Browsing by Subject "Uric Acid"

Now showing 1 - 5 of 5
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    Dissecting the Domains of Parkinson's Disease: Insights from Longitudinal Item Response Theory Modeling.
    (Movement disorders : official journal of the Movement Disorder Society, 2022-09) Luo, Sheng; Zou, Haotian; Stebbins, Glenn T; Schwarzschild, Michael A; Macklin, Eric A; Chan, James; Oakes, David; Simuni, Tanya; Goetz, Christopher G; Parkinson Study Group SURE-PD3 Investigators

    Background

    Longitudinal item response theory (IRT) models previously suggested that the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor examination has two salient domains, tremor and nontremor, that progress in time and in response to treatment differently.

    Objective

    Apply longitudinal IRT modeling, separating tremor and nontremor domains, to reanalyze outcomes in the previously published clinical trial (Study of Urate Elevation in Parkinson's Disease, Phase 3) that showed no overall treatment effects.

    Methods

    We applied unidimensional and multidimensional longitudinal IRT models to MDS-UPDRS motor examination items in 298 participants with Parkinson's disease from the Study of Urate Elevation in Parkinson's Disease, Phase 3 (placebo vs. inosine) study. We separated 10 tremor items from 23 nontremor items and used Bayesian inference to estimate progression rates and sensitivity to treatment in overall motor severity and tremor and nontremor domains.

    Results

    The progression rate was faster in the tremor domain than the nontremor domain before levodopa treatment. Inosine treatment had no effect on either domain relative to placebo. Levodopa treatment was associated with greater slowing of progression in the tremor domain than the nontremor domain regardless of inosine exposure. Linear patterns of progression were observed. Despite different domain-specific progression patterns, tremor and nontremor severities at baseline and over time were significantly correlated.

    Conclusions

    Longitudinal IRT analysis is a novel statistical method addressing limitations of traditional linear regression approaches. It is particularly useful because it can simultaneously monitor changes in different, but related, domains over time and in response to treatment interventions. We suggest that in neurological diseases with distinct impairment domains, clinical or anatomical, this application may identify patterns of change unappreciated by standard statistical methods. © 2022 International Parkinson and Movement Disorder Society.
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    ItemOpen Access
    Field-Based Assessments of Behavioral Patterns During Shiftwork in Police Academy Trainees Using Wearable Technology.
    (Journal of biological rhythms, 2022-06) Erickson, Melissa L; Wang, Will; Counts, Julie; Redman, Leanne M; Parker, Daniel; Huebner, Janet L; Dunn, Jessilyn; Kraus, William E
    Circadian misalignment, as occurs in shiftwork, is associated with numerous negative health outcomes. Here, we sought to improve data labeling accuracy from wearable technology using a novel data pre-processing algorithm in 27 police trainees during shiftwork. Secondarily, we explored changes in four metabolic salivary biomarkers of circadian rhythm during shiftwork. Using a two-group observational study design, participants completed in-class training during dayshift for 6 weeks followed by either dayshift or nightshift field-training for 6 weeks. Using our novel algorithm, we imputed labels of circadian misaligned sleep episodes that occurred during daytime, which were previously were mislabeled as non-sleep by Garmin, supported by algorithm performance analysis. We next assessed changes to resting heart rate and sleep regularity index during dayshift versus nightshift field-training. We also examined changes in field-based assessments of salivary cortisol, uric acid, testosterone, and melatonin during dayshift versus nightshift. Compared to dayshift, nightshift workers experienced larger changes to resting heart rate, sleep regularity index (indicating reduced sleep regularity), and alterations in sleep/wake activity patterns accompanied by blunted salivary cortisol. Salivary uric acid and testosterone did not change. These findings show wearable technology combined with specialized data pre-processing can be used to monitor changes in behavioral patterns during shiftwork.
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    Homeostatic imbalance of purine catabolism in first-episode neuroleptic-naïve patients with schizophrenia.
    (PLoS One, 2010-03-03) Yao, Jeffrey K; Dougherty, George G; Reddy, Ravinder D; Keshavan, Matcheri S; Montrose, Debra M; Matson, Wayne R; McEvoy, Joseph; Kaddurah-Daouk, Rima
    BACKGROUND: Purine catabolism may be an unappreciated, but important component of the homeostatic response of mitochondria to oxidant stress. Accumulating evidence suggests a pivotal role of oxidative stress in schizophrenia pathology. METHODOLOGY/PRINCIPAL FINDINGS: Using high-pressure liquid chromatography coupled with a coulometric multi-electrode array system, we compared 6 purine metabolites simultaneously in plasma between first-episode neuroleptic-naïve patients with schizophrenia (FENNS, n = 25) and healthy controls (HC, n = 30), as well as between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment. Significantly higher levels of xanthosine (Xant) and lower levels of guanine (G) were seen in both patient groups compared to HC subjects. Moreover, the ratios of G/guanosine (Gr), uric acid (UA)/Gr, and UA/Xant were significantly lower, whereas the ratio of Xant/G was significantly higher in FENNS-BL than in HC. Such changes remained in FENNS-4w with exception that the ratio of UA/Gr was normalized. All 3 groups had significant correlations between G and UA, and Xan and hypoxanthine (Hx). By contrast, correlations of UA with each of Xan and Hx, and the correlation of Xan with Gr were all quite significant for the HC but not for the FENNS. Finally, correlations of Gr with each of UA and G were significant for both HC and FENNS-BL but not for the FENNS-4w. CONCLUSIONS/SIGNIFICANCE: During purine catabolism, both conversions of Gr to G and of Xant to Xan are reversible. Decreased ratios of product to precursor suggested a shift favorable to Xant production from Xan, resulting in decreased UA levels in the FENNS. Specifically, the reduced UA/Gr ratio was nearly normalized after 4 weeks of antipsychotic treatment. In addition, there are tightly correlated precursor and product relationships within purine pathways; although some of these correlations persist across disease or medication status, others appear to be lost among FENNS. Taken together, these results suggest that the potential for steady formation of antioxidant UA from purine catabolism is altered early in the course of illness.
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    ItemOpen Access
    Monosodium urate crystal induced macrophage inflammation is attenuated by chondroitin sulphate: pre-clinical model for gout prophylaxis?
    (BMC Musculoskelet Disord, 2014-09-27) Orlowsky, EW; Stabler, TV; Montell, E; Vergés, J; Kraus, VB
    BACKGROUND: Chondroitin Sulphate (CS), a natural glycosaminoglycan of the extracellular matrix, has clinical benefit in symptomatic osteoarthritis but has never been tested in gout. In vitro, CS has anti-inflammatory and positive effects on osteoarthritic chondrocytes, synoviocytes and subchondral bone osteoblasts, but its effect on macrophages is unknown. The purpose of our study was to evaluate the in vitro effects of CS on monosodium urate (MSU)-stimulated cytokine production by macrophages. METHODS: THP-1 monocytes were differentiated into mature macrophages using a phorbol ester, pretreated for 4 hours with CS in a physiologically achievable range of concentrations (10-200 μg/ml) followed by MSU crystal stimulation for 24 hours. Cell culture media were analyzed by immunoassay for factors known to be upregulated during gouty inflammation including IL-1β, IL-8 and TNFα. The specificity of inflammasome activation by MSU crystals was tested with a caspase-1 inhibitor (0.01 μM-10 μM). RESULTS: MSU crystals ≥10 mg/dl increased macrophage production of IL-1β, IL-8 and TNFα a mean 7-, 3- and 4-fold respectively. Induction of IL-1β by MSU was fully inhibited by a caspase-1 inhibitor confirming inflammasome activation as the mechanism for generating this cytokine. In a dose-dependent manner, CS significantly inhibited IL-1β (p = 0.003), and TNFα (p = 0.02) production from macrophages in response to MSU. A similar trend was observed for IL-8 but was not statistically significant (p = 0.41). CONCLUSIONS: CS attenuated MSU crystal induced macrophage inflammation, suggesting a possible role for CS in gout prophylaxis.
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    ItemOpen Access
    Monosodium urate crystal induced macrophage inflammation is attenuated by chondroitin sulphate: pre-clinical model for gout prophylaxis?
    (BMC musculoskeletal disorders, 2014-09-27) Orlowsky, Eric W; Stabler, Thomas V; Montell, Eulàlia; Vergés, Josep; Kraus, Virginia Byers
    Chondroitin Sulphate (CS), a natural glycosaminoglycan of the extracellular matrix, has clinical benefit in symptomatic osteoarthritis but has never been tested in gout. In vitro, CS has anti-inflammatory and positive effects on osteoarthritic chondrocytes, synoviocytes and subchondral bone osteoblasts, but its effect on macrophages is unknown. The purpose of our study was to evaluate the in vitro effects of CS on monosodium urate (MSU)-stimulated cytokine production by macrophages.THP-1 monocytes were differentiated into mature macrophages using a phorbol ester, pretreated for 4 hours with CS in a physiologically achievable range of concentrations (10-200 μg/ml) followed by MSU crystal stimulation for 24 hours. Cell culture media were analyzed by immunoassay for factors known to be upregulated during gouty inflammation including IL-1β, IL-8 and TNFα. The specificity of inflammasome activation by MSU crystals was tested with a caspase-1 inhibitor (0.01 μM-10 μM).MSU crystals ≥10 mg/dl increased macrophage production of IL-1β, IL-8 and TNFα a mean 7-, 3- and 4-fold respectively. Induction of IL-1β by MSU was fully inhibited by a caspase-1 inhibitor confirming inflammasome activation as the mechanism for generating this cytokine. In a dose-dependent manner, CS significantly inhibited IL-1β (p = 0.003), and TNFα (p = 0.02) production from macrophages in response to MSU. A similar trend was observed for IL-8 but was not statistically significant (p = 0.41).CS attenuated MSU crystal induced macrophage inflammation, suggesting a possible role for CS in gout prophylaxis.