Browsing by Author "Kraus, Virginia B"

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A flexible statistical model for alignment of label-free proteomics data--incorporating ion mobility and product ion information.
(BMC Bioinformatics, 2013-12-16) Benjamin, Ashlee M; Thompson, J Will; Soderblom, Erik J; Geromanos, Scott J; Henao, Ricardo; Kraus, Virginia B; Moseley, M Arthur; Lucas, Joseph E
BACKGROUND: The goal of many proteomics experiments is to determine the abundance of proteins in biological samples, and the variation thereof in various physiological conditions. High-throughput quantitative proteomics, specifically label-free LC-MS/MS, allows rapid measurement of thousands of proteins, enabling large-scale studies of various biological systems. Prior to analyzing these information-rich datasets, raw data must undergo several computational processing steps. We present a method to address one of the essential steps in proteomics data processing--the matching of peptide measurements across samples. RESULTS: We describe a novel method for label-free proteomics data alignment with the ability to incorporate previously unused aspects of the data, particularly ion mobility drift times and product ion information. We compare the results of our alignment method to PEPPeR and OpenMS, and compare alignment accuracy achieved by different versions of our method utilizing various data characteristics. Our method results in increased match recall rates and similar or improved mismatch rates compared to PEPPeR and OpenMS feature-based alignment. We also show that the inclusion of drift time and product ion information results in higher recall rates and more confident matches, without increases in error rates. CONCLUSIONS: Based on the results presented here, we argue that the incorporation of ion mobility drift time and product ion information are worthy pursuits. Alignment methods should be flexible enough to utilize all available data, particularly with recent advancements in experimental separation methods.
Open Access
A novel inflammatory biomarker, GlycA, associates with disease activity in rheumatoid arthritis and cardio-metabolic risk in BMI-matched controls.
(Arthritis Res Ther, 2016-04-12) Bartlett, David B; Connelly, Margery A; AbouAssi, Hiba; Bateman, Lori A; Tune, K Noelle; Huebner, Janet L; Kraus, Virginia B; Winegar, Deborah A; Otvos, James D; Kraus, William E; Huffman, Kim M
BACKGROUND: RA and CVD both have inflammation as part of the underlying biology. Our objective was to explore the relationships of GlycA, a measure of glycosylated acute phase proteins, with inflammation and cardiometabolic risk in RA, and explore whether these relationships were similar to those for persons without RA. METHODS: Plasma GlycA was determined for 50 individuals with mild-moderate RA disease activity and 39 controls matched for age, gender, and body mass index (BMI). Regression analyses were performed to assess relationships between GlycA and important markers of traditional inflammation and cardio-metabolic health: inflammatory cytokines, disease activity, measures of adiposity and insulin resistance. RESULTS: On average, RA activity was low (DAS-28 = 3.0 ± 1.4). Traditional inflammatory markers, ESR, hsCRP, IL-1β, IL-6, IL-18 and TNF-α were greater in RA versus controls (P < 0.05 for all). GlycA concentrations were significantly elevated in RA versus controls (P = 0.036). In RA, greater GlycA associated with disease activity (DAS-28; RDAS-28 = 0.5) and inflammation (RESR = 0.7, RhsCRP = 0.7, RIL-6 = 0.3: P < 0.05 for all); in BMI-matched controls, these inflammatory associations were absent or weaker (hsCRP), but GlycA was related to IL-18 (RhsCRP = 0.3, RIL-18 = 0.4: P < 0.05). In RA, greater GlycA associated with more total abdominal adiposity and less muscle density (Rabdominal-adiposity = 0.3, Rmuscle-density = -0.3, P < 0.05 for both). In BMI-matched controls, GlycA associated with more cardio-metabolic markers: BMI, waist circumference, adiposity measures and insulin resistance (R = 0.3-0.6, P < 0.05 for all). CONCLUSIONS: GlycA provides an integrated measure of inflammation with contributions from traditional inflammatory markers and cardio-metabolic sources, dominated by inflammatory markers in persons with RA and cardio-metabolic factors in those without.
Open Access
Age-Related Adverse Inflammatory and Metabolic Changes Begin Early in Adulthood.
(The journals of gerontology. Series A, Biological sciences and medical sciences, 2018-05-22) Parker, Daniel; Sloane, Richard; Pieper, Carl F; Hall, Katherine S; Kraus, Virginia B; Kraus, William E; Huebner, Janet L; Ilkayeva, Olga R; Bain, James R; Newby, L Kristin; Cohen, Harvey Jay; Morey, Miriam C
Aging is characterized by deleterious immune and metabolic changes, but the onset of these changes is unknown. We measured immune and metabolic biomarkers in adults beginning at age 30. To our knowledge, this is the first study to evaluate these biomarkers in adults aged 30 to over 80. Biomarkers were quantified in 961 adults. Tumor necrosis factor alpha (TNF-α), tumor necrosis factor receptor I (TNFR-I), tumor necrosis factor receptor II (TNFR-II), interleukin (IL)-2, IL-6, VCAM-I, D-Dimer, G-CSF, regulated on activation, normal T cell expressed and secreted (RANTES), matrix metalloproteinase-3 (MMP-3), adiponectin, and paraoxonase activity were measured by ELISA. Acylcarnitines and amino acids (AAs) were measured by mass spectrometry and reduced to a single factor using principal components analysis (PCA). Glycine was analyzed separately. The relationship between age and biomarkers was analyzed by linear regression with sex, race, and body mass index (BMI) as covariates. Age was positively correlated with TNF-α, TNFR-I, TNFR-II, IL-6, IL-2, VCAM-1, D-Dimer, MMP-3, adiponectin, acylcarnitines, and AAs. Age was negative correlated with G-CSF, RANTES, and paraoxonase activity. BMI was significant for all biomarkers except IL-2, VCAM-1, RANTES, paraoxonase activity, and the AA factor. Excluding MMP-3, greater BMI was associated with potentially adverse changes in biomarker concentrations. Age-related changes in immune and metabolic biomarkers, known to be associated with poor outcomes in older adults, begin as early as the thirties.
Open Access
Association between general joint hypermobility and knee, hip, and lumbar spine osteoarthritis by race: a cross-sectional study.
(Arthritis research & therapy, 2018-04-18) Flowers, Portia PE; Cleveland, Rebecca J; Schwartz, Todd A; Nelson, Amanda E; Kraus, Virginia B; Hillstrom, Howard J; Goode, Adam P; Hannan, Marian T; Renner, Jordan B; Jordan, Joanne M; Golightly, Yvonne M
BACKGROUND:Osteoarthritis (OA) prevalence differs by race. General joint hypermobility (GJH) may be associated with OA, but differences by race are not known. This community-based study examined the frequency of GJH and its relationship with knee, hip, and lumbar spine OA by race (African American vs. Caucasian). METHODS:Data were from the Johnston County OA project, collected 2003-2010. GJH was defined as Beighton score ≥4. OA symptoms were defined as the presence of pain, aching, or stiffness on most days separately at the knee, hip, and lower back. Radiographic OA (rOA) of the knee or hip was defined as Kellgren-Lawrence grade 2-4. Lumbar spine rOA was disc space narrowing grade ≥1 and osteophyte grade ≥2 in ≥ 1 at the same lumbar level. Lumbar spine facet rOA was present in ≥ 1 lumbar levels. Separate logistic regression models stratified by race were used to examine the association between hypermobility and rOA or OA symptoms at each joint site, adjusting for age, sex, previous joint injury, and body mass index (BMI). RESULTS:Of 1987 participants, 1/3 were African-American and 2/3 were women (mean age 65 years, mean BMI 31 kg/m2). Nearly 8% of Caucasians were hypermobile vs. 5% of African-Americans (p = 0.03). Hypermobility was associated with lower back symptoms in Caucasians (adjusted odds ratio (aOR) 1.54, 95% confidence interval (CI) 1.00, 2.39), but not in African-Americans (aOR 0.77, 95% CI 0.34, 1.72). Associations between hypermobility and other knee, hip, or lumbar spine/facet OA variables were not statistically significant. CONCLUSIONS:General joint hypermobility was more common in Caucasians than African-Americans. Although there were no associations between hypermobility and rOA, the association between hypermobility and lower back symptoms may differ by race.
Open Access
Association of Biomarkers with Individual and Multiple Body Sites of Pain: The Johnston County Osteoarthritis Project.
(Journal of pain research, 2022-01) Norman, Katherine S; Goode, Adam P; Alvarez, Carolina; Hu, David; George, Steven Z; Schwartz, Todd A; Danyluk, Stephanie T; Fillipo, Rebecca; Kraus, Virginia B; Huebner, Janet L; Cleveland, Rebecca J; Jordan, Joanne M; Nelson, Amanda E; Golightly, Yvonne M
Introduction
Biochemical biomarkers may provide insight into musculoskeletal pain reported at individual or multiple body sites. The purpose of this study was to determine if biomarkers or pressure-pain threshold (PPT) were associated with individual or multiple sites of pain.
Methods
This cross-sectional analysis included 689 community-based participants. Self-reported symptoms (ie, pain, aching, or stiffness) were ascertained about the neck, upper back/thoracic, low back, shoulders, elbows, wrist, hands, hips, knees, ankles, and feet. Measured analytes included CXCL-6, RANTES, HA, IL-6, BDNF, OPG and NPY. A standard dolorimeter measured PPT. Logistic regression was used determine the association between biomarkers and PPT with individual and summed sites of pain.
Results
Increased IL-6 and HA were associated with knee pain (OR=1.30, 95% CI 1.03, 1.64) and (OR=1.32, 95% CI 1.01, 1.73) respectively; HA was also associated with elbow/wrist/hand pain (OR=1.60, 95% CI 1.22, 2.09). Those with increased NPY levels were less likely to have shoulder pain (OR=0.56, 95% CI 0.33, 0.93). Biomarkers HA (OR=1.50, 95% CI 1.07, 2.10), OPG (OR=1.74, 95% CI 1.00, 3.03), CXCL-6 (OR=1.75, 95% CI 1.02, 3.01) and decreased PPT (OR=3.97, 95% CI 2.22, 7.12) were associated with multiple compared to no sites of pain. Biomarker HA (OR=1.57, 95% CI 1.06, 2.32) and decreased PPT (OR=3.53, 95% CI 1.81, 6.88) were associated with multiple compared to a single site of pain.
Conclusion
Biomarkers of inflammation (HA, OPG, IL-6 and CXCL-6), pain (NPY) and PPT may help to understand the etiology of single and multiple pain sites.
Open Access
Caloric restriction alters the metabolic response to a mixed-meal: results from a randomized, controlled trial.
(PLoS One, 2012) Huffman, Kim M; Redman, Leanne M; Landerman, Lawrence R; Pieper, Carl F; Stevens, Robert D; Muehlbauer, Michael J; Wenner, Brett R; Bain, James R; Kraus, Virginia B; Newgard, Christopher B; Ravussin, Eric; Kraus, William E
OBJECTIVES: To determine if caloric restriction (CR) would cause changes in plasma metabolic intermediates in response to a mixed meal, suggestive of changes in the capacity to adapt fuel oxidation to fuel availability or metabolic flexibility, and to determine how any such changes relate to insulin sensitivity (S(I)). METHODS: Forty-six volunteers were randomized to a weight maintenance diet (Control), 25% CR, or 12.5% CR plus 12.5% energy deficit from structured aerobic exercise (CR+EX), or a liquid calorie diet (890 kcal/d until 15% reduction in body weight)for six months. Fasting and postprandial plasma samples were obtained at baseline, three, and six months. A targeted mass spectrometry-based platform was used to measure concentrations of individual free fatty acids (FFA), amino acids (AA), and acylcarnitines (AC). S(I) was measured with an intravenous glucose tolerance test. RESULTS: Over three and six months, there were significantly larger differences in fasting-to-postprandial (FPP) concentrations of medium and long chain AC (byproducts of FA oxidation) in the CR relative to Control and a tendency for the same in CR+EX (CR-3 month P = 0.02; CR-6 month P = 0.002; CR+EX-3 month P = 0.09; CR+EX-6 month P = 0.08). After three months of CR, there was a trend towards a larger difference in FPP FFA concentrations (P = 0.07; CR-3 month P = 0.08). Time-varying differences in FPP concentrations of AC and AA were independently related to time-varying S(I) (P<0.05 for both). CONCLUSIONS: Based on changes in intermediates of FA oxidation following a food challenge, CR imparted improvements in metabolic flexibility that correlated with improvements in S(I). TRIAL REGISTRATION: ClinicalTrials.gov NCT00099151.
Open Access
Cartilage mechanics in the guinea pig model of osteoarthritis studied with an osmotic loading method.
(Osteoarthritis and cartilage, 2004-05) Flahiff, Charlene M; Kraus, Virginia B; Huebner, Janet L; Setton, Lori A
To determine the material properties of articular cartilage in the Hartley guinea pig model of spontaneous osteoarthritis.Cartilage-bone samples from the medial femoral condyle and tibial plateau of 12 month-old guinea pig knees were subjected to osmotic loading. Site-matched swelling strains and fixed charge density values were used in a triphasic theoretical model for cartilage swelling to determine the modulus of the cartilage solid matrix. The degree of cartilage degeneration was assessed in adjacent tissue sections using a semi-quantitative histological grading scheme.Decreased values for both moduli and surface zone fixed charge density were associated with increasing grades of cartilage degeneration. Decreases in moduli reflect damage to the collagen matrix, which give rise to greater swelling strains.Histological evidence of cartilage degeneration was associated with impaired cartilage mechanics in the aging Hartley guinea pig.
Open Access
Changes in midbrain pain receptor expression, gait and behavioral sensitivity in a rat model of radiculopathy.
(Open Orthop J, 2012) Hwang, Priscilla Y; Allen, Kyle D; Shamji, Mohammed F; Jing, Liufang; Mata, Brian A; Gabr, Mostafa A; Huebner, Janet L; Kraus, Virginia B; Richardson, William J; Setton, Lori A
Intervertebral disc herniation may contribute to inflammatory processes that associate with radicular pain and motor deficits. Molecular changes at the affected dorsal root ganglion (DRG), spinal cord, and even midbrain, have been documented in rat models of radiculopathy or nerve injury. The objective of this study was to evaluate gait and the expression of key pain receptors in the midbrain in a rodent model of radiculopathy. Radiculopathy was induced by harvesting tail nucleus pulposus (NP) and placing upon the right L5 DRG in rats (NP-treated, n=12). Tail NP was discarded in sham-operated animals (n=12). Mechanical allodynia, weight-bearing, and gait were evaluated in all animals over time. At 1 and 4 weeks after surgery, astrocyte and microglial activation was tested in DRG sections. Midbrain sections were similarly evaluated for immunoreactivity to serotonin (5HT(2B)), mu-opioid (µ-OR), and metabotropic glutamate (mGluR4 and 5) receptor antibodies. NP-treated animals placed less weight on the affected limb 1 week after surgery and experienced mechanical hypersensitivity over the duration of the study. Astroctye activation was observed at DRGs only at 4 weeks after surgery. Findings for pain receptors in the midbrain of NP-treated rats included an increased expression of 5HT(2B) at 1, but not 4 weeks; increased expression of µ-OR and mGluR5 at 1 and 4 weeks (periaqueductal gray region only); and no changes in expression of mGluR4 at any point in this study. These observations provide support for the hypothesis that the midbrain responds to DRG injury with a transient change in receptors regulating pain responses.
Open Access
Changes in serum and synovial fluid biomarkers after acute injury (NCT00332254).
(Arthritis Res Ther, 2010) Catterall, Jonathan B; Stabler, Thomas V; Flannery, Carl R; Kraus, Virginia B
INTRODUCTION: Acute trauma involving the anterior cruciate ligament is believed to be a major risk factor for the development of post-traumatic osteoarthritis 10 to 20 years post-injury. In this study, to better understand the early biological changes which occur after acute injury, we investigated synovial fluid and serum biomarkers. METHODS: We collected serum from 11 patients without pre-existing osteoarthritis from a pilot intervention trial (5 placebo and 6 drug treated) using an intra-articular interleukin-1 receptor antagonist (IL-1Ra) therapy, 9 of which also supplied matched synovial fluid samples at presentation to the clinic after acute knee injury (mean 15.2 ± 7.2 days) and at the follow-up visit for reconstructive surgery (mean 47.6 ± 12.4 days). To exclude patients with pre-existing osteoarthritis (OA), the study was limited to individuals younger than 40 years of age (mean 23 ± 3.5) with no prior history of joint symptoms or trauma. We profiled a total of 21 biomarkers; 20 biomarkers in synovial fluid and 13 in serum with 12 biomarkers measured in both fluids. Biomarkers analyzed in this study were found to be independent of treatment (P > 0.05) as measured by Mann-Whitney and two-way ANOVA. RESULTS: We observed significant decreases in synovial fluid (sf) biomarker concentrations from baseline to follow-up for (sf)C-Reactive protein (CRP) (P = 0.039), (sf)lubricin (P = 0.008) and the proteoglycan biomarkers: (sf)Glycosaminoglycan (GAG) (P = 0.019), and (sf)Alanine-Arginine-Glycine-Serine (ARGS) aggrecan (P = 0.004). In contrast, we observed significant increases in the collagen biomarkers: (sf)C-terminal crosslinked telopeptide type II collagen (CTxII) (P = 0.012), (sf)C1,2C (P = 0.039), (sf)C-terminal crosslinked telopeptide type I collagen (CTxI) (P = 0.004), and (sf)N-terminal telopeptides of type I collagen (NTx) (P = 0.008). The concentrations of seven biomarkers were significantly higher in synovial fluid than serum suggesting release from the signal knee: IL-1β (P < 0.0001), fetal aggrecan FA846 (P = 0.0001), CTxI (P = 0.0002), NTx (P = 0.012), osteocalcin (P = 0.012), Cartilage oligomeric matrix protein (COMP) (P = 0.0001) and matrix metalloproteinase (MMP)-3 (P = 0.0001). For these seven biomarkers we found significant correlations between the serum and synovial fluid concentrations for only CTxI (P = 0.0002), NTx (P < 0.0001), osteocalcin (P = 0.0002) and MMP-3 (P = 0.038). CONCLUSIONS: These data strongly suggest that the biology after acute injury reflects that seen in cartilage explant models stimulated with pro-inflammatory cytokines, which are characterized by an initial wave of proteoglycan loss followed by subsequent collagen loss. As the rise of collagen biomarkers in synovial fluid occurs within the first month after injury, and as collagen loss is thought to be irreversible, very early treatment with agents to either reduce inflammation and/or reduce collagen loss may have the potential to reduce the onset of future post-traumatic osteoarthritis. TRIAL REGISTRATION: The samples used in this study were derived from a clinical trial NCT00332254 registered with ClinicalTrial.gov.
Open Access
Colchicine effectiveness in symptom and inflammation modification in knee osteoarthritis (COLKOA): study protocol for a randomized controlled trial.
(Trials, 2015-04-30) Leung, Ying-Ying; Thumboo, Julian; Wong, Bak Siew; Haaland, Ben; Chowbay, Balram; Chakraborty, Bibhas; Tan, Mann Hong; Kraus, Virginia B
BACKGROUND: Despite the high prevalence and global impact of knee osteoarthritis (KOA), current treatments are palliative. No disease modifying anti-osteoarthritic drug (DMOAD) has been approved. We recently demonstrated significant involvement of uric acid and activation of the innate immune response in osteoarthritis (OA) pathology and progression, suggesting that traditional gout therapy may be beneficial for OA. We therefore assess colchicine, an existing commercially available agent for gout, for a new therapeutic application in KOA. METHODS/DESIGN: COLKOA is a double-blind, placebo-controlled, randomized trial comparing a 16-week treatment with standard daily dose oral colchicine to placebo for KOA. A total of 120 participants with symptomatic KOA will be recruited from a single center in Singapore. The primary end point is 30% improvement in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at week 16. Secondary end points include improvement in pain, physical function, and quality of life and change in serum, urine and synovial fluid biomarkers of cartilage metabolism and inflammation. A magnetic resonance imaging (MRI) substudy will be conducted in 20 participants to evaluate change in synovitis. Logistic regression will be used to compare changes between groups in an intention-to-treat analysis. DISCUSSION: The COLKOA trial is designed to evaluate whether commercially available colchicine is effective for improving signs and symptoms of KOA, and reducing synovial fluid, serum and urine inflammatory and biochemical joint degradation biomarkers. These biomarkers should provide insights into the underlying mechanism of therapeutic response. This trial will potentially provide data to support a new treatment option for KOA. TRIAL REGISTRATION: The trial has been registered at clinicaltrials.gov as NCT02176460 . Date of registration: 26 June 2014.
Open Access
Collagen biomarkers for arthritis applications.
(Biomark Insights, 2007-02-07) Birmingham, James D; Vilim, Vladimir; Kraus, Virginia B
Open Access
Combined Inflammation and Metabolism Biomarker Indices of Robust and Impaired Physical Function in Older Adults.
(Journal of the American Geriatrics Society, 2018-05-08) Zuo, Xintong; Luciano, Alison; Pieper, Carl F; Bain, James R; Kraus, Virginia B; Kraus, William E; Morey, Miriam C; Cohen, Harvey J
To determine whether combinations of inflammatory markers are related to physical function.secondary analysis of baseline of three observational studies of community-dwelling older adults MEASUREMENTS: The baseline data from 3 cohorts of older adults with different health and disease status were employed. Twenty markers of inflammation and metabolism were individually assessed for correlation with usual gait speed and were separated into robust and impairment quartiles. For the robustness and impairment indices, individual markers were selected using step-wise regression over bootstrapping iterations, and regression coefficients were estimated for the markers individually and collectively as an additive score.We developed a robustness index involving 6 markers and an impairment index involving 8 markers corresponding positively and negatively with gait speed. Two markers, glycine and tumor necrosis factor receptor 1 (TNFR1), appeared only in the robustness index, and TNFR2; regulated on activation, normal T-cell expressed and secreted; the amino acid factor; and matrix metallopeptidase 3; appeared only in the impairment index.Indices of biomarkers were associated with robust and impaired physical performance but differ, in composition suggesting potential biological differences that may contribute to robustness and impairment.
Open Access
CXCL10 is Upregulated in Synovium and Cartilage following Articular Fracture.
(J Orthop Res, 2017-09-14) Furman, Bridgette D; Kent, Collin L; Huebner, Janet L; Kraus, Virginia B; McNulty, Amy L; Guilak, Farshid; Olson, Steven A
The objective of this study was to investigate the expression of the chemokine CXCL10 and its role in joint tissues following articular fracture. We hypothesized that CXCL10 is upregulated following articular fracture and contributes to cartilage degradation associated with post-traumatic arthritis (PTA). To evaluate CXCL10 expression following articular fracture, gene expression was quantified in synovial tissue from knee joints of C57BL/6 mice that develop PTA following articular fracture, and MRL/MpJ mice that are protected from PTA. CXCL10 protein expression was assessed in human cartilage in normal, osteoarthritic (OA), and post-traumatic tissue using immunohistochemistry. The effects of exogenous CXCL10, alone and in combination with IL-1, on porcine cartilage explants were assessed by quantifying the release of catabolic mediators. Synovial tissue gene expression of CXCL10 was upregulated by joint trauma, peaking one day in C57BL/6 mice (25-fold) vs. three days post-fracture in MRL/MpJ mice (15-fold). CXCL10 protein in articular cartilage was most highly expressed following trauma compared with normal and OA tissue. In a dose dependent manner, exogenous CXCL10 significantly reduced total matrix metalloproteinase (MMP) and aggrecanase activity of culture media from cartilage explants. CXCL10 also trended toward a reduction in IL-1α-stimulated total MMP activity (p=0.09) and S-GAG (p=0.09), but not NO release. In conclusion, CXCL10 was upregulated in synovium and chondrocytes following trauma. However, exogenous CXCL10 did not induce a catabolic response in cartilage. CXCL10 may play a role in modulating the chondrocyte response to inflammatory stimuli associated with joint injury and the progression of PTA. This article is protected by copyright. All rights reserved.
Open Access
Cytokine biomarkers in tear film for primary open-angle glaucoma.
(Clin Ophthalmol, 2017) Gupta, Divakar; Wen, Joanne C; Huebner, Janet L; Stinnett, Sandra; Kraus, Virginia B; Tseng, Henry C; Walsh, Molly
PURPOSE: To determine the utility of tear film cytokines as biomarkers for early primary open-angle glaucoma (POAG). METHODS: Patients without POAG and eye drop-naïve patients with newly diagnosed POAG were recruited from an academic hospital-based glaucoma practice. Tear films of recruited patients were obtained and analyzed using a multiplex, high-sensitivity electrochemiluminescent enzyme-linked immunosorbent assay for proinflammatory cytokines (IFNγ, IL-10, IL-12p70, IL-13, IL-1β, IL-2, IL-4, IL-6, IL-8, and TNFα). RESULTS: Mean concentrations of tear film cytokines were lower in the glaucoma group for 8 of 10 cytokines tested. IL-12p70 (3.94±2.19 pg/mL in control vs 2.31±1.156 pg/mL in POAG;P=0.035) was significantly lower in the tear film of patients with newly diagnosed POAG. CONCLUSION: Proinflammatory cytokines were lower in eye drop-naïve newly diagnosed glaucoma patients. Tear film cytokine profiles may be used as biomarkers of early POAG.
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Diet-induced obesity differentially regulates behavioral, biomechanical, and molecular risk factors for osteoarthritis in mice.
(Arthritis Res Ther, 2010) Griffin, Timothy M; Fermor, Beverley; Huebner, Janet L; Kraus, Virginia B; Rodriguiz, Ramona M; Wetsel, William C; Cao, Li; Setton, Lori A; Guilak, Farshid
INTRODUCTION: Obesity is a major risk factor for the development of osteoarthritis in both weight-bearing and nonweight-bearing joints. The mechanisms by which obesity influences the structural or symptomatic features of osteoarthritis are not well understood, but may include systemic inflammation associated with increased adiposity. In this study, we examined biomechanical, neurobehavioral, inflammatory, and osteoarthritic changes in C57BL/6J mice fed a high-fat diet. METHODS: Female C57BL/6J mice were fed either a 10% kcal fat or a 45% kcal fat diet from 9 to 54 weeks of age. Longitudinal changes in musculoskeletal function and inflammation were compared with endpoint neurobehavioral and osteoarthritic disease states. Bivariate and multivariate analyses were conducted to determine independent associations with diet, percentage body fat, and knee osteoarthritis severity. We also examined healthy porcine cartilage explants treated with physiologic doses of leptin, alone or in combination with IL-1α and palmitic and oleic fatty acids, to determine the effects of leptin on cartilage extracellular matrix homeostasis. RESULTS: High susceptibility to dietary obesity was associated with increased osteoarthritic changes in the knee and impaired musculoskeletal force generation and motor function compared with controls. A high-fat diet also induced symptomatic characteristics of osteoarthritis, including hyperalgesia and anxiety-like behaviors. Controlling for the effects of diet and percentage body fat with a multivariate model revealed a significant association between knee osteoarthritis severity and serum levels of leptin, adiponectin, and IL-1α. Physiologic doses of leptin, in the presence or absence of IL-1α and fatty acids, did not substantially alter extracellular matrix homeostasis in healthy cartilage explants. CONCLUSIONS: These results indicate that diet-induced obesity increases the risk of symptomatic features of osteoarthritis through changes in musculoskeletal function and pain-related behaviors. Furthermore, the independent association of systemic adipokine levels with knee osteoarthritis severity supports a role for adipose-associated inflammation in the molecular pathogenesis of obesity-induced osteoarthritis. Physiologic levels of leptin do not alter extracellular matrix homeostasis in healthy cartilage, suggesting that leptin may be a secondary mediator of osteoarthritis pathogenesis.
Open Access
Dietary Patterns Associated with Cognitive Function among the Older People in Underdeveloped Regions: Finding from the NCDFaC Study.
(Nutrients, 2018-04-09) Yin, Zhaoxue; Chen, Jing; Zhang, Jian; Ren, Zeping; Dong, Kui; Kraus, Virginia B; Wang, Zhuoqun; Zhang, Mei; Zhai, Yi; Song, Pengkun; Zhao, Yanfang; Pang, Shaojie; Mi, Shengquan; Zhao, Wenhua
Although dietary patterns are crucial to cognitive function, associations of dietary patterns with cognitive function have not yet been fully understood. This cross-sectional study explored dietary patterns associated with cognitive function among the older adults in underdeveloped regions, using 1504 community-dwelling older adults aged 60 and over. Diet was assessed using a food frequency questionnaire and 24-h dietary recall. Factor analysis was used to extract dietary patterns. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE). Two dietary patterns, a "mushroom, vegetable, and fruits" (MVF) pattern and a "meat and soybean products" (MS) pattern, were identified. The MVF pattern, characterized by high consumption of mushrooms, vegetables, and fruits was significantly positively associated with cognitive function (p < 0.05), with an odds ratio of (95% CIs) 0.60 (0.38, 0.94) for cognitive impairment and β (95% CIs) 0.15 (0.02, 0.29) for -log (31-MMSE score). The MS pattern, characterized by high consumption of soybean products and meat, was also associated with better cognitive function, with an odds ratio of 0.47 (95% CIs 0.30, 0.74) for cognitive impairment and β (95% CIs) 0.34 (0.21, 0.47) for -log (31-MMSE score). Our results suggested that both the MVF and MS patterns were positively associated with better cognitive function among older adults in underdeveloped regions.
Open Access
Differential microRNA profiles of intramuscular and secreted extracellular vesicles in human tissue-engineered muscle.
(Frontiers in physiology, 2022-01) Vann, Christopher G; Zhang, Xin; Khodabukus, Alastair; Orenduff, Melissa C; Chen, Yu-Hsiu; Corcoran, David L; Truskey, George A; Bursac, Nenad; Kraus, Virginia B
Exercise affects the expression of microRNAs (miR/s) and muscle-derived extracellular vesicles (EVs). To evaluate sarcoplasmic and secreted miR expression in human skeletal muscle in response to exercise-mimetic contractile activity, we utilized a three-dimensional tissue-engineered model of human skeletal muscle ("myobundles"). Myobundles were subjected to three culture conditions: no electrical stimulation (CTL), chronic low frequency stimulation (CLFS), or intermittent high frequency stimulation (IHFS) for 7 days. RNA was isolated from myobundles and from extracellular vesicles (EVs) secreted by myobundles into culture media; miR abundance was analyzed by miRNA-sequencing. We used edgeR and a within-sample design to evaluate differential miR expression and Pearson correlation to evaluate correlations between myobundle and EV populations within treatments with statistical significance set at p < 0.05. Numerous miRs were differentially expressed between myobundles and EVs; 116 miRs were differentially expressed within CTL, 3 within CLFS, and 2 within IHFS. Additionally, 25 miRs were significantly correlated (18 in CTL, 5 in CLFS, 2 in IHFS) between myobundles and EVs. Electrical stimulation resulted in differential expression of 8 miRs in myobundles and only 1 miR in EVs. Several KEGG pathways, known to play a role in regulation of skeletal muscle, were enriched, with differentially overrepresented miRs between myobundle and EV populations identified using miEAA. Together, these results demonstrate that in vitro exercise-mimetic contractile activity of human engineered muscle affects both their expression of miRs and number of secreted EVs. These results also identify novel miRs of interest for future studies of the role of exercise in organ-organ interactions in vivo.
Open Access
Effect of high-intensity interval training on muscle remodeling in rheumatoid arthritis compared to prediabetes.
(Arthritis research & therapy, 2018-12-27) Andonian, Brian J; Bartlett, David B; Huebner, Janet L; Willis, Leslie; Hoselton, Andrew; Kraus, Virginia B; Kraus, William E; Huffman, Kim M
BACKGROUND:Sarcopenic obesity, associated with greater risk of cardiovascular disease (CVD) and mortality in rheumatoid arthritis (RA), may be related to dysregulated muscle remodeling. To determine whether exercise training could improve remodeling, we measured changes in inter-relationships of plasma galectin-3, skeletal muscle cytokines, and muscle myostatin in patients with RA and prediabetes before and after a high-intensity interval training (HIIT) program. METHODS:Previously sedentary persons with either RA (n = 12) or prediabetes (n = 9) completed a 10-week supervised HIIT program. At baseline and after training, participants underwent body composition (Bod Pod®) and cardiopulmonary exercise testing, plasma collection, and vastus lateralis biopsies. Plasma galectin-3, muscle cytokines, muscle interleukin-1 beta (mIL-1β), mIL-6, mIL-8, muscle tumor necrosis factor-alpha (mTNF-α), mIL-10, and muscle myostatin were measured via enzyme-linked immunosorbent assays. An independent cohort of patients with RA (n = 47) and age-, gender-, and body mass index (BMI)-matched non-RA controls (n = 23) were used for additional analyses of galectin-3 inter-relationships. RESULTS:Exercise training did not reduce mean concentration of galectin-3, muscle cytokines, or muscle myostatin in persons with either RA or prediabetes. However, training-induced alterations varied among individuals and were associated with cardiorespiratory fitness and body composition changes. Improved cardiorespiratory fitness (increased absolute peak maximal oxygen consumption, or VO2) correlated with reductions in galectin-3 (r = -0.57, P = 0.05 in RA; r = -0.48, P = 0.23 in prediabetes). Training-induced improvements in body composition were related to reductions in muscle IL-6 and TNF-α (r < -0.60 and P <0.05 for all). However, the association between increased lean mass and decreased muscle IL-6 association was stronger in prediabetes compared with RA (Fisher r-to-z P = 0.0004); in prediabetes but not RA, lean mass increases occurred in conjunction with reductions in muscle myostatin (r = -0.92; P <0.05; Fisher r-to-z P = 0.026). Subjects who received TNF inhibitors (n = 4) or hydroxychloroquine (n = 4) did not improve body composition with exercise training. CONCLUSION:Exercise responses in muscle myostatin, cytokines, and body composition were significantly greater in prediabetes than in RA, consistent with impaired muscle remodeling in RA. To maximize physiologic improvements with exercise training in RA, a better understanding is needed of skeletal muscle and physiologic responses to exercise training and their modulation by RA disease-specific features or pharmacologic agents or both. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02528344 . Registered on August 19, 2015.
Open Access
Effects of a Single Intra-Articular Injection of a Microsphere Formulation of Triamcinolone Acetonide on Knee Osteoarthritis Pain: A Double-Blinded, Randomized, Placebo-Controlled, Multinational Study.
(The Journal of bone and joint surgery. American volume, 2018-04) Conaghan, Philip G; Hunter, David J; Cohen, Stanley B; Kraus, Virginia B; Berenbaum, Francis; Lieberman, Jay R; Jones, Deryk G; Spitzer, Andrew I; Jevsevar, David S; Katz, Nathaniel P; Burgess, Diane J; Lufkin, Joelle; Johnson, James R; Bodick, Neil; FX006-2014-008 Participating Investigators
Intra-articular corticosteroids relieve osteoarthritis pain, but rapid systemic absorption limits efficacy. FX006, a novel, microsphere-based, extended-release triamcinolone acetonide (TA) formulation, prolongs TA joint residence and reduces systemic exposure compared with standard TA crystalline suspension (TAcs). We assessed symptomatic benefits and safety of FX006 compared with saline-solution placebo and TAcs.In this Phase-3, multicenter, double-blinded, 24-week study, adults ≥40 years of age with knee osteoarthritis (Kellgren-Lawrence grade 2 or 3) and average-daily-pain (ADP)-intensity scores of ≥5 and ≤9 (0 to 10 numeric rating scale) were centrally randomized (1:1:1) to a single intra-articular injection of FX006 (32 mg), saline-solution placebo, or TAcs (40 mg). The primary end point was change from baseline to week 12 in weekly mean ADP-intensity scores for FX006 compared with saline-solution placebo. Secondary end points were area-under-effect (AUE) curves of the change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with saline-solution placebo, AUE curves of the change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with TAcs, change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with TAcs, and AUE curves of the change in weekly mean ADP-intensity scores from baseline to week 24 for FX006 compared with saline-solution placebo. Exploratory end points included week-12 changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Knee Injury and Osteoarthritis Outcome Score Quality of Life (KOOS-QOL) subscale scores for FX006 compared with saline-solution placebo and TAcs. Adverse events were elicited at each inpatient visit.The primary end point was met. Among 484 treated patients (n = 161 for FX006, n = 162 for saline-solution placebo, and n = 161 for TAcs), FX006 provided significant week-12 improvement in ADP intensity compared with that observed for saline-solution placebo (least-squares mean change from baseline: -3.12 versus -2.14; p < 0.0001) indicating ∼50% improvement. FX006 afforded improvements over saline-solution placebo for all secondary and exploratory end points (p < 0.05). Improvements in osteoarthritis pain were not significant for FX006 compared with TAcs using the ADP-based secondary measures. Exploratory analyses of WOMAC-A, B, and C and KOOS-QOL subscales favored FX006 (p ≤ 0.05). Adverse events were generally mild, occurring at similar frequencies across treatments.FX006 provided significant, clinically meaningful pain reduction compared with saline-solution placebo at week 12 (primary end point).Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
Restricted
First qualification study of serum biomarkers as indicators of total body burden of osteoarthritis.
(PLoS One, 2010-03-17) Kraus, Virginia B; Kepler, Thomas B; Stabler, Thomas; Renner, Jordan; Jordan, Joanne
BACKGROUND: Osteoarthritis (OA) is a debilitating chronic multijoint disease of global proportions. OA presence and severity is usually documented by x-ray imaging but whole body imaging is impractical due to radiation exposure, time and cost. Systemic (serum or urine) biomarkers offer a potential alternative method of quantifying total body burden of disease but no OA-related biomarker has ever been stringently qualified to determine the feasibility of this approach. The goal of this study was to evaluate the ability of three OA-related biomarkers to predict various forms or subspecies of OA and total body burden of disease. METHODOLOGY/PRINCIPAL FINDINGS: Female participants (461) with clinical hand OA underwent radiography of hands, hips, knees and lumbar spine; x-rays were comprehensively scored for OA features of osteophyte and joint space narrowing. Three OA-related biomarkers, serum hyaluronan (sHA), cartilage oligomeric matrix protein (sCOMP), and urinary C-telopeptide of type II collagen (uCTX2), were measured by ELISA. sHA, sCOMP and uCTX2 correlated positively with total osteophyte burden in models accounting for demographics (age, weight, height): R(2) = 0.60, R(2) = 0.47, R(2) = 0.51 (all p<10(-6)); sCOMP correlated negatively with total joint space narrowing burden: R(2) = 0.69 (p<10(-6)). Biomarkers and demographics predicted 35-38% of variance in total burden of OA (total joint space narrowing or osteophyte). Joint size did not determine the contribution to the systemic biomarker concentration. Biomarker correlation with disease in the lumbar spine resembled that in the rest of the skeleton. CONCLUSIONS/SIGNIFICANCE: We have suspected that the correlation of systemic biomarkers with disease has been hampered by the inability to fully phenotype the burden of OA in a patient. These results confirm the hypothesis, revealed upon adequate patient phenotyping, that systemic joint tissue concentrations of several biomarkers can be quantitative indicators of specific subspecies of OA and of total body burden of disease.

Browsing by Author "Kraus, Virginia B"

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