food challenge at screening. Patients were randomly assigned in a 3:1 ratio to receive either TNX-901 (150, 300, or 450 mg) or placebo subcutaneously every four weeks for four doses. The patients underwent a final oral food challenge within two to four weeks after the fourth dose. results From a mean base-line threshold of sensitivity of 178 to 436 mg of peanut flour in the various groups, the mean increases in the oral-food-challenge threshold were 710 mg in the placebo group, 913 mg in the group given 150 mg of TNX-901, 1650 mg in the group given 300 mg of TNX-901, and 2627 mg in the group given 450 mg of TNX-901 (P<0.001 for the comparison of the 450-mg dose with placebo, and P for trend with increasing dose <0.001). TNX-901 was well tolerated. conclusions A 450-mg dose of TNX-901 significantly and substantially increased the threshold of sensitivity to peanut on oral food challenge from a level equal to approximately half a peanut (178 mg) to one equal to almost nine peanuts (2805 mg), an effect that should translate into protection against most unintended ingestions of peanuts.

Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12.

Abstract: During apoptosis, phosphatidylserine, which is normally restricted to the inner leaflet of the plasma membrane, is exposed on the surface of apoptotic cells and has been suggested to act as an “eat-me” signal to trigger phagocytosis. It is unclear how phagocytes recognize phosphatidylserine. Recently, a putative phosphatidylserine receptor (PSR) was identified and proposed to mediate recognition of phosphatidylserine and phagocytosis. We report that psr-1, the Caenorhabditis elegans homolog of PSR, is important for cell corpse engulfment. In vitro PSR-1 binds preferentially phosphatidylserine or cells with exposed phosphatidylserine. In C. elegans, PSR-1 acts in the same cell corpse engulfment pathway mediated by intracellular signaling molecules CED-2 (homologous to the human CrkII protein), CED-5 (DOCK180), CED-10 (Rac GTPase), and CED-12 (ELMO), possibly through direct interaction with CED-5 and CED-12. Our findings suggest that PSR-1 is likely an upstream receptor for the signaling pathway containing CED-2, CED-5, CED-10, and CED-12 proteins and plays an important role in recognizing phosphatidylserine during phagocytosis.

Two year prognosis of sarcoidosis: The ACCESS experience

Abstract: A cohort of 215 sarcoidosis patients from the ACCESS study underwent a clinical evaluation at study enrollment and two years later. Approximately 80% of subjects had an improved or stable FVC, FEV1, chest radiograph determined by Scadding stage, and dyspnea scale. African-Americans had less improvement in FVC than Caucasians (p = 0.04). Patients with erythema nodosum at presentation were more likely to have improvement in the chest radiograph at two-year follow-up (p = 0.007). Patients with a lower annual family income were more likely to worsen with respect to dyspnea (p = 0.01) and more likely to have new organ involvement at two-year follow-up (p = 0.045). The development of new organ involvement over the two year follow-up period was more common in African-Americans compared to Caucasians (p = 0.002) and more likely in those with extrapulmonary involvement at study entry (p = 0.003). There was an excellent concordance between changes in FVC and FEV1 over the two-year period. However, changes in FVC alone were inadequate to describe the change in pulmonary status of the patients, as changes in chest radiographic findings or the level of dyspnea did often but not always move in the same direction as FVC. In conclusion, data from this heterogeneous United States sarcoidosis population indicate that sarcoidosis tends to improve or remain stable over two years in the majority of patients. Several factors associated with improved or worse outcome over two years were identified.

First do no harm: Managing antihistamine impairment in patients with allergic rhinitis

Abstract: Antihistamines are effective medications that have been used for decades in the management of allergic rhinitis; however, they may be administered or selected in an inappropriate fashion and may be the source of drug-related morbidity. Our objective is to present relevant background information and an expert consensus statement on the use of antihistamines in treatment of allergic rhinitis. In July 2002, 14 experts in allergy, clinical immunology, pharmacology, and impairment assessment were invited to participate in a roundtable conference to present current concepts and develop a consensus statement on the clinical management of allergic rhinitis with antihistamines. Many of the antihistamines used to treat allergic rhinitis, as well as the disease itself, may produce sedation, impairment, and reduced quality of life. Allergic rhinitis is more appropriately managed with the relatively nonimpairing second-generation antihistamines (eg, loratadine, desloratadine, cetirizine, and fexofenadine), because older agents (eg, diphenhydramine, chlorpheniramine, and brompheniramine) produce sedation and impairment and worsen sleep architecture. Although there is some debate surrounding the varying degrees of efficacy of second-generation antihistamines, it is known that some agents may produce varying levels of drowsiness or impairment, especially at higher than recommended doses. The differences with regard to safety among the second-generation antihistamines are smaller than are the differences between the first and second generations. A nonsedating, nonimpairing (even at higher than recommended doses), second-generation antihistamine is preferred for all patients, particularly those with a higher risk for the development of adverse effects. We recommend that primary care and specialist physicians, nurse practitioners, physician assistants, pharmacists, and all other health professionals involved in the diagnosis and treatment of allergic rhinitis follow this consensus document and share this information with patients for whom antihistamine therapy is recommended. In addition, further epidemiologic studies on the effects of antihistamines should be performed.

Microarray analysis of lipopolysaccharide-treated human neutrophils.

Abstract: Neutrophils respond to infection by degranulation, release of reactive oxygen intermediates, and secretion of chemokines and cytokines; however, activation of neutrophil transcriptional machinery has been little appreciated. Recent findings suggest that gene expression may represent an additional neutrophil function after exposure to lipopolysaccharide (LPS). We performed microarray gene expression analysis of 4,608 mostly nonredundant genes on LPS-stimulated human neutrophils. Analysis of three donors indicated some variability but also a high degree of reproducibility in gene expression. Twenty-eight verifiable, distinct genes were induced by 4 h of LPS treatment, and 13 genes were repressed. Genes other than cytokines and chemokines are regulated; interestingly, genes involved in cell growth regulation and survival, transcriptional regulation, and interferon response are among those induced, whereas genes involved in cytoskeletal regulation are predominantly repressed. In addition, we identified monocyte chemoattractant protein-1 as a novel LPS-regulated chemokine in neutrophils. Included in these lists are five clones with no defined function. These data suggest molecular mechanisms by which neutrophils respond to infection and indicate that the transcriptional potential of neutrophils is greater than previously thought.

Inhibition of complement activation decreases airway inflammation and hyperresponsiveness

Abstract: Studies in murine models have suggested the involvement of the complement anaphylatoxins (C3a and C5a) in the development of allergic asthma. We investigated the effects of inhibiting complement activation after sensitization but before allergen challenge on the development of allergic airway inflammation and airway hyperresponsiveness. To prevent complement activation, we used a recombinant soluble form of the mouse membrane complement inhibitor complement receptor-related gene y (Crry) fused to the IgG1 hinge, CH2 and CH3 domains (Crry-Ig), which has decay-accelerating activity for both the classic and alternative pathways of complement as well as cofactor activity for factor I-mediated cleavage of C3b and C4b. C57BL/6 mice were sensitized (Days 1 and 14) and challenged (Days 24–26) with ovalbumin. Crry-Ig was administered after allergen sensitization either as an intraperitoneal injection or by nebulization before allergen challenge. Crry-Ig significantly prevented the development of airway hyperrespon...

Cost-effectiveness analysis of tacrolimus ointment versus high-potency topical corticosteroids in adults with moderate to severe atopic dermatitis.

Abstract: Background: Few cost-effectiveness analyses have been conducted on topical therapies for atopic dermatitis. Objective: We sought to compare cost-effectiveness of high-potency topical corticosteroids (HPTCs) and tacrolimus ointment for the treatment of moderate to severe atopic dermatitis for patients who are not responsive to or not well controlled with mid-potency topical corticosteroids. Methods: A Markov model represented the cyclic nature of atopic dermatitis. Clinical outcomes were derived from published literature. "Efficacy" was defined as disease-controlled days on which patients experienced a greater than 75% improvement in their disease. Resource use and changes in management were on the basis of opinions of a physician panel; secondary treatment was an oral antibiotic with topical corticosteroids. Sensitivity analyses were conducted for all variables. Results: The model was sensitive to duration of continuous treatment with HPTCs. HPTCs, when limited to 2-week treatment cycles, were associated with the highest total costs ($1682 per year) and the least efficacy (185 disease-controlled days). HPTCs in 4-week treatment intervals and tacrolimus ointment were similar in total costs and efficacy ($1317 vs $1323 for 194 vs 190 disease-controlled days, respectively). Although primary drug costs were higher for patients treated with tacrolimus ointment, patients treated with regimens of HPTCs incurred higher secondary drug costs. Conclusion: In the base case analyses, tacrolimus ointment was more cost-effective than HPTCs administered in 2-week treatment cycles, and similar in cost-effectiveness to 4-week cycles of HPTCs. (J Am Acad Dermatol 2003;48:553-63.)

Transient Neutrophil Infiltration After Allergen Challenge Is Dependent on Specific Antibodies and FcγIII Receptors

Abstract: Following allergen challenge of sensitized mice, neutrophils are the first inflammatory cells found in bronchoalveolar lavage (BAL) fluid. To determine the underlying mechanism for their accumulation, mice were sensitized to OVA on days 0 and 14, and received, on day 28, a single intranasal challenge (s.i.n.) with either OVA or ragweed. Eight hours after the s.i.n., BAL fluid was obtained. BALB/c mice sensitized and challenged with OVA showed significantly higher total cell counts and numbers of neutrophils in BAL fluid compared to the OVA-sensitized and ragweed-challenged or nonsensitized mice. Levels of neutrophil chemokines in BAL fluid supernatants were markedly elevated in the sensitized and OVA-challenged mice; Fc epsilon RI-deficient mice showed comparable numbers of neutrophils and neutrophil chemokines in BAL fluid after s.i.n. But in sensitized mice lacking the Fc common gamma-chain and B cell-deficient mice, the number of neutrophils and levels of neutrophil chemokines in BAL fluid were significantly lower. Further, mice lacking the FcgammaRIII did not develop this early neutrophil influx. Neutrophil infiltration could be induced in naive mice following intranasal instillation of allergen combined with allergen-specific IgG1. In addition, macrophages from sensitized mice were stimulated with allergen and activated to produce neutrophil chemokines. These results demonstrate that neutrophil influx after allergen challenge requires prior sensitization, is allergen-specific, is mediated through FcgammaRIII, and is dependent on the presence of Ab.

Induction of regulated upon activation, normal T cells expressed and secreted (RANTES) and transforming growth factor-β1 in airway epithelial cells by Mycoplasma pneumoniae

Abstract: Mycoplasma pneumoniae infection exacerbates asthma in children and may play a role in the pathogenesis of chronic asthma. Because the airway epithelium is a preferential site for M. pneumoniae infection and a major source of the chemokine regulated on activation, normal T cells expressed and secreted (RANTES) and transforming growth factor (TGF)-β1, we postulated that this microorganism may contribute to the disease by inducing these mediators through direct interaction with airway epithelial cells. We investigated the effects of M. pneumoniae on RANTES and TGF-β1 production in primary cultures of normal human bronchial epithelial (NHBE) cells and small airway epithelial (SAEC) cells. Both cell types were permissive to M. pneumoniae infection in vitro, but their responses were different. TGF-β1 was induced at higher levels in NHBE than in SAEC cultures, whereas RANTES was induced in SAEC cultures but not in NHBE cultures. These effects were attenuated by erythromycin and dexamethasone. In vitro adherence ...

Assessment of exhaled nitric oxide kinetics in healthy infants

Abstract: Exhaled nitric oxide (Fe NO) measurements provide a noninvasive approach to the evaluation of airway inflammation. Flow-independent NO exchange parameters [airway NO transfer factor (DNO) and airwa...

Methods for treatment of thiol-containing compound deficient conditions

Abstract: Methods for therapy of cystic fibrosis and other conditions are provided. The methods comprise one or more agents capable of increasing thiol-containing compound transport via a transporter system (i.e. ABC transporters such as MDR-1 or MRP-2) in cells. Other embodiments include the use of agents to modulate transport of thiol-containing compounds within the cell. Therapeutic methods involve the administration of such agents to a patient afflicted with cystic fibrosis and/or another condition responsive to stimulation of thiol-containing compound transport.

MEF2C regulates c-Jun but not TNF-α gene expression in stimulated mast cells

Abstract: Mitogen-activated protein kinase (MAPK) cascades play essential roles in the transduction of extracellular signals to cytoplasmic and nuclear effectors. The MAPK kinase kinase MEKK2 is essential for activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 5 (ERK5). These pathways are important for expression of specific cytokine genes in mast cells following cross-linking of the high-affinity IgE receptor (FcϵRI). A consequence of ERK5 activation is activation of the transcriptional factor myocyte enhancing factor-2C (MEF2C), leading to increased c-Jun expression. We have investigated the role of MEF2C activation in mast cells and demonstrated that it requires sequential activation of the signaling cascade of MEKK2-MEK5-ERK5. Following phosphorylation of MEF2C, activated MEF2C regulates transcription of c-Jun but not TNF-α. Inhibition of ERK5, MEK5 activation or activation of MEKK2-deficient mast cells was associated with inhibition of MEF2C phosphorylation and a decrease in c-Jun expression. Thus, these data define an activation module, MEKK2-MEK5-ERK5-MEF2C in the transcriptional activation of c-Jun in mast cells following FcϵRI cross-linking. These results demonstrate the novel and important, MEKK2-dependent role of MEF2C in induction of c-Jun expression in mast cells activated through FcϵRI, a pathway distinct from that involving MEKK2-MEK5-ERK5 in the regulation of mast cell cytokine production.

One-Year Outcomes from a Disease Management Program for Chronic Obstructive Pulmonary Disease

Abstract: Objective: to present the results of our 1-year, telephonic disease management interventions for 349 patients with mild to severe chronic obstructive pulmonary disease (COPD). Methods: parameters measuring utilization of medical services, days lost from work, and quality-of-life measurements (utilizing the St. George’s Questionnaire) were determined for the 12-month period prior to enrollment of patients and compared with those observed during the 12-month participation in the program. Results: there was a statistically significant reduction in all utilization measurements and a statistically significant improvement in quality of life. Emergency room (ER) visits decreased by 57% (p < 0.001), hospitalizations by 53% (p < 0.001), intensive care unit admissions by 66% (p = 0.001), unscheduled office visits by 67% (p < 0.001), and oral antibacterial bursts by 48% (p < 0.001). Of the 114 employed patients, days missed from work were reduced by 77% (p < 0.001). The total saving from reduction in hospitalizations and ER visits was $US672 000. This was against an approximate cost of the program of $US223 500 (average of $US635 per enrollee). Costs associated with medications and physician visits were not obtained. Conclusions: these outcomes suggest that, with ongoing patient support, the provision of physical rehabilitation, and improved communication between those engaged in the healing process, it is possible to reduce utilization and overall healthcare expenditures and improve the quality of life for a population of patients with moderate to severe COPD. This intervention was both cost effective and medically effective. Our experience suggests that further trials of COPD disease management are warranted.

Interferon- γ for delayed pulmonary toxicity syndrome resistant to steroids

Abstract: Delayed pulmonary toxicity syndrome, characterized by interstitial pneumonia and pulmonary fibrosis, is common following high-dose bischloroethylnitrosourea (BCNU) (carmustine, [1,3-bis (2-chloroethyl)-1-nitrosourea]) containing chemotherapeutic regimens. Depending upon the treatment protocol, it may develop in over 70% of patients. Early and aggressive corticosteroid treatment leads to improvement in the majority of patients. However, up to 8% of affected patients may fail to respond to corticosteroids and develop progressive respiratory failure leading to death. No alternatives to corticosteroids have thus far been shown useful. We report the symptomatic and physiological improvement of a patient with severe steroid-resistant delayed pulmonary toxicity syndrome, following treatment with interferon-γ.

Fibulin-5 and uses thereof

Abstract: Disclosed are methods for the use of Fibulin-5 as a marker for cancer diagnostics and other cancer screening assays, including to monitor the treatment of a patient with cancer, and for the use of Fibulin-5 as a cancer therapeutic and/or anti-angiogenesis therapeutic. Also disclosed are methods for identifying regulators of TGFβ activity and methods for identifying regulators of tumorigenicity and angiogenesis.

Validation of expert opinion in identifying comorbidities associated with atopic dermatitis/eczema.

Abstract: healthcare utilisation; however, few studies have attempted to assess the validity of assumptions derived from such sources. Objective: To examine the use of such expert opinion in determining comorbidities associated with atopic dermatitis/eczema (AD/E), which were assessed as part of a recent third-party payer cost-of-illness study. Design: To identify the disease-related comorbidities that would represent costs associated with AD/E, physicians on an expert panel were asked individually and then collectively to group all International Classification of Diseases, 9th Edition–Clinical Modification (ICD-9-CM) diagnosis codes as ‘most likely’, ‘possibly’ or ‘definitely not’ related to the costs of identifying and treating patients with AD/E. Claims representing $US464 million in payer reimbursements from nearly 125 000 patients with AD/E were identified within two separate claims databases (1997 values). Over 850 ICD-9-CM diagnosis codes were identified in the first-listed position from these claims. For each group of ‘most likely’, ‘possibly’

Covalent binding of leukotriene A4 to nucleosides, nucleotides, and nucleic acids.

Abstract: The chemical reactivity of leukotriene A4 (LTA4) is widely appreciated following the detailed studies of its stability in aqueous solutions, solutions containing organic solvents, and solutions containing albumin [1]. The half-life of LTA4 is less than one second unless a stabilizing substance is present in aqueous buffers. This has led to the concept that intracellular LTA4 exists only for a brief period of time before it is either nonenzymatically hydrolyzed to 6-trans-LTB4 isomers or converted by LTA4 hydrolase or LTC4 synthase into the biologically active leukotrienes, LTB4 and LTC4, respectively [[2]]. The reactivity of LTA4 is due to its electrophilic character and within the cell various nucleophiles are present including nucleic acids which could, in theory, donate electrons into the conjugated triene epoxide moiety of LTA4.

Challenges in assessing asthma severity in clinical practice

Abstract: The National Heart, Lung, and Blood Institute’s 1997 National Asthma Education and Prevention Program (NAEPP) classifies asthma severity on the basis of lung function and symptoms, and most clinicians use either or both of these measures to assess patients. Severity-based stratification of patients provides a useful framework for therapeutic decision making, but this approach should not be adopted without an understanding of its delimitations and challenges. Accurate assessment of asthma severity is crucial in ensuring the patient’s health and well-being. The consequences of misappraisal of patients’ clinical status include unnecessary prescription of medication when severity is overestimated and failure to intervene with resulting deterioration of asthma control—possibly culminating in death— when severity is underestimated. This review reveals that applying the NAEPP’s severity-based classification of patients with asthma in clinical practice can be challenging, particularly in the care of patients at the mild end of the asthma severity continuum. The variable nature of asthma, the poor concordance among measures of asthma severity, and patients’ tendency to underreport their asthma symptoms can contribute to inaccurate severity assessments, which can lead to inappropriate therapeutic choices, such as undertreatment. Undertreatment of the patient with mild asthma can be as dangerous as undertreatment of patients with more severe disease. By keeping the challenges associated with severity-based stratification of patients top-of-mind, healthcare providers may be better able to overcome them in clinical practice. (Adv Stud Med. 2003;3(5A):S372-S378)

AMID protein, nucleic acid molecules, and uses thereof

Abstract: Described here is the cloning and characterization of a novel AIF homologous molecule designated AMID, which is co-localized with mitochondria, and which induces cell death with characteristic apoptotic morphology, independent of caspase activation and p53. Bcl2. Disclosed herein are AMID proteins, fragments and homologues, as well as nucleic acid molecules encoding such proteins, and methods of making and using the same.

Il-4-induced lipid mediators class switching in human normal mononuclear phagocytes.

Abstract: Leukotrienes (LT) are important molecules arising from arachidonic acid, knokn to play an important role in inflammatory reactions [1]. Their synthesis is limited to a restricted number of cell involved in the inflammatory response, such as mast cells, neutrophils, eosinophils and monocyte/macrophages.