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1.  Fibroblast Growth Factor-23 and Cardiovascular Disease in the General Population: The Multi-Ethnic Study of Atherosclerosis 
Circulation. Heart failure  2014;7(3):409-417.
Fibroblast growth factor-23 (FGF-23) is a phosphate regulatory hormone that directly stimulates left ventricular hypertrophy in experimental models. The role of FGF-23 in cardiovascular disease development in the general population is unclear. We tested associations of FGF-23 with major subclinical and clinical cardiovascular disease outcomes in a large prospective cohort.
Methods and Results
We evaluated 6,547 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who were initially free of cardiovascular disease. We measured serum FGF-23 using the Kainos immunoassay. The MESA measured left ventricular (LV) mass by magnetic resonance imaging, coronary calcium (CAC) by computed tomography, and carotid intima-medial thickness (IMT) by ultrasound. The MESA adjudicated incident heart failure, coronary heart disease, and stoke by medical record review. After adjustment, the highest FGF-23 quartile was associated with an estimated 2.4 gram greater LV mass (95% CI 0.4, 4.5 greater) and a 26% greater odds of higher CAC scores (95% CI 9% to 46% greater) compared to the lowest quartile. Over 7.5 years follow-up, each 20-pg/mL higher FGF-23 concentration was associated with a 19% greater risk of heart failure (95% CI 3% to 37% greater) and a 14% greater risk of coronary heart disease (95% CI 1% to 28% greater). FGF-23 was not associated with carotid IMT or stroke.
Higher serum FGF-23 concentrations are associated with subclinical cardiac disease and with new heart failure and coronary disease events, but not with carotid IMT or stroke. FGF-23 may be a novel cardiovascular risk factor in the general population.
PMCID: PMC4031265  PMID: 24668259
Fibroblast growth factor-23; FGF-23; left ventricular mass; left ventricular hypertrophy; coronary artery calcium; carotid intima-media thickness; heart failure; coronary heart disease; stroke; cardiovascular disease
2.  Duffy Antigen Facilitates Movement of Chemokine Across the Endothelium In Vitro and Promotes Neutrophil Transmigration In Vitro and In Vivo1 
The Duffy Ag expressed on RBCs, capillaries, and postcapillary venular endothelial cells binds selective CXC and CC chemokines with high affinity. Cells transfected with the Duffy Ag internalize but do not degrade chemokine ligand. It has been proposed that Duffy Ag transports chemokines across the endothelium. We hypothesized that Duffy Ag participates in the movement of chemokines across the endothelium and, by doing so, modifies neutrophil transmigration. We found that the Duffy Ag transfected into human endothelial cells facilitates movement of the radiolabeled CXC chemokine, growth related oncogene-α/CXC chemokine ligand 1 (GRO-α/CXCL1), across an endothelial monolayer. In addition, neutrophil migration toward GRO-α/CXCL1 and IL-8 (IL-8/CXCL8) was enhanced across an endothelial monolayer expressing the Duffy Ag. Furthermore, GRO-α/CXCL1 stimulation of endothelial cells expressing the Duffy Ag did not affect gene expression by oligonucleotide microarray analysis. These in vitro observations are supported by the finding that IL-8/CXCL8-driven neutrophil recruitment into the lungs was markedly attenuated in transgenic mice lacking the Duffy Ag. We conclude that Duffy Ag has a role in enhancing leukocyte recruitment to sites of inflammation by facilitating movement of chemokines across the endothelium.
PMCID: PMC4357319  PMID: 12734373
3.  A Prospective Study of Frailty in Nephrology-Referred Patients With CKD 
Frailty is a construct developed to characterize a state of reduced functional capacity among older adults. However, there are limited data describing the prevalence or consequences of frailty among middle-aged CKD patients.
Study Design
Observational study
Setting & Participants
336 non-dialysis-dependent stage 1–4 CKD patients with eGFR< 90ml/min/1.73m2 (by the CKD-EPI [CKD Epidemiology Collaboration] serum creatinine–based equation) or evidence of microalbuminuria enrolled in the Seattle Kidney Study, a clinic-based cohort study. Findings were compared to community dwelling older adults in the Cardiovascular Health Study.
Prevalence and determinants of frailty in addition to its association with the combined outcome of all-cause mortality or renal replacement therapy.
We defined frailty according to established criteria as ≥3 of the following characteristics: slow gait, weakness, unintentional weight loss, exhaustion, and low physical activity. We estimated kidney function using serum cystatin C concentrations (eGFRcys) to minimize confounding due to relationships of serum creatinine levels with muscle mass and frailty.
The mean age of the study population was 59 years and mean eGFRcys was 51 ml/min/1.73m2. The prevalence of frailty (14.0%) was twice that of the much older non-CKD reference population (P<0.01). The most common frailty components were physical inactivity and exhaustion. After adjustment including diabetes, eGFRcys categories of <30 and 30–44 ml/min/1.73m2 were associated with a 2.8 (95% CI, 1.3–6.3) and 2.1 (95% CI, 1.0–4.7)-fold greater prevalence of frailty compared to GFRcys ≥60 ml/min/1.73m2. There were 63 events during a median of 987 days of follow-up. After adjustment, the frailty phenotype was associated with an estimated 2.5 (95% CI, 1.4–4.4)- fold greater risk of death or dialysis.
Cross-sectional study design obscures inference regarding temporal relationships between CKD and frailty.
Frailty is relatively common among middle-aged CKD patients and is associated with lower eGFRcys as well as increased risk of death or dialysis.
PMCID: PMC3491110  PMID: 22770927
4.  The serum 24,25-dihydroxyvitamin D concentration, a marker of vitamin D catabolism, is reduced in chronic kidney disease 
Kidney international  2012;82(6):693-700.
Chronic kidney disease is characterized, in part, as a state of decreased production of 1,25-dihydroxyvitamin D (1,25(OH)2D); however, this paradigm overlooks the role of vitamin D catabolism. We developed a mass spectrometric assay to quantify serum concentration of 24,25-dihydroxyvitamin D (24,25(OH)2D), the first metabolic product of 25-hydroxyvitamin D (25(OH)D) by CYP24A1, and determined its clinical correlates and associated outcomes among 278 participants with chronic kidney disease in the Seattle Kidney Study. For eGFRs of 60 or more, 45–59, 30–44, 15–29, and under 15 ml/min/1.73m2, the mean serum 24,25(OH)2D concentrations significantly trended lower from 3.6, 3.2, 2.6, 2.6, to 1.7 ng/ml, respectively. Non-Hispanic Black race, diabetes, albuminuria, and lower serum bicarbonate were also independently and significantly associated with lower 24,25(OH)2D concentrations. The 24,25(OH)2D concentration was more strongly correlated with that of parathyroid hormone than was 25(OH)D or 1,25(OH)2D. A 24,25(OH)2D concentration below the median was associated with increased risk of mortality in unadjusted analysis, but this was attenuated with adjustment for potential confounding variables. Thus, chronic kidney disease is a state of stagnant vitamin D metabolism characterized by decreases in both 1,25(OH)2D production and vitamin D catabolism.
PMCID: PMC3434313  PMID: 22648296
5.  A Phase II Randomized Placebo-Controlled Trial of Omega-3 Fatty Acids for the Treatment of Acute Lung Injury 
Critical care medicine  2011;39(7):1655-1662.
Administration of eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA), omega-3 fatty acids in fish oil, has been associated with improved patient outcomes in acute lung injury (ALI) when studied in a commercial enteral formula. However, fish oil has not been tested independently in ALI. We therefore sought to determine if enteral fish oil alone would reduce pulmonary and systemic inflammation in patients with ALI.
Phase II randomized controlled trial.
Four North American medical centers.
Mechanically ventilated patients with ALI ≥ 18 years of age.
Subjects were randomized to receive enteral fish oil (9.75g EPA and 6.75g DHA daily) or saline placebo for up to 14 days.
Measurements and Main Results
Bronchoalveolar lavage fluid (BALF) and blood were collected at baseline (day 0), day 4±1, and day 8±1. The primary endpoint was BALF interleukin (IL)-8 levels. Forty-one participants received fish oil and 49 received placebo. Enteral fish oil administration was associated with increased serum EPA concentration (p<0.0001). However, there was no significant difference in the change in BALF IL-8 from baseline to day 4 (p=0.37) or day 8 (p=0.55) between treatment arms. There were no appreciable improvements in other BALF or plasma biomarkers in the fish oil group compared to the control group. Similarly, organ failure score, ventilator-free days, ICU-free days, and 60-day mortality did not differ between the groups.
Fish oil did not reduce biomarkers of pulmonary or systemic inflammation in patients with ALI, and the results do not support the conduct of a larger clinical trial in this population with this agent. This experimental approach is feasible for proof of concept studies evaluating new treatments for ALI.
PMCID: PMC3125670  PMID: 21423000
Acute lung injury; randomized controlled trial; eicosapentaenoic acid; docosahexaenoic acid; acute respiratory distress syndrome; fish oils
6.  Breast Milk α-Defensins Are Associated with HIV Type 1 RNA and CC Chemokines in Breast Milk But Not Vertical HIV Type 1 Transmission 
α-Defensins are proteins exhibiting in vitro anti-HIV-1 activity that may protect against mother-to-child transmission of HIV-1 via breast milk. Correlates of α-defensins in breast milk and transmission risk were determined in a cohort of HIV-1-infected pregnant women in Nairobi followed for 12 months postpartum with their infants. Maternal blood was collected antenatally and at delivery for HIV-1 viral load and infant HIV-1 infection status was determined <48 h after birth and at months 1, 3, 6, 9, and 12. Breast milk specimens collected at month 1 were assayed for α-defensins, HIV-1 RNA, subclinical mastitis, and CC and CXC chemokines. We detected α-defensins in breast milk specimens from 108 (42%) of 260 HIV-1-infected women. Women with detectable α-defensins (≥50 pg/ml) had a median concentration of 320 pg/ml and significantly higher mean breast milk HIV-1 RNA levels than women with undetectable α-defensins (2.9 log10 copies/ml versus 2.5 log10 copies/ml, p = 0.003). Increased α-defensins concentrations in breast milk were also associated with subclinical mastitis (Na+/K+ ratio > 1) and increased breast milk chemokine levels. Overall, 40 (15%) infants were HIV-1 uninfected at birth and subsequently acquired HIV-1. There was no significant association between month 1 α-defensins and risk of HIV-1 transmission. In conclusion, α-defensins were associated with breast milk HIV-1 viral load, chemokine levels, and subclinical mastitis, all of which may alter risk of infant HIV-1 acquisition. Despite these associations there was no significant relationship between breast milk α-defensins and mother-to-child transmission, suggesting a complex interplay between breast milk HIV-1, inflammation, and antiinfective factors.
PMCID: PMC3382116  PMID: 17331027
7.  Toll-like Receptor 1 Polymorphisms Affect Innate Immune Responses and Outcomes in Sepsis 
Rationale: Polymorphisms affecting Toll-like receptor (TLR)–mediated responses could predispose to excessive inflammation during an infection and contribute to an increased risk for poor outcomes in patients with sepsis.
Objectives: To identify hypermorphic polymorphisms causing elevated TLR-mediated innate immune cytokine and chemokine responses and to test whether these polymorphisms are associated with increased susceptibility to death, organ dysfunction, and infections in patients with sepsis.
Methods: We screened single-nucleotide polymorphisms (SNPs) in 43 TLR-related genes to identify variants affecting TLR-mediated inflammatory responses in blood from healthy volunteers ex vivo. The SNP associated most strongly with hypermorphic responses was tested for associations with death, organ dysfunction, and type of infection in two studies: a nested case–control study in a cohort of intensive care unit patients with sepsis, and a case–control study using patients with sepsis, patients with sepsis-related acute lung injury, and healthy control subjects.
Measurements and Main Results: The SNP demonstrating the most hypermorphic effect was the G allele of TLR1−7202A/G (rs5743551), which associated with elevated TLR1-mediated cytokine production (P < 2 × 10−20). TLR1−7202G marked a coding SNP that causes higher TLR1-induced NF-κB activation and higher cell surface TLR1 expression. In the cohort of patients with sepsis TLR1−7202G predicted worse organ dysfunction and death (odds ratio, 1.82; 95% confidence interval, 1.07–3.09). In the case-control study TLR1−7202G was associated with sepsis-related acute lung injury (odds ratio, 3.40; 95% confidence interval, 1.59–7.27). TLR1−7202G also associated with a higher prevalence of gram-positive cultures in both clinical studies.
Conclusions: Hypermorphic genetic variation in TLR1 is associated with increased susceptibility to organ dysfunction, death, and gram-positive infection in sepsis.
PMCID: PMC2556453  PMID: 18635889
innate immunity; genetic variation; genetic predisposition
8.  Proteomic and Computational Analysis of Bronchoalveolar Proteins during the Course of the Acute Respiratory Distress Syndrome 
Rationale: Acute lung injury causes complex changes in protein expression in the lungs. Whereas most prior studies focused on single proteins, newer methods allowing the simultaneous study of many proteins could lead to a better understanding of pathogenesis and new targets for treatment.
Objectives: The purpose of this study was to examine the changes in protein expression in the bronchoalveolar lavage fluid (BALF) of patients during the course of the acute respiratory distress syndrome (ARDS).
Methods: Using two-dimensional difference gel electrophoresis (DIGE), the expression of proteins in the BALF from patients on Days 1 (n = 7), 3 (n = 8), and 7 (n = 5) of ARDS were compared with findings in normal volunteers (n = 9). The patterns of protein expression were analyzed using principal component analysis (PCA). Biological processes that were enriched in the BALF proteins of patients with ARDS were identified using Gene Ontology (GO) analysis. Protein networks that model the protein interactions in the BALF were generated using Ingenuity Pathway Analysis.
Measurements and Main Results: An average of 991 protein spots were detected using DIGE. Of these, 80 protein spots, representing 37 unique proteins in all of the fluids, were identified using mass spectrometry. PCA confirmed important differences between the proteins in the ARDS and normal samples. GO analysis showed that these differences are due to the enrichment of proteins involved in inflammation, infection, and injury. The protein network analysis showed that the protein interactions in ARDS are complex and redundant, and revealed unexpected central components in the protein networks.
Conclusions: Proteomics and protein network analysis reveals the complex nature of lung protein interactions in ARDS. The results provide new insights about protein networks in injured lungs, and identify novel mediators that are likely to be involved in the pathogenesis and progression of acute lung injury.
PMCID: PMC2556452  PMID: 18658106
acute respiratory distress syndrome; acute lung injury; proteomic analysis; bronchoalveolar lavage; 2D gel electrophoresis
9.  Parasite Burden and CD36-Mediated Sequestration Are Determinants of Acute Lung Injury in an Experimental Malaria Model 
PLoS Pathogens  2008;4(5):e1000068.
Although acute lung injury (ALI) is a common complication of severe malaria, little is known about the underlying molecular basis of lung dysfunction. Animal models have provided powerful insights into the pathogenesis of severe malaria syndromes such as cerebral malaria (CM); however, no model of malaria-induced lung injury has been definitively established. This study used bronchoalveolar lavage (BAL), histopathology and gene expression analysis to examine the development of ALI in mice infected with Plasmodium berghei ANKA (PbA). BAL fluid of PbA-infected C57BL/6 mice revealed a significant increase in IgM and total protein prior to the development of CM, indicating disruption of the alveolar–capillary membrane barrier—the physiological hallmark of ALI. In contrast to sepsis-induced ALI, BAL fluid cell counts remained constant with no infiltration of neutrophils. Histopathology showed septal inflammation without cellular transmigration into the alveolar spaces. Microarray analysis of lung tissue from PbA-infected mice identified a significant up-regulation of expressed genes associated with the gene ontology categories of defense and immune response. Severity of malaria-induced ALI varied in a panel of inbred mouse strains, and development of ALI correlated with peripheral parasite burden but not CM susceptibility. Cd36−/− mice, which have decreased parasite lung sequestration, were relatively protected from ALI. In summary, parasite burden and CD36-mediated sequestration in the lung are primary determinants of ALI in experimental murine malaria. Furthermore, differential susceptibility of mouse strains to malaria-induced ALI and CM suggests that distinct genetic determinants may regulate susceptibility to these two important causes of malaria-associated morbidity and mortality.
Author Summary
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) can occur in adult malaria infections with a case fatality rate of 70%–100%. ALI and ARDS are characterized by protein-rich fluid in the lungs, with reduced gas exchange, and in malaria, often accompany high parasite levels and severe or cerebral disease. In this work we have examined lung physiology, pathology and genomics in mouse malaria—Plasmodium berghei ANKA—to show that mice develop malaria-induced ALI. Infected mice have proteinaceous fluid in their lungs, have a migration of inflammatory cells from the blood into the lung walls, and express immune response–related genes. We also found that severity of ALI depended on high parasite levels, both overall and specifically in the lung tissue, but was not consistent with whether the mice developed cerebral malaria. ALI due to Plasmodium berghei ANKA infection models prominent characteristics of human malaria-associated ALI, and we have better defined this model of malaria ALI so it may be used to further explore disease mechanisms and eventual treatment.
PMCID: PMC2364663  PMID: 18483551
10.  Fas/Fas Ligand System Mediates Epithelial Injury, but Not Pulmonary Host Defenses, in Response to Inhaled Bacteria 
Infection and Immunity  2001;69(9):5768-5776.
The Fas/Fas ligand (FasL) system has been implicated in alveolar epithelial cell apoptosis during pulmonary fibrosis and acute respiratory distress syndrome. However, Fas ligation can also lead to cell activation and cytokine production. The goal of this study was to determine the role of the Fas/FasL system in host defenses against Escherichia coli, Staphylococcus aureus, and Streptococcus pneumoniae. We administered bacteria by aerosolization into the lungs of Fas-deficient (lpr) mice and wild-type (C57BL/6) mice and measured bacterial clearance at 6 and 12 h. One hour prior to euthanasia, the mice received an intraperitoneal injection of human serum albumin (HSA) for alveolar permeability determinations. At all times after bacterial challenges, the lungs of the lpr mice contained similar or lower numbers of bacteria than those of the C57BL/6 mice. Alveolar permeability changes, as determined by bronchoalveolar lavage fluid HSA concentrations, were less severe in the lpr mice 6 h after the challenges. In response to E. coli, the lpr mice had significantly more polymorphonuclear leukocytes (PMN) and macrophage inflammatory protein 2 in the lungs, whereas histopathologic changes were less severe. In contrast, in response to the gram-positive cocci, the lpr animals had similar or lower numbers of PMN. We conclude that the Fas/FasL system contributes to the development of permeability changes and tissue injury during-gram negative bacterial pneumonia. The Fas/FasL system did not have a major role in the clearance of aerosolized bacteria from the lungs at the bacterial doses tested.
PMCID: PMC98694  PMID: 11500454

Results 1-10 (10)