Richard udebush Va Medical Center

United States

Richard udebush Va Medical Center

United States
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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.

Lahm T.,Richard udebush Va Medical Center | Tuder R.M.,University of Colorado at Denver | Petrache I.,Richard udebush Va Medical Center
American Journal of Physiology - Lung Cellular and Molecular Physiology | Year: 2014

Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with marked morbidity and mortality. Even though being female represents one of the most powerful risk factors for PAH, multiple questions about the underlying mechanisms remain, and two "estrogen paradoxes" in PAH exist. First, it is puzzling why estrogens have been found to be protective in various animal models of PAH, whereas PAH registries uniformly demonstrate a female susceptibility to the disease. Second, despite the pronounced tendency for the disease to develop in women, female PAH patients exhibit better survival than men. Recent mechanistic studies in classical and in novel animal models of PAH, as well as recent studies in PAH patients, have significantly advanced the field. In particular, it is now accepted that estrogen metabolism and receptor signaling, as well as estrogen interactions with key pathways in PAH development, appear to be potent disease modifiers. A better understanding of these interactions may lead to novel PAH therapies. It is the purpose of this review to 1) review sex hormone synthesis, metabolism, and receptor physiology; 2) assess the context in which sex hormones affect PAH pathogenesis; 3) provide a potential explanation for the observed estrogen paradoxes and gender differences in PAH; and 4) identify knowledge gaps and future research opportunities. Because the majority of published studies investigated 17β-estradiol and/or its metabolites, this review will primarily focus on pulmonary vascular and right ventricular effects of estrogens. Data for other sex hormones will be discussed very briefly. © 2014 the American Physiological Society.

Moorthy R.S.,Indiana University | Moorthy R.S.,St Vincent Hospital | Valluri S.,Indiana University | Valluri S.,Richard udebush Va Medical Center | And 2 more authors.
Survey of Ophthalmology | Year: 2012

The nontuberculous (also called " atypical" ) mycobacteria have become increasingly important causes of systemic as well as ocular morbidity in recent decades. All ocular tissues can become infected with these organisms, particularly in patients who are predisposed following ocular trauma, surgery, use of corticosteroids, or are immunocompromised. Because of their relative resistance to available antibiotics, multidrug parenteral therapy continues to be the mainstay of treatment of more serious ocular and adnexal infections caused by nontuberculous mycobacteria (NTM). Periocular cutaneous, adnexal, and orbital NTM infections remain rare and require surgical debridement and long-term parenteral antibiotic therapy. NTM scleritis may occur after trauma or scleral buckling and can cause chronic disease that responds only to appropriate antibiotic therapy and, in some cases, surgical debridement and explant removal. NTM infectious keratitis following trauma or refractive surgical procedures is commonly confused with other infections such as Herpes simplex keratitis and requires aggressive topical therapy and possible surgical debridement, particularly in those cases occuring after laser in situ keratomileusis. Only 18 cases of endophthalmitis due to NTM have been reported. Systemic and intraocular antibiotic therapy and multiple vitrectomies may be needed in NTM endophthalmitis; the prognosis remains poor, however. Disseminated NTM choroiditis in acquired immune deficiency syndrome patients with immune reconstitution during highly active anti-retroviral therapy is a rare infection that can present as a necrotizing chorioretinitis with dense vitritis, mimicking many other entities and needs to be recognized so that timely, life-saving treatment can be administered. Regardless of which ocular tissue is infected, all NTM ocular infections present similar challenges of recognition and of therapeutic intervention. We clarify diagnosis and delineate modern, effective therapy for these conditions. © 2012 Elsevier Inc.

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.

Kang K.S.,Indiana University | Robling A.G.,Indiana University | Robling A.G.,Indiana University – Purdue University Indianapolis | Robling A.G.,Richard udebush Va Medical Center
Frontiers in Endocrinology | Year: 2015

Mechanical loading is essential to maintain normal bone metabolism and the balance between bone formation and resorption. The cellular mechanisms that control mechanotransduction are not fully defined, but several key pathways have been identified. We discuss the roles of several components of the Wnt signaling cascade, namely Lrp5, Lrp6, and β-catenin in mechanical loading-induced bone formation. Lrp5 is an important Wnt co-receptor for regulating bone mass and mechanotransduction, and appears to function principally by augmenting bone formation. Lrp6 also regulates bone mass but its action might involve resorption as well as formation. The role of Lrp6 in mechanotransduction is unclear. Studies addressing the role of β-catenin in bone metabolism and mechanotransduction highlight the uncertainties in downstream modulators of Lrp5 and Lrp6. Taken together, these data indicate that mechanical loading might affect bone regulation triggering the canonical Wnt signaling (and perhaps other pathways) not only via Lrp5 but also via Lrp6. Further work is needed to clarify the role of the Wnt signaling pathway in Lrp5 and/or Lrp6-mediated mechanotransduction, which could eventually lead to powerful therapeutic agents that might mimic the anabolic effects of mechanical stimulation. © 2015 Kang and Robling.

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.

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

Background. Intradialytic blood pressure (BP) profiles have been associated with all-cause mortality, but its pathophysiology remains unknown. We tested the hypothesis that intradialytic changes in BP reflect excess volume.Methods. The dry weight reduction in hypertensive haemodialysis patients (DRIP) trial probed dry weight in 100 prevalent haemodialysis patients; 50 patients who did not have their dry weight probed served as time controls. In this post hoc analysis, intradialytic BP was recorded at each of the 30 dialysis treatments during the trial. The slope of intradialytic BP over dialysis was calculated by the log of BP regressed over time. Using a linear mixed model, we compared these slopes between control and ultrafiltration groups at baseline and over time, tested the effect of dry weight reduction on these slopes and finally tested the ability of change in intradialytic slopes to predict change in interdialytic systolic BP. Results. At baseline, intradialytic systolic and diastolic BP dropped at a rate of ~3%/h (P < 0.0001). Over the course of the trial, compared to the control group, the slopes steepened in the ultrafiltration group for systolic but not diastolic BP. Those who lost the most post-dialysis weight from baseline to 4 weeks and baseline to 8 weeks also experienced the greatest steepening of slopes. Each percent per hour steepening of the intradialytic systolic BP slope was associated with 0.71 mmHg [95% confidence interval (CI) 0.01-1.42, P = 0. 048] reduction in interdialytic ambulatory systolic pressure. Conclusions. Intradialytic BP changes appear to be associated with change in dry weight among haemodialysis patients. Among long-term haemodialysis patients, intradialytic hypertension may, thus, be a sign of volume overload. © The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Agarwal R.,Indiana University | Agarwal R.,Richard udebush Va Medical Center | Michael Bouldin J.,Indiana University | Light R.P.,Indiana University | Garg A.,Arizona
Clinical Journal of the American Society of Nephrology | Year: 2011

Background and objectives Hypervolemia is an important and modifiable cause of hypertension. Hypertension improves with probing dry weight, but its effect on echocardiographic measures of volume is unknown. Design, setting, participants, & measurements Shortly after dialysis, echocardiograms were obtained at baseline and longitudinally every 4 weeks on two occasions. Among 100 patients in the additional ultrafiltration group, 198 echocardiograms were performed; among 50 patients in the control group, 104 echocardiograms were performed. Results Baseline inferior vena cava (IVC)insp diameter was approximately 5.1 mm/m2; with ultrafiltration, change in IVCinsp diameter was -0.95 mm/m2 more compared with the control group at 4 weeks and -1.18 mm/m2 more compared with the control group at 8 weeks. From baseline IVCexp diameter of approximately 8.2 mm/m2, ultrafiltration-induced change at 4 weeks was -1.06 mm/m2 more and at 8 weeks was -1.07 mm/m2 more (P = 0.044). From a baseline left atrial diameter of 2.1 cm/m2, ultrafiltration-induced change at 4 weeks was -0.14 cm/m2 more and at 8 weeks was -0.15 cm/m2 more. At baseline, there was no relationship between interdialytic ambulatory BP and echocardiographic parameters of volume. The reduction in interdialytic ambulatory BP was also independent of change in the echocardiographic volume parameters. Conclusions The inferior vena cava and left atrial diameters are echocardiographic parameters that are responsive to probing dry weight; thus, they reflect excess volume. However, echocardiographic volume parameters are poor determinants of interdialytic BP, and their change does not predict the BP response to probing dry weight. © 2011 by the American Society of Nephrology.

Kahi C.J.,Indiana University | Kahi C.J.,Richard udebush Va Medical Center | Hewett D.G.,Indiana University | Norton D.L.,Indiana University | And 2 more authors.
Clinical Gastroenterology and Hepatology | Year: 2011

Background & Aims: Colonoscopy may have a greater protective effect for distal colorectal cancer (CRC) than proximal CRC. Serrated polyps are frequently located in the proximal colon, can be missed during colonoscopy, and may progress to CRC. We investigated the prevalence and endoscopist detection rates of proximal serrated polyps in a large cohort of average risk patients undergoing screening colonoscopy. Methods: Screening colonoscopies performed by 15 attending gastroenterologists at 2 academic endoscopy units between 2000 and 2009 were reviewed. Serrated polyps included hyperplastic polyps, sessile serrated adenomas, and traditional serrated adenomas. Endoscopist-level detection rates for adenomas and serrated polyps were calculated. Pearson correlation coefficients were calculated to evaluate the associations of adenoma and proximal serrated polyp detection rates. Logistic regression was used to compare endoscopists' detection rates. Results: A total of 11,049 polyps were detected in 6681 colonoscopies (adenomas: 5637, 51%; serrated: 3984, 36%; proximal serrated: 1238, 11%). The proportion of colonoscopies with at least one proximal serrated polyp was 13% (range 1%-18%). Proximal serrated polyp detection rates per colonoscopy ranged from 0.01 to 0.26. Adenoma and proximal serrated polyp detection rates per colonoscopy were strongly correlated (R = 0.76, P = .0005). The odds of detecting at least one proximal serrated polyp for individual endoscopists ranged from 0.05 to 0.67 compared to the highest level detector. Endoscopist (P < .0001), but not patient age (P = .76) or gender (P = .95), was associated with proximal serrated polyp detection. Conclusions: In an average-risk screening cohort, the detection of proximal serrated polyps was highly variable and endoscopist dependent. A significant proportion of proximal serrated polyps may be missed during colonoscopy. High-quality colonoscopy is important for the detection and resection of all polyps with neoplastic potential. © 2011 AGA Institute.

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.

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