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Bowler R.P.,National Jewish Health | Jacobson S.,National Jewish Health | Cruickshank C.,National Jewish Health | Hughes G.J.,University of Colorado at Denver | And 7 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2015

Rationale: Chronic obstructive pulmonary disease (COPD) occurs in a minority of smokers and is characterized by intermittent exacerbations and clinical subphenotypes such as emphysema and chronic bronchitis. Although sphingolipids as a class are implicated in the pathogenesis of COPD, the particular sphingolipid species associated with COPD subphenotypes remain unknown. Objectives: To use mass spectrometry to determine which plasma sphingolipids are associated with subphenotypes of COPD. Methods: One hundred twenty-nine current and former smokers from the COPDGene cohort had 69 distinct sphingolipid species detected in plasma by targeted mass spectrometry. Of these, 23 were also measured in 131 plasma samples (117 independent subjects) using an untargeted platform in an independent laboratory. Regression analysis with adjustment for clinical covariates, correction for false discovery rate, and metaanalysis were used to test associations between COPD subphenotypes and sphingolipids. Peripheral blood mononuclear cells were used to test associations between sphingolipid gene expression and plasma sphingolipids. Measurements and Main Results: Of the measured plasma sphingolipids, five sphingomyelins were associated with emphysema; four trihexosylceramides and three dihexosylceramides were associated with COPD exacerbations. Three sphingolipids were strongly associated with sphingolipid gene expression, and 15 sphingolipid gene/metabolite pairs were differentially regulated between COPD cases and control subjects. Conclusions: There is evidence of systemic dysregulation of sphingolipid metabolism in patients with COPD. Subphenotyping suggests that sphingomyelins are strongly associated with emphysema and glycosphingolipids are associated with COPD exacerbations. Copyright © 2015 by the American Thoracic Society.

Agarwal R.,Indiana University | Agarwal R.,Richard udebush Va Medical Center
Nephrology Dialysis Transplantation | Year: 2010

Background. Current disease-centred therapies for CKD focus on preserving the GFR but often ignore patient-reported symptoms. This purpose of this report is to describe the development of an instrument to measure the presence and severity of a wide range of symptoms commonly attributable to CKD.Methods. A 37-item questionnaire was administered along with the Kidney Disease Quality of Life instrument to 92 patients with CKD not on dialysis (24 black, 5 women, mean age 68 years, 68 with diabetes mellitus). To discover groups of symptoms, agglomerative cluster analysis followed by exploratory common factor analysis was performed. Construct validity, internal reliability, convergent and discriminant validity, test-retest reliability and finally the association of various symptom domains with objective measurements such as estimated GFR and haemoglobin were tested.Results. The top five symptoms of at least moderate severity in decreasing order of prevalence were 'tire easily', limited physical activity, nocturia, joint pain and 'stop and rest often'. Four common factors emerged that could be broadly classified into neuropsychiatric, cardiovascular, uraemia and anaemia symptoms accounting for 73 of the total variance in the sample. The coefficient alpha for each of these factors approached 0.9. The test-retest reliability in 41 patients over 8 weeks was likewise high. There was good convergent and divergent validity. However, there was little relationship between estimated GFR and symptom scores.Conclusions. The assessment of symptom burden among patients with CKD may be facilitated by incorporating this instrument in routine practice and clinical trials.

Kukla M.,Indiana University - Purdue University Indianapolis | Lysaker P.H.,Richard udebush Va Medical Center | Lysaker P.H.,Indiana University | Salyers M.P.,Indiana University - Purdue University Indianapolis
Psychiatry Research | Year: 2013

Research suggests that persons with schizophrenia experience deficits in the ability to synthesize complex and integrated representations of themselves and others. While impairments in these metacognitive capacities are hypothetically related to the ability to make sense of the challenges of schizophrenia, little is known about their relationship with the subjective experience of recovery from mental illness. To examine this question, this study investigated whether persons with stronger self-reported recovery had better metacognitive capacity, after controlling for severity of psychiatric symptoms. Forty-six outpatients with schizophrenia spectrum disorders who were taking part in a study of the Illness Management and Recovery program were concurrently administered the Recovery Assessment Scale, the Positive and Negative Syndrome Scale, and the Indiana Psychiatric Illness Interview which was scored using the Abbreviated Metacognitive Assessment Scale. Analysis of covariance revealed that metacognitive capabilities reflecting self-reflectivity and decentration were differentially related to several components of recovery beyond the effects of psychiatric symptoms. The metacognitive abilities to think about oneself in a sophisticated way and form integrated ideas about oneself and others within the larger world, understanding that none are the metaphorical center are present in individuals holding strong perceptions of recovery. © 2013.

Travers J.B.,Richard udebush Va Medical Center | Travers J.B.,Indiana University
Journal of Investigative Dermatology | Year: 2014

Patients with atopic dermatitis (AD) are commonly colonized/infected with Staphylococcus aureus, and this bacterium is known to worsen the dermatitis. In this issue, Brauweiler et al. demonstrate a newly discovered mechanism by which Th2 cytokines involved in AD augment the toxicity of the lytic staphylococcal protein alpha toxin. This review presents mechanisms by which Th2 cytokines may interact with S. aureus to the detriment of the dermatitis. © 2014 The Society for Investigative Darmatology.

Agarwal R.,Indianapolis | Agarwal R.,Richard udebush Va Medical Center
Current Opinion in Nephrology and Hypertension | Year: 2010

Purpose of review: Circadian variation is commonly seen in healthy people; aberration in these biological rhythms is an early sign of disease. Impaired circadian variation of blood pressure (BP) has been shown to be associated with greater target organ damage and with an elevated risk of cardiovascular events independent of the BP load. The purpose of this review is to examine the physiology of circadian BP variation and propose a tripartite model that explains the regulation of circadian BP. Recent findings: The time-keeper in mammals resides centrally in the suprachiasmatic nucleus. Apart from this central clock, molecular clocks exist in most peripheral tissues including vascular tissue and the kidney. These molecular clocks regulate sodium balance, sympathetic function and vascular tone. A physiological model is proposed that integrates our understanding of molecular clocks in mice with the circadian BP variation among humans. The master regulator in this proposed model is the sleep-activity cycle. The equivalents of peripheral clocks are endothelial and adrenergic functions. Thus, in the proposed model, the variation in circadian BP is dependent upon three major factors: physical activity, autonomic function, and sodium sensitivity. Summary: The integrated consideration of physical activity, autonomic function, and sodium sensitivity appears to explain the physiology of circadian BP variation and the pathophysiology of disrupted BP rhythms in various conditions and disease states. Our understanding of molecular clocks in mice may help to explain the provenance of blunted circadian BP variation even among astronauts. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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