Showing papers by "National Jewish Health published in 2010"

2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

Abstract: Objective The 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classifi cation criteria for rheumatoid arthritis (RA) have been criticised for their lack of sensitivity in early disease. This work was undertaken to develop new classifi cation criteria for RA. Methods A joint working group from the ACR and the European League Against Rheumatism developed, in three phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated infl ammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/ or erosive disease—this being the appropriate current paradigm underlying the disease construct ‘RA’. Results In the new criteria set, classifi cation as ‘defi nite RA’ is based on the confi rmed presence of synovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (range 0–5), serological abnormality (range 0–3), elevated acute-phase response (range 0–1) and symptom duration (two levels; range 0–1). Conclusion This new classifi cation system redefi nes the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defi ning the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimise the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct ‘RA’.

2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

Abstract: Objective The 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticised for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. Methods A joint working group from the ACR and the European League Against Rheumatism developed, in three phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease—this being the appropriate current paradigm underlying the disease construct ‘RA’. Results In the new criteria set, classification as ‘definite RA’ is based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (range 0–5), serological abnormality (range 0–3), elevated acute-phase response (range 0–1) and symptom duration (two levels; range 0–1). Conclusion This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimise the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct ‘RA’.

The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: Phase 2 methodological report

Abstract: Objective. The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set. Methods. Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of "developing RA," complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis. Results. The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach. Conclusion. The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set.

Physical activity, health status and risk of hospitalization in patients with severe chronic obstructive pulmonary disease.

Abstract: Background: Chronic obstructive pulmonary disease (COPD) is a leading cause of death and 70% of the cost of COPD is due to hospitalizations. Self-reported daily physical activity an

Aging adversely affects the cigarette smoke-induced glutathione adaptive response in the lung.

Abstract: Rationale: Cigarette smoke (CS) is the leading cause of chronic obstructive pulmonary disease, accounting for more than 90% of cases. The prevalence of chronic obstructive pulmonary disease is much higher in the elderly, suggesting an age dependency. A prominent defense against the oxidant burden caused by CS is the glutathione (GSH) adaptive response in the lung epithelial lining fluid (ELF) and tissue. However, as one ages the ability to maintain GSH levels declines. Objectives:ExaminetheeffectofagingontheGSHadaptiveresponse toCSandresultinglungsensitizationtoinflammationandoxidation. Methods: Both young (2 mo old) and aged (8, 13, 19, and 26 mo old) mice were used to study the effects of age on the GSH adaptive response after an acute exposure to CS. Measurements and Main Results: Young mice had a robust sixfold

The role of endothelin-1 in the pathogenesis of idiopathic pulmonary fibrosis.

Abstract: The endothelin system participates in a number of critical biologic pathways, including normal wound healing. In addition, emerging basic science, and animal and human data all suggest that endothelin-1 (EDN1, also known as ET-1) is a potentially important contributor in the pathobiology of fibrosing disorders, including those that affect the lung. For example, EDN1 drives fibroblast activation, proliferation, as well as differentiation into myofibroblasts - processes that lead to excessive collagen deposition. Patients with idiopathic pulmonary fibrosis (IPF) have increased levels of EDN1 in both their bronchoalveolar lavage fluid and lung tissue. Beyond this, rodent models suggest that endothelin receptor antagonists can limit bleomycin-induced lung fibrosis. This suggests a biologic rationale for the blockade of EDN1 to limit the evolution of lung fibrosis in humans. Initial results from a trial examining the efficacy of a dual endothelin receptor antagonist suggest that this approach may delay disease progression in a subset of patients with IPF.

Relationship between infant weight gain and later asthma.

Abstract: Like obesity, the prevalence of asthma has increased over the past several decades. Accelerated patterns of infant growth have been associated with obesity and its co-morbidities. We aimed to determine if infant weight gain pattern is associated with asthma development later in childhood. Birth weight, growth, pulmonary function, and symptom data were collected in a trial of 2- to 3-yr-old children at-risk for asthma randomized to a 2-yr treatment with inhaled corticosteroids or placebo followed by a 1-yr observation period of study medication. Patterns of infant weight gain between birth and study enrollment were categorized as accelerated, average, or decelerated. Regression analyses were used to test the effects of infant weight gain pattern prior to study enrollment on outcomes during the observation year and at study conclusion while adjusting for demographics, baseline symptom severity, study treatment, and atopic indicators. Among the 197 study participants, early life weight gain pattern was not associated with daily asthma symptoms or lung function at the study's conclusion. However, both prednisone courses (p = 0.01) and urgent physician visits (p < 0.001) were significantly associated with weight gain pattern with fewer exacerbations occurring amongst those with a decelerated weight gain pattern. We conclude that early life patterns of weight change were associated with subsequent asthma exacerbations, but were not associated with asthma symptoms or pulmonary function during the pre-school years for these children at-risk for asthma.

Quality of life and dyspnoea in patients treated with bosentan for idiopathic pulmonary fibrosis (BUILD-1).

Abstract: No therapy is known to improve health-related quality of life (HRQoL) or dyspnoea in patients with idiopathic pulmonary fibrosis. The present study investigated longitudinal changes in HRQoL and dyspnoea and explored the effects of bosentan on these end-points during the Bosentan Use in Interstitial Lung Disease (BUILD)-1 trial. In total, 154 subjects received oral bosentan (n = 71) or placebo (n = 83). Changes in HRQoL and dyspnoea from baseline to month (M) 6 and up to M12 were measured using the St George's Respiratory Questionnaire (SGRQ), 36-item short-form health survey (SF-36), Transition Dyspnoea Index and Borg dyspnoea index. Overall, minimal changes occurred in measures of HRQoL and dyspnoea among placebo-treated subjects during the study. The effects of bosentan treatment on HRQoL and dyspnoea in the all-treated population were minimal. However, in the subset of subjects who had undergone surgical lung biopsy for diagnosis of idiopathic pulmonary fibrosis, treatment effects were observed up to M12 in the impact domain of the SGRQ and the physical functioning, general health and role emotional domains of the SF-36. HRQoL and dyspnoea changed minimally during the course of the present study. Observations from exploratory analyses suggested benefits of bosentan on HRQoL among patients who had undergone surgical lung biopsy for diagnosis, and they merit further investigation

Dual-specificity phosphatase 1 as a pharmacogenetic modifier of inhaled steroid response among asthmatic patients

Abstract: Background Inhaled corticosteroids (ICSs) are considered first-line treatment for persistent asthma, yet there is significant variability in treatment response. Dual-specificity phosphatase 1 ( DUSP1 ) appears to mediate the anti-inflammatory action of corticosteroids. Objective We sought to determine whether variants in the DUSP1 gene are associated with clinical response to ICS treatment. Methods Study participants with asthma were drawn from the following multiethnic cohorts: the Genetics of Asthma in Latino Americans (GALA) study; the Study of African Americans, Asthma, Genes & Environments (SAGE); and the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). We screened GALA study participants for genetic variants that modified the relationship between ICS use and bronchodilator response. We then replicated our findings in SAGE and SAPPHIRE participants. In a group of SAPPHIRE participants treated with ICSs for 6 weeks, we examined whether a DUSP1 polymorphism was associated with changes in FEV 1 and self-reported asthma control. Results The DUSP1 polymorphisms rs881152 and rs34507926 localized to different haplotype blocks and appeared to significantly modify the relationship between ICS use and bronchodilator response among GALA study participants. This interaction was also seen for rs881152 among SAPPHIRE but not SAGE participants. Among the group of SAPPHIRE participants prospectively treated with ICSs for 6 weeks, rs881152 genotype was significantly associated with changes in self-reported asthma control but not FEV 1 . Conclusion DUSP1 polymorphisms were associated with clinical response to ICS therapy and therefore might be useful in the future to identify asthmatic patients more likely to respond to this controller treatment.

Haplotype variation, recombination, and gene conversion within the turkey MHC-B locus

Abstract: The major histocompatibility complex (MHC) is a gene dense region with profound effects on the disease phenotype. In many species, characterizations of MHC polymorphisms have focused on identifying allelic haplotypes of the highly polymorphic class I and class II loci through direct immunological approaches such as monoclonal antibodies specific for the major antigens or indirectly through DNA sequence-based approaches. Invariably, these studies fail to assess the broader range of variation at the other loci within the MHC. This study examines variation in the turkey MHC by resequencing 15 interspersed amplicons (∼14 kb) spaced across the MHC-B locus in a representative sampling of 52 commercial birds. Over 200 single nucleotide polymorphisms (SNPs) were identified with high levels of polymorphism (1 SNP/70 bp) and heterozygosity (average minor allele frequency of 0.15). SNP genotypes were used to identify the major haplotypes segregating in the commercial lines. Sequencing of the peptide binding region (PBR, exon 2) of the class IIB loci of select individuals identified 10 PBR alleles/isotypes among the major MHC haplotypes. Examination of pedigreed families provides direct evidence of gene conversion and recombination within the B locus. Results of this study demonstrate the MHC diversity available in commercial flocks and provide genomic resources for studying the effect of this diversity (alleles and/or haplotypes) on disease susceptibility and resistance.

Identification of inhibitors of Plasmodium falciparum phosphoethanolamine methyltransferase using an enzyme-coupled transmethylation assay

Abstract: The phosphoethanolamine methyltransferase, PfPMT, of the human malaria parasite Plasmodium falciparum, a member of a newly identified family of phosphoethanolamine methyltransferases (PMT) found solely in some protozoa, nematodes, frogs, and plants, is involved in the synthesis of the major membrane phospholipid, phosphatidylcholine. PMT enzymes catalyze a three-step S-adenosylmethionine-dependent methylation of the nitrogen atom of phosphoethanolamine to form phosphocholine. In P. falciparum, this activity is a limiting step in the pathway of synthesis of phosphatidylcholine from serine and plays an important role in the development, replication and survival of the parasite within human red blood cells. We have employed an enzyme-coupled methylation assay to screen for potential inhibitors of PfPMT. In addition to hexadecyltrimethylammonium, previously known to inhibit PfPMT, two compounds dodecyltrimethylammonium and amodiaquine were also found to inhibit PfPMT activity in vitro. Interestingly, PfPMT activity was not inhibited by the amodiaquine analog, chloroquine, or other aminoquinolines, amino alcohols, or histamine methyltransferase inhibitors. Using yeast as a surrogate system we found that unlike wild-type cells, yeast mutants that rely on PfPMT for survival were sensitive to amodiaquine, and their phosphatidylcholine biosynthesis was inhibited by this compound. Furthermore NMR titration studies to characterize the interaction between amoidaquine and PfPMT demonstrated a specific and concentration dependent binding of the compound to the enzyme. The identification of amodiaquine as an inhibitor of PfPMT in vitro and in yeast, and the biophysical evidence for the specific interaction of the compound with the enzyme will set the stage for the development of analogs of this drug that specifically inhibit this enzyme and possibly other PMTs.

Default network response to a working memory challenge after withdrawal of continuous positive airway pressure treatment for obstructive sleep apnea.

Abstract: Lower working memory performance and altered brain activity have been reported in studies of obstructive sleep apnea (OSA) patients. However, little is known about the effect of treatment of OSA on brain function, particularly effects on default network processing. We previously reported increased brain response to a working memory challenge in active regions and decreased response in relatively deactivated a priori regions of interest (ROIs) following withdrawal of continuous positive airway pressure (CPAP) treatment. This follow-up analysis was conducted to examine the effects of CPAP withdrawal on default network processing using empirically defined ROIs analyses (i.e., in ROIs exhibiting significant deactivation in the sample). Ten OSA patients performed a 2-Back working memory task during functional magnetic resonance imaging in two separate conditions, following regular CPAP use, and after two nights of CPAP withdrawal. Eleven clusters of significant 2-Back-related deactivation consistent with the default network were identified and further examined for CPAP withdrawal effects. Significant further deactivation relative to the treatment adherent baseline was observed in the majority of these ROIs during the withdrawal condition. The magnitude of deactivation during withdrawal was significantly associated with better working memory performance in the posterior cingulate and right postcentral gyrus, and greater sleepiness in the left and right medial frontal gyrus. Results suggest that default network functions are further suspended as a result of a shifting of attention towards a more difficult active task in the context of lowered attentional capacity related to sleepiness.

Food Allergy: Transfused and Transplanted

Abstract: The inadvertent transfer of food allergy from an allergic donor to an unsuspecting recipient by transfusion or organ donation is a relatively rare but intriguing event with potentially catastrophic consequences Additionally, the development of food allergy in the recipient of a transplant from a donor who was not food allergic poses questions about why this occurs, why it is observed more frequently in some situations than others, and the mechanisms that may be involved In this review, the transfer of food allergy by transfusion, bone marrow transplantation, and the transplantation of different solid organs is explored, and potential mechanisms in addition to the importance of careful monitoring are discussed

Effects of β-Carotene Supplementation on Molecular Markers of Lung Carcinogenesis in Male Smokers

Abstract: Two primary prevention trials unexpectedly showed adverse effects of supplemental beta-carotene on lung cancer incidence in cigarette smokers. To elucidate the molecular mechanisms that might underlie these effects, we studied the immunohistochemical expression of cytochrome P450 1A1, 1A2, and 2E1, retinoic acid receptor beta, activated protein-1 elements, cyclin D1, and Ki67 in lung tumors and, when available, adjacent normal tissues obtained from incident cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Archival lung tissue was available from 52 men randomized to receive 20 mg of beta-carotene per day and 30 men randomized to the placebo arm, all of whom were diagnosed with incident non-small-cell lung carcinoma during the course of the trial and subsequently underwent radical pulmonary resection. In normal-appearing bronchial epithelium, positive staining for cyclin D1 was observed in 23% of cases in the beta-carotene group and 0% of cases in the placebo group (based on only 3 of 13 versus 0 of 11 cases staining positively, however; P = 0.04), with no differences in expression noted in lung tumor tissue (P = 0.48). There were no statistically significant differences in Ki67 expression in normal or cancerous lung tissue between intervention groups, although a small increase in staining in tumors was noted among cases in the beta-carotene versus placebo group (88% versus 71% of cases stained positive, respectively; P = 0.13). Contrary to expectation, beta-carotene supplementation had no apparent effect on retinoic acid receptor-beta expression. These findings suggest that male smokers supplemented with beta-carotene may have had an increased risk of lung cancer due to aberrant cell growth, although our results are based on a relatively small number of cases and require confirmation in other completed trials of beta-carotene supplementation.

Discovery and verification of protein differences between Er positive/Her2/neu negative breast tumor tissue and matched adjacent normal breast tissue

Abstract: This study was designed to quantify and identify differences in protein levels between tumor and adjacent normal breast tissue from the same breast in 18 women with stage I/II ER positive/Her2/neu negative invasive breast cancer Eighteen separate difference gel electrophoresis (DIGE) gels were run (1 gel per patient) Relative quantification was based on DIGE analysis After excision and tryptic digestion, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and peptide mass mapping were used to identify protein spots Two hundred and forty-three spots were differentially abundant between normal and cancer tissues Fifty spots were identified: 41 were over abundant and nine were less abundant in cancers than in normal breast tissue Western blotting provided independent confirmation for three of the most biologically and statistically interesting proteins All 18 gels were replicated by another technician and 32% of the differentially abundant proteins were verified by the duplicate analysis Follow-up studies are now examining these proteins as biomarkers in blood

Disposable vial holder and method to prevent needle stick injuries

Abstract: A vial holder is provided to protect a user's hand from needle sticks. The holder includes a handle and a shield attached to a distal end of the handle. An opening is formed in the distal end of the handle to receive a vial. The vial is placed through the opening and into a passageway of the handle with the upper end of the vial exposed. A user grasps the handle which holds the vial in a stabilized manner. A needle may then safely approach the vial in which inadvertent slippage or movement of the needle results in contact with the needle against the shield and not contact with the user's hand.

Predicting moderate improvement and decline in pediatric asthma quality of life over 24 months.

Abstract: To determine factors associated with 24-month change in quality of life in children with asthma and their parents during the Childhood Asthma Management Program (CAMP). Participants from 4 CAMP clinical centers were administered the Pediatric Asthma Quality of Life questionnaire and protocol measures of asthma symptoms, lung function, and psychological measures. Multivariate logistic regression analyses determined predictors of moderate change in quality of life. Subclinical levels of depression predicted moderate improvement in child-reported quality of life. Level of depressed affect together with clinical asthma features predicted moderate decline. Improvement in parent quality of life was predicted by perception of illness burden, whereas family features and a child missing school predicted moderate decline. This ancillary study provided an opportunity to examine the determinants of 24-month change in parent and child of quality of life within a subset of the CAMP participants. Moderate changes in quality of life occur in clinical studies and have both psychosocial correlates and illness characteristics.

Impact of Medication Delivery Method on Patient Adherence

Abstract: In this chapter, we provide a systematic review of randomized controlled trials, meta-analysis, case-control, or cohort studies that compared patient adherence with, or preference for, oral or inhaled controller medication for asthma. Among 17 studies meeting inclusion criteria for our review, patients were more adherent to oral than inhaled medications. Where queried, patients or parents expressed preference for oral medications. These findings were consistent across study designs, using contrasting measures of adherence, over varied time periods and including many with 12-month follow-up, and with patients who knew they were being monitored as well as those included in an anonymous database. Indirect evidence indicates that patient’s preference for oral medication is not related to dosing frequency.

Hypoxia-Inducible Factors and Adenosine Signaling in Vascular Growth

Abstract: Low oxygen environment or hypoxia is conducive towards vascular growth and endothelial proliferation. Therefore it is an essential element in both disease and development. Hypoxia stabilizes the hypoxia-inducible transcription factors -1α and -2α and also increases adenosine levels thereby activating the adenosine receptor signaling pathways. While these pathways have been described independently to a greater extent, increasing evidence suggests that there is significant crosstalk. Here we will summarize the contributions and interdependence of hypoxia-inducible transcription factors and the adenosine receptor pathways in vascular growth.

Stem and Progenitor Cells of the Airway Epithelium

Abstract: This chapter argues that the hierarchical stem cell model should be adapted to reflect the specialized progenitor cell types that maintain the conducing airway epithelium. The conducting airway epithelium serves as the interface between the lung and the environment. Basic epithelial functions, such as barrier maintenance, are characteristic of all airway regions. However, other epithelial activities that are necessary to protect the lung from the environment vary along the proximal to distal axis of the airway. These adaptive modifications are manifest as differences in cellular composition and in the structure/function of specific cell types. Studies in humans and mice suggest that this specialization is a consequence of distinct progenitor cell pools. Each pool includes a tissue-specific stem cell and one or more facultative progenitor cell types. Facultative progenitors perform differentiated functions in the steady state but maintain the ability to proliferate in response to cellular injury. We propose that the facultative progenitor cells comprise a unique tier(s) within distinct stem cell hierarchies that maintain the proximal and distal conducing airway epithelium