205 results on '"Eells, J."'
Search Results
102. Comparative Effectiveness of Bimekizumab and Risankizumab in Patients with Psoriatic Arthritis at 52 Weeks Assessed Using a Matching-Adjusted Indirect Comparison.
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Mease PJ, Warren RB, Nash P, Grouin JM, Lyris N, Willems D, Taieb V, Eells J, and McInnes IB
- Abstract
Introduction: The relative efficacy of bimekizumab and risankizumab in patients with PsA who were biologic disease-modifying anti-rheumatic drug naïve (bDMARD naïve) or with previous inadequate response or intolerance to tumor necrosis factor inhibitors (TNFi-IR) was assessed at 52 weeks (Wk52) using matching-adjusted indirect comparisons (MAIC)., Methods: Relevant trials were systematically identified. For patients who were bDMARD naïve, individual patient data (IPD) from BE OPTIMAL (NCT03895203; N = 431) were matched with summary data from KEEPsAKE-1 (NCT03675308; N = 483). For patients who were TNFi-IR, IPD from BE COMPLETE (NCT03896581; N = 267) were matched with summary data from the TNFi-IR patient subgroup in KEEPsAKE-2 (NCT03671148; N = 106). To adjust for cross-trial differences, patients from the bimekizumab trials were re-weighted to match the baseline characteristics of patients in the risankizumab trials. Adjustment variables were selected based on expert consensus (n = 5) and adherence to established MAIC guidelines. Recalculated bimekizumab Wk52 outcomes for American College of Rheumatology (ACR) 20/50/70 response criteria and minimal disease activity (MDA) index (non-responder imputation) were compared with risankizumab outcomes via non-placebo-adjusted comparisons., Results: In patients who were bDMARD naïve, bimekizumab had a significantly greater likelihood of response than risankizumab at Wk52 for ACR50 (odds ratio [95% confidence interval]: 1.52 [1.11, 2.09]) and ACR70 (1.80 [1.29, 2.51]). In patients who were TNFi-IR, bimekizumab had a significantly greater likelihood of response than risankizumab at Wk52 for ACR20 (1.78 [1.08, 2.96]), ACR50 (3.05 [1.74, 5.32]), ACR70 (3.69 [1.82, 7.46]), and MDA (2.43 [1.37, 4.32])., Conclusions: Using MAIC, bimekizumab demonstrated a greater likelihood of efficacy in most ACR and MDA outcomes than risankizumab in patients with PsA who were bDMARD naïve and TNFi-IR at Wk52., Trial Registration: NCT03895203, NCT03896581, NCT03675308, NCT03671148., (© 2024. The Author(s).)
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- 2024
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103. Comparative Effectiveness of Bimekizumab and Ustekinumab in Patients with Psoriatic Arthritis at 52 Weeks Assessed Using a Matching-Adjusted Indirect Comparison.
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Mease PJ, Warren RB, Nash P, Grouin JM, Lyris N, Taieb V, Eells J, and McInnes IB
- Abstract
Introduction: A matching-adjusted indirect comparison (MAIC) was conducted to assess the relative efficacy at 52 weeks (Wk52) of bimekizumab 160 mg every 4 weeks (Q4W) and ustekinumab 45 or 90 mg every 12 weeks (Q12W) in patients with psoriatic arthritis (PsA) who were biologic disease-modifying anti-rheumatic drug naïve (bDMARD naïve) or who had a previous inadequate response or an intolerance to tumor necrosis factor inhibitors (TNFi-IR)., Methods: Relevant trials were systematically identified. Individual patient data from the bimekizumab trials BE OPTIMAL (NCT03895203; N = 431) and BE COMPLETE (NCT03896581; N = 267) were matched with summary data on patients receiving ustekinumab in the PSUMMIT 1 trial (NCT01009086; 45 mg, N = 205; 90 mg; N = 204) and a subgroup of TNFi-IR patients receiving ustekinumab in the PSUMMIT 2 trial (NCT01077362; 45 mg, N = 60; 90 mg, N = 58), respectively. Patients from the bimekizumab trials were re-weighted using propensity scores to match the baseline characteristics of the ustekinumab trial patients. Adjustment variables were selected based on expert consensus (n = 5) and adherence to established MAIC guidelines. Non-placebo-adjusted comparisons of recalculated bimekizumab and ustekinumab outcomes for the American College of Rheumatology (ACR) 20/50/70 response criteria (non-responder imputation) were analyzed., Results: In patients who were bDMARD naïve, bimekizumab had a greater likelihood of response than ustekinumab at Wk52 for ACR20 (odds ratio [95% confidence interval] 45 mg: 2.14 [1.35, 3.40]; 90 mg: 1.98 [1.24, 3.16]), ACR50 (45 mg: 2.74 [1.75, 4.29]; 90 mg: 2.29 [1.48, 3.55]), and ACR70 (45 mg: 3.33 [2.04, 5.46]; 90 mg: 3.05 [1.89, 4.91]). In patients who were TNFi-IR, bimekizumab had a greater likelihood of response than ustekinumab at Wk52 for ACR20 (45 mg: 4.17 [2.13, 8.16]; 90 mg: 4.19 [2.07, 8.49]), ACR50 (45 mg: 5.00 [2.26, 11.05]; 90 mg: 3.86 [1.70, 8.79]), and ACR70 (45 mg: 9.85 [2.79, 34.79]; 90 mg: 6.29 [1.98, 20.04])., Conclusions: Using MAIC, bimekizumab showed greater efficacy than ustekinumab in achieving all ACR responses in patients with PsA who were bDMARD naïve and TNFi-IR at Wk52., Trial Registration: NCT03895203, NCT03896581, NCT01009086, NCT01077362., (© 2024. The Author(s).)
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- 2024
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104. Comparative Effectiveness of Bimekizumab and Secukinumab in Patients with Psoriatic Arthritis at 52 Weeks Using a Matching-Adjusted Indirect Comparison.
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Mease PJ, Warren RB, Nash P, Grouin JM, Lyris N, Willems D, Taieb V, Eells J, and McInnes IB
- Abstract
Introduction: Matching-adjusted indirect comparisons (MAICs) were used to compare the efficacy of bimekizumab and secukinumab 150 mg and 300 mg at 52 weeks for the treatment of psoriatic arthritis (PsA) in patients who were biologic disease-modifying anti-rheumatic drug-naïve (bDMARD-naïve) or with previous inadequate response or intolerance to tumor necrosis factor inhibitors (TNFi-IR)., Methods: Relevant trials were systematically identified. Individual patient data from bimekizumab randomized controlled trials, BE OPTIMAL (N = 431) and BE COMPLETE (N = 267), were matched to aggregate data from bDMARD-naïve and TNFi-IR patient subgroups from FUTURE 2 using secukinumab 150 mg and 300 mg doses (bDMARD-naïve: N = 63/37; TNFi-IR: N = 67/33). To adjust for cross-trial differences, patients from the bimekizumab trials were re-weighted using propensity scores to match the baseline characteristics of patients in the secukinumab trials. Unanchored comparisons of recalculated bimekizumab and secukinumab 52-week non-responder imputation outcomes for 20/50/70% improvement in American College of Rheumatology score (ACR20/50/70) and minimal disease activity (MDA) index were analyzed., Results: In patients who were bDMARD-naïve, bimekizumab had a greater likelihood of ACR70 response than secukinumab 150 mg (odds ratio [95% confidence interval] 2.39 [1.26, 4.53]; p = 0.008) and secukinumab 300 mg (2.03 [1.11, 3.72]; p = 0.021) at 52 weeks. In patients who were TNFi-IR, bimekizumab had a greater likelihood of response compared to secukinumab 150 mg for ACR20 (3.50 [1.64-7.49]; p = 0.001), ACR50 (3.32 [1.41, 7.80]; p = 0.006), ACR70 (2.95 [1.08, 8.07]; p = 0.035) and MDA (3.52 [1.38, 8.99]; p = 0.009), and a greater likelihood of response compared to secukinumab 300 mg for ACR50 (2.44 [1.06, 5.65]; p = 0.037) and MDA (2.92 [1.20, 7.09]; p = 0.018) at 52 weeks., Conclusion: In this MAIC analysis, the efficacy of bimekizumab, as demonstrated by the likelihood of ACR20/50/70 and MDA response at 52 weeks, was greater or comparable to secukinumab 150 mg and 300 mg for patients with PsA who were bDMARD-naïve and TNFi-IR., Trial Registration Numbers: NCT03895203, NCT03896581, NCT04009499, NCT01752634, NCT01989468, NCT02294227, NCT02404350., (© 2024. The Author(s).)
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- 2024
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105. Comparative Effectiveness of Bimekizumab and Guselkumab in Patients with Psoriatic Arthritis at 52 Weeks Assessed Using a Matching-Adjusted Indirect Comparison.
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Warren RB, McInnes IB, Nash P, Grouin JM, Lyris N, Willems D, Taieb V, Eells J, and Mease PJ
- Abstract
Introduction: Matching-adjusted indirect comparisons (MAIC) were used to assess the relative efficacy of bimekizumab 160 mg every 4 weeks (Q4W) compared to guselkumab 100 mg Q4W or every 8 weeks (Q8W) at 48/52 weeks in patients with psoriatic arthritis (PsA) who were biologic disease-modifying antirheumatic drug-naïve (bDMARD-naïve) or with previous inadequate response or intolerance to tumor necrosis factor inhibitors (TNFi-IR)., Methods: Relevant trials were identified as part of a systematic literature review. For patients who were bDMARD-naïve, individual patient data (IPD) from BE OPTIMAL (N = 431) was matched to summary data from DISCOVER-2 (Q4W, n = 245; Q8W, n = 248). For patients who were TNFi-IR, IPD from BE COMPLETE (n = 267) and summary data from COSMOS (Q8W, N = 189). Trial populations were re-weighted using propensity scores. Unanchored comparisons of recalculated bimekizumab and guselkumab 48- or 52-week non-responder imputation outcomes for 20/50/70% improvement in American College of Rheumatology score (ACR20/50/70) and minimal disease activity (MDA) index were analyzed., Results: In patients who were bDMARD-naïve, bimekizumab was associated with a greater likelihood of ACR50 (odds ratio [95% confidence interval] 1.62 [1.07, 2.44]; p = 0.021), ACR70 (2.20 [1.43, 3.38]; p < 0.001), and MDA (1.82 [1.20, 2.76]; p = 0.005) compared to guselkumab Q4W at week 52. Bimekizumab also had a greater likelihood of ACR70 response (2.08 [1.34, 3.22]; p = 0.001) and MDA (2.07 [1.35, 3.17]; p < 0.001) compared to guselkumab Q8W at week 52. In patients who were TNFi-IR, bimekizumab had a greater likelihood in achieving all evaluated outcomes compared to guselkumab Q8W at week 48/52 (ACR20, 1.77 [1.15, 2.72]; p = 0.010; ACR50, 1.56 [1.03, 2.36]; p = 0.037; ACR70, 1.66 [1.05, 2.61]; p = 0.028; and MDA, 1.95 [1.27, 3.02]; p = 0.003)., Conclusions: According to MAICs, bimekizumab demonstrated greater or comparable efficacy on ACR50/70 and MDA outcomes than guselkumab in patients with PsA who were bDMARD-naïve and TNFi-IR at week 48/52. Bimekizumab had a more favorable likelihood than guselkumab in achieving more stringent treatment outcomes., Trial Registrations: NCT03895203, NCT03896581, NCT04009499, NCT03158285, NCT03796858., (© 2024. The Author(s).)
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- 2024
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106. Effect of bimekizumab on symptoms and impact of disease in patients with psoriatic arthritis over 3 years: results from BE ACTIVE.
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Mease PJ, Asahina A, Gladman DD, Tanaka Y, Tillett W, Ink B, Assudani D, de la Loge C, Coarse J, Eells J, and Gossec L
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- Humans, Male, Middle Aged, Female, Quality of Life, Fatigue drug therapy, Fatigue etiology, Double-Blind Method, Pain, Treatment Outcome, Arthritis, Psoriatic diagnosis
- Abstract
Objectives: Evaluate effects of long-term bimekizumab treatment on patient-reported outcome (PRO) measures, symptoms and the impact of PsA on patients., Methods: Patients with active PsA were enrolled into BE ACTIVE, a 48-week randomised controlled trial (NCT02969525). After Week 48, patients could enter a 104-week open-label extension (NCT03347110), receiving bimekizumab 160 mg every four weeks. PRO measures assessed included arthritis pain visual analogue scale (VAS), PsA Impact of Disease (PsAID)-9, 36-Item Short Form Survey (SF-36) and HAQ-Disability Index (HAQ-DI). Results were analysed as mean (S.E.M.) changes from baseline (CfB) from Week 0 to the end of the open-label extension (3 years) and as percentage of patients reaching patient-acceptable symptom state (PASS) for global impact (PsAID-9 total score ≤4) and normal function (HAQ-DI total score <0.5). Non-responder imputation was applied to missing binary outcomes., Results: In 206 patients (mean age 49.3 years, 51.0% male), completion rate was high; 161 (78.2%) patients completed Week 152. Bimekizumab treatment was associated with long-term sustained improvements in pain [arthritis pain VAS CfB; Week 48: -29.9 (1.9); Week 152: -32.0 (1.9)] and fatigue [PsAID-9 fatigue CfB; -2.4 (0.2); -2.7 (0.2)]. High percentages of patients achieved acceptable symptom state (PsAID-9 PASS: 75.2%; 65.0%) and normalised function (HAQ-DI <0.5: 49.0%; 46.1%). Improvements in patient global assessment and SF-36 Physical Component Summary were also sustained., Conclusions: Bimekizumab treatment was associated with long-term sustained improvements in pain and fatigue, reducing overall impact of PsA on patients. Physical function and quality of life improved up to 3 years., Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02969525, NCT03347110., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
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- 2023
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107. Adherence to and changes in mental and physiological health during an 8-week yoga intervention: A pilot study.
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Forseth B, Polfuss M, Brondino M, Hunter SD, Lawlor MW, Beatka MJ, Prom MJ, Eells J, and Lyons JA
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- Adult, Exercise, Female, Humans, Male, Pilot Projects, Students, Meditation, Yoga psychology
- Abstract
Background: Participating in yoga may be ideal for college students to increase physical activity and improve mental health., Purpose: To investigate the feasibility and impact of an 8-week yoga intervention within a university setting on mental and physiologic heath., Methods: This 8-week yoga intervention included twelve yoga-naïve adults, (23.8 ± 4.6 years; 71% female). Participants attended two 60-min yoga classes/week in addition to baseline, mid- and post-lab visits., Results: 83% of participants attended ≥75% of yoga classes. Stress and depression symptoms decreased by 11% and 25%, respectively and erythrocyte sedimentation rate (ESR) reduced by 28%. Participants who did not meet physical activity recommendations observed greater improvements in stress, depression symptoms, ESR, and C-reactive protein compared to participants who met recommendations., Conclusion: The majority of participants attended ≥12 of 16 yoga classes. Exploratory analyses provide preliminary support for the impact of yoga on reducing stress, symptoms of depression, and ESR. Participants who were not meeting physical activity guidelines prior to starting the intervention received greater benefits., Competing Interests: Declaration of competing interest Disclosures: Dr. Lawlor is a member of advisory boards for Audentes Therapeutics, Solid Biosciences, and Ichorion Therapeutics, and has received research support from these entities. He is also a consultant for Dynacure and AGADA Biosciences; these relationships did not impact the methodology or results of this study. No other authors have disclosures., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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108. Association between yoga, physiologic and psychologic health: A cross sectional study.
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Forseth B, Polfuss M, Brondino M, Lawlor MW, Beatka MJ, Prom MJ, Eells J, and Lyons JA
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- Cross-Sectional Studies, Depression therapy, Humans, Inflammation, Meditation, Yoga
- Abstract
Purpose: To compare markers of health associated with chronic diseases between yoga and non-yoga participants., Methods: 30 participants were categorized as either: 1) "Yoga" engaging in yoga ≥2 times/week for ≥6 months, or 2) "Non-yoga" not engaging in yoga., Results: Perceived Stress Scale (PSS) and Beck Depression Inventory-II (BDI-II) scores were significantly different between the yoga and non-yoga groups (PSS: 8.0 vs. 17.5, respectively, p < 0.05; BDI-II: 1.0 vs. 5.5, respectively, p < 0.05). No significant differences were evident between groups for inflammatory markers nor Complex V of the mitochondrial electron transport chain. The erythrocyte sedimentation rate values differed between groups based on clinical cutoffs, with yoga participants categorized as normal (11.0 mm) and non-yoga above normal (21.5 mm)., Conclusion: This research supports that yoga participation is associated with lower PSS and BDI-II scores but does not support a relationship with markers of inflammation. Further research is warranted., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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109. Acquired Resilience: An Evolved System of Tissue Protection in Mammals.
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Stone J, Mitrofanis J, Johnstone DM, Falsini B, Bisti S, Adam P, Nuevo AB, George-Weinstein M, Mason R, and Eells J
- Abstract
This review brings together observations on the stress-induced regulation of resilience mechanisms in body tissues. It is argued that the stresses that induce tissue resilience in mammals arise from everyday sources: sunlight, food, lack of food, hypoxia and physical stresses. At low levels, these stresses induce an organised protective response in probably all tissues; and, at some higher level, cause tissue destruction. This pattern of response to stress is well known to toxicologists, who have termed it hormesis. The phenotypes of resilience are diverse and reports of stress-induced resilience are to be found in journals of neuroscience, sports medicine, cancer, healthy ageing, dementia, parkinsonism, ophthalmology and more. This diversity makes the proposing of a general concept of induced resilience a significant task, which this review attempts. We suggest that a system of stress-induced tissue resilience has evolved to enhance the survival of animals. By analogy with acquired immunity, we term this system 'acquired resilience'. Evidence is reviewed that acquired resilience, like acquired immunity, fades with age. This fading is, we suggest, a major component of ageing. Understanding of acquired resilience may, we argue, open pathways for the maintenance of good health in the later decades of human life., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.S. is a director of CSCM Pty Ltd. R.M. has received consultancy fees over the past 3 years from Australian Doctor Eduction. M.G.W. is coinventor on the patent: Compositions and Methods for the Treatment of Lens Fibrotic Disease WO2010065920 A1, licensed by Genisphere, LLC. S.B. holds a nonremunerative relationship with Hortus Novus s.r.l.
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- 2018
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110. Immunomodulation By Subchronic Low Dose 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Experimental Autoimmune Encephalomyelitis in the Absence of Pertussis Toxin.
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Yang EJ, Stokes JV, Kummari E, Eells J, and Kaplan BL
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- Animals, Basic Helix-Loop-Helix Transcription Factors agonists, Basic Helix-Loop-Helix Transcription Factors metabolism, Cells, Cultured, Cytochrome P-450 CYP1A1 genetics, Cytochrome P-450 CYP1A1 metabolism, Dose-Response Relationship, Drug, Encephalomyelitis, Autoimmune, Experimental genetics, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental metabolism, Female, Interferon-gamma immunology, Interleukin-17 immunology, Mice, Inbred C57BL, Myelin-Oligodendrocyte Glycoprotein, Peptide Fragments, Receptors, Aryl Hydrocarbon agonists, Receptors, Aryl Hydrocarbon metabolism, Th1 Cells immunology, Th1 Cells metabolism, Th17 Cells immunology, Th17 Cells metabolism, Time Factors, Encephalomyelitis, Autoimmune, Experimental drug therapy, Immunosuppressive Agents pharmacology, Interferon-gamma metabolism, Interleukin-17 metabolism, Polychlorinated Dibenzodioxins pharmacology, Th1 Cells drug effects, Th17 Cells drug effects
- Abstract
Multiple sclerosis (MS) is an autoimmune neurodegenerative disorder, characterized by demyelination of neurons in the central nervous system. To investigate the pathogenicity of various T cell types in MS, especially IFN-γ- or IL-17-producing CD4(+ )cells (TH1 or TH17 cells, respectively), the mouse model, experimental autoimmune encephalomyelitis (EAE), is commonly used. One method by which EAE is induced is immunization with myelin oligodendrocyte glycoprotein (MOG) peptide (MOG35-55) followed by subsequent injections of pertussis toxin (PTX) as an adjuvant. We have an interest in the mechanisms by which EAE occurs in the absence of PTX because it induces a milder disease state more consistent with autoimmune disease onset and PTX inactivates Gi/o protein-coupled receptors, many of which contribute to immune homeostasis. Another receptor that plays a role in immune homeostasis is the aryl hydrocarbon receptor (AHR). In fact, the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to attenuate EAE pathogenesis by affecting CD4(+ )T and regulatory T (Treg) cells in an AHR-dependent manner. However, many of these studies have been conducted with an acute high dose TCDD. Thus, the goal of this work was to investigate the modulation of MOG-specific immune responses with subchronic low dose TCDD (0.1-1.0 μg/kg/d for 12 days) in EAE without PTX. The results demonstrate that subchronic, low dose exposure of TCDD attenuates the immune responses in EAE development in the absence of PTX, which is due in part to suppression of MOG-specific IL-17A and IFN-γ responses., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
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- 2016
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111. Optical imaging of mitochondrial redox state in rodent model of retinitis pigmentosa.
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Maleki S, Gopalakrishnan S, Ghanian Z, Sepehr R, Schmitt H, Eells J, and Ranji M
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- Analysis of Variance, Animals, Disease Models, Animal, Mitochondria pathology, NAD metabolism, Oxidation-Reduction, Oxidative Stress physiology, Rats, Rats, Sprague-Dawley, Rats, Transgenic, Retinitis Pigmentosa pathology, Image Processing, Computer-Assisted methods, Mitochondria metabolism, Optical Imaging methods, Retinitis Pigmentosa metabolism
- Abstract
Oxidative stress (OS) and mitochondrial dysfunction contribute to photoreceptor cell loss in retinal degenerative disorders. The metabolic state of the retina in a rodent model of retinitis pigmentosa (RP) was investigated using a cryo-fluorescence imaging technique. The mitochondrial metabolic coenzymes nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) are autofluorescent and can be monitored without exogenous labels using optical techniques. The cryo-fluorescence redox imaging technique provides a quantitative assessment of the metabolism. More specifically, the ratio of the fluorescence intensity of these fluorophores (NADH/FAD), the NADH redox ratio (RR), is a marker of the metabolic state of the tissue. The NADH RR and retinal function were examined in an established rodent model of RP, the P23H rat compared to that of nondystrophic Sprague-Dawley (SD) rats. The NADH RR mean values were 1.11 ± 0.03 in the SD normal and 0.841 ± 0.01 in the P23H retina, indicating increased OS in the P23H retina. Electroretinographic data revealed a significant reduction in photoreceptor function in P23H animals compared to SD nozrmal rats. Thus, cryo-fluorescence redox imaging was used as a quantitative marker of OS in eyes from transgenic rats and demonstrated that alterations in the oxidative state of eyes occur during the early stages of RP.
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- 2013
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112. Photobiomodulation protects the retina from light-induced photoreceptor degeneration.
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Albarracin R, Eells J, and Valter K
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- Animals, Calcium-Binding Proteins metabolism, Ciliary Neurotrophic Factor metabolism, Electroretinography, Fibroblast Growth Factor 2 genetics, Fibroblast Growth Factor 2 metabolism, Fluorescent Antibody Technique, Indirect, Glial Fibrillary Acidic Protein genetics, Glial Fibrillary Acidic Protein metabolism, Immunomodulation, Microfilament Proteins metabolism, Radiation Injuries, Experimental etiology, Radiation Injuries, Experimental metabolism, Rats, Rats, Sprague-Dawley, Retina metabolism, Retinal Degeneration etiology, Retinal Degeneration metabolism, Reverse Transcriptase Polymerase Chain Reaction, Stress, Physiological, Infrared Rays, Light adverse effects, Phototherapy, Radiation Injuries, Experimental therapy, Retina radiation effects, Retinal Degeneration therapy
- Abstract
Purpose: In this study, the hypothesis that near-infrared (NIR) light treatment (photobiomodulation) attenuates bright-light damage in the albino rat retina was tested., Methods: Young adult Sprague-Dawley (SD) albino rats were raised in dim (5 lux), cyclic light and then exposed to bright (1000 lux), continuous light for 24 hours. The animals were treated with 670-nm light (9 J/cm(2)) in an LED array before, during, or after exposure to light. The retinas were examined for function, structural changes, cell loss, and markers of stress and inflammation at 1 week and 1 month after exposure to damaging white light., Results: Bright light caused photoreceptor-specific cell death in control retinas. Significant upregulation of stress and neuroprotective factors and the presence of activated microglia were also noted after light-induced damage. Photobiomodulation profoundly attenuated histopathologic alterations in all three treatment groups. NIR treatment also abolished microglial invasion of the retina and significantly reduced the presence of stress and neuroprotectant molecules. Bright-light-induced reductions in photoreceptor function were significantly ameliorated by photobiomodulation in animals treated before and during exposure to damaging light. Photoreceptor function was initially reduced in animals treated after bright-light-induced damage, but recovered by 1 month after exposure., Conclusions: NIR photobiomodulation is protective against bright-light-induced retinal degeneration, even when NIR treatment is applied after exposure to light. This protective effect appears to involve a reduction of cell death and inflammation. Photobiomodulation has the potential to become an important treatment modality for the prevention or treatment of light-induced stress in the retina. More generally, it could be beneficial in the prevention and treatment of retinal conditions involving inflammatory mechanisms.
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- 2011
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113. Gene and noncoding RNA regulation underlying photoreceptor protection: microarray study of dietary antioxidant saffron and photobiomodulation in rat retina.
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Natoli R, Zhu Y, Valter K, Bisti S, Eells J, and Stone J
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- Animals, Cell Death drug effects, Cluster Analysis, Crocus chemistry, Cytoprotection drug effects, Cytoprotection radiation effects, Diet, Gene Expression Profiling, Gene Expression Regulation radiation effects, Immunologic Factors pharmacology, Photoreceptor Cells, Vertebrate drug effects, Photoreceptor Cells, Vertebrate metabolism, Photoreceptor Cells, Vertebrate radiation effects, Rats, Rats, Sprague-Dawley, Reproducibility of Results, Retina drug effects, Retina radiation effects, Reverse Transcriptase Polymerase Chain Reaction, Antioxidants pharmacology, Gene Expression Regulation drug effects, Light, Oligonucleotide Array Sequence Analysis, Photoreceptor Cells, Vertebrate cytology, RNA, Untranslated genetics, Retina metabolism
- Abstract
Purpose: To identify the genes and noncoding RNAs (ncRNAs) involved in the neuroprotective actions of a dietary antioxidant (saffron) and of photobiomodulation (PBM)., Methods: We used a previously published assay of photoreceptor damage, in which albino Sprague Dawley rats raised in dim cyclic illumination (12 h 5 lux, 12 h darkness) were challenged by 24 h exposure to bright (1,000 lux) light. Experimental groups were protected against light damage by pretreatment with dietary saffron (1 mg/kg/day for 21 days) or PBM (9 J/cm(2) at the eye, daily for 5 days). RNA from one eye of four animals in each of the six experimental groups (control, light damage [LD], saffron, PBM, saffronLD, and PBMLD) was hybridized to Affymetrix rat genome ST arrays. Quantitative real-time PCR analysis of 14 selected genes was used to validate the microarray results., Results: LD caused the regulation of 175 entities (genes and ncRNAs) beyond criterion levels (p<0.05 in comparison with controls, fold-change >2). PBM pretreatment reduced the expression of 126 of these 175 LD-regulated entities below criterion; saffron pretreatment reduced the expression of 53 entities (50 in common with PBM). In addition, PBM pretreatment regulated the expression of 67 entities not regulated by LD, while saffron pretreatment regulated 122 entities not regulated by LD (48 in common with PBM). PBM and saffron, given without LD, regulated genes and ncRNAs beyond criterion levels, but in lesser numbers than during their protective action. A high proportion of the entities regulated by LD (>90%) were known genes. By contrast, ncRNAs were prominent among the entities regulated by PBM and saffron in their neuroprotective roles (73% and 62%, respectively)., Conclusions: Given alone, saffron and (more prominently) PBM both regulated significant numbers of genes and ncRNAs. Given before retinal exposure to damaging light, thus while exerting their neuroprotective action, they regulated much larger numbers of entities, among which ncRNAs were prominent. Further, the downregulation of known genes and of ncRNAs was prominent in the protective actions of both neuroprotectants. These comparisons provide an overview of gene expression induced by two neuroprotectants and provide a basis for the more focused study of their mechanisms.
- Published
- 2010
114. Ocular and systemic safety evaluation of calcium formate as a dietary supplement.
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Altaweel MM, Hanzlik RP, Ver Hoeve JN, Eells J, and Zhang B
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- Administration, Oral, Adult, Bone Density Conservation Agents blood, Dietary Supplements, Drug Administration Schedule, Electroretinography, Evoked Potentials, Visual drug effects, Female, Formates blood, Humans, Middle Aged, Osteoporosis drug therapy, Prospective Studies, Vision Tests, Visual Acuity drug effects, Visual Fields drug effects, Bone Density Conservation Agents adverse effects, Color Vision drug effects, Formates adverse effects
- Abstract
Purpose: The objective of this study was to perform a preliminary evaluation of the ocular and systemic safety of calcium formate, a dietary calcium supplement for prevention and management of osteoporosis. Although formate is an endogenous product of metabolism, high concentrations are associated with toxicity during methanol overdose., Methods: In this prospective clinical trial, 12 healthy women ingested calcium formate (1,300 mg) three times a day for 14 days. Study evaluations included physical and ocular examination, extensive laboratory testing, serum calcium and formate levels, Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity, color vision, visual fields, visual evoked potential (VEP), and full-field, pattern, and multifocal electroretinograms (MERG)., Results: The mean baseline serum level of formate was 0.572 +/- 0.06 mM. Peak serum levels and final serum formate did not differ significantly from baseline. The final concentration was 0.582 +/- 0.091 mM. Accumulation of serum formate did not occur. There was also no evidence of toxicity with calcium formate ingestion. All examinations and tests remained normal, including optic nerve and retinal function. Three subjects had mild transient symptoms attributable to any calcium formulation., Conclusions: Calcium formate is highly bioavailable and well-tolerated. Serum formate remained at basal levels and did not accumulate with repeated dosing. Systemic and ocular safety was demonstrated by objective testing. Given its high oral bioavailability, calcium formate may be a good choice for calcium supplementation in the prevention and management of osteoporosis. Further study will be needed to evaluate its long-term safety in a larger group of subjects representing more varied age, health, dietary, and nutritional status.
- Published
- 2009
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115. Near-infrared light via light-emitting diode treatment is therapeutic against rotenone- and 1-methyl-4-phenylpyridinium ion-induced neurotoxicity.
- Author
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Liang HL, Whelan HT, Eells JT, and Wong-Riley MT
- Subjects
- Adenosine Triphosphate metabolism, Analysis of Variance, Animals, Animals, Newborn, Cell Death drug effects, Cell Death radiation effects, Cells, Cultured, Cerebral Cortex cytology, Cyanates toxicity, Dose-Response Relationship, Radiation, Electron Transport Complex IV metabolism, Male, Nitric Oxide metabolism, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species metabolism, Rotenone toxicity, Tyrosine analogs & derivatives, Tyrosine metabolism, 1-Methyl-4-phenylpyridinium toxicity, Infrared Rays therapeutic use, Lasers, Semiconductor therapeutic use, Neurons drug effects, Neurons physiology, Neurons radiation effects, Neurotoxins toxicity, Rotenone analogs & derivatives
- Abstract
Parkinson's disease is a common progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Mitochondrial dysfunction has been strongly implicated in the pathogenesis of Parkinson's disease. Thus, therapeutic approaches that improve mitochondrial function may prove to be beneficial. Previously, we have documented that near-infrared light via light-emitting diode (LED) treatment was therapeutic to neurons functionally inactivated by tetrodotoxin, potassium cyanide (KCN), or methanol intoxication, and LED pretreatment rescued neurons from KCN-induced apoptotic cell death. The current study tested our hypothesis that LED treatment can protect neurons from both rotenone- and MPP(+)-induced neurotoxicity. Primary cultures of postnatal rat striatal and cortical neurons served as models, and the optimal frequency of LED treatment per day was also determined. Results indicated that LED treatments twice a day significantly increased cellular adenosine triphosphate content, decreased the number of neurons undergoing cell death, and significantly reduced the expressions of reactive oxygen species and reactive nitrogen species in rotenone- or MPP(+)-exposed neurons as compared with untreated ones. These results strongly suggest that LED treatment may be therapeutic to neurons damaged by neurotoxins linked to Parkinson's disease by energizing the cells and increasing their viability.
- Published
- 2008
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116. Harnessing the cell's own ability to repair and prevent neurodegenerative disease.
- Author
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Whelan H, Desmet K, Buchmann E, Henry M, Wong-Riley M, Eells J, and Verhoeve J
- Abstract
Near-IR light treatment modifies cellular function, promotes cell survival, and improves outcomes in laboratory and mouse models of Parkinson's disease.
- Published
- 2008
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117. Early postnatal isolation reduces dopamine levels, elevates dopamine turnover and specifically disrupts prepulse inhibition in Nurr1-null heterozygous mice.
- Author
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Eells JB, Misler JA, and Nikodem VM
- Subjects
- Animals, Animals, Newborn, DNA-Binding Proteins physiology, Dopamine genetics, Genetic Predisposition to Disease, Genotype, Mice, Mice, Knockout, Nuclear Receptor Subfamily 4, Group A, Member 2, Restraint, Physical psychology, Transcription Factors physiology, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, Dopamine metabolism, Inhibition, Psychological, Reflex, Startle genetics, Social Isolation psychology, Transcription Factors deficiency, Transcription Factors genetics
- Abstract
Sensorimotor gating is a phenomenon that is linked with dopamine neurotransmission in limbic and cortical areas, and disruption of sensorimotor gating has been consistently demonstrated in schizophrenia patients. The nuclear receptor Nurr1 is essential for development of dopamine neurons and, using Nurr1-null heterozygous mice, has been found to be important for normal dopamine neurotransmission as null heterozygous mice have reduced limbic and cortical dopamine levels and elevated open-field locomotor activity. The current investigation compared sensorimotor gating, as measured by prepulse inhibition of the acoustic startle response, in Nurr1 wild-type and null heterozygous mice. When mice were weaned between 19 and 21 days of age either into isolation or groups of three to five and tested 12 weeks later, prepulse inhibition was elevated in group-raised null heterozygous mice and significantly disrupted in isolated null heterozygous mice as compared with isolation-raised wild-type mice and group-raised null heterozygous mice. Isolation had no effect on prepulse inhibition in wild-type mice. Isolation reduced tissue dopamine levels and elevated dopamine turnover in the nucleus accumbens and striatum in both wild-type and null heterozygous mice. In the prefrontal cortex, isolation reduced dopamine and 3,4-dihydroxyphenylacetic acid levels in null heterozygous as compared with isolation-raised wild-type mice, whereas no differences were observed between group-raised wild-type and null heterozygous mice. Neither the null heterozygous genotype nor isolation had any effect on basal or stress-induced corticosterone levels. These data suggest that the Nurr1 null heterozygous genotype predisposes these mice to isolation-induced disruption of prepulse inhibition that may be related to the interactions between intrinsic deficiencies in dopamine neurotransmission as a result of the null heterozygous genotype and isolation-induced changes in dopamine neurotransmission. Post-weaning isolation of Nurr1 null heterozygous mice provides a model to explore the interactions of genetic predisposition and environment/neurodevelopment on dopamine function that has important relevance to neuropsychiatric disorders.
- Published
- 2006
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118. Photobiomodulation partially rescues visual cortical neurons from cyanide-induced apoptosis.
- Author
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Liang HL, Whelan HT, Eells JT, Meng H, Buchmann E, Lerch-Gaggl A, and Wong-Riley M
- Subjects
- Animals, Apoptosis radiation effects, Blotting, Western methods, Caspase 3, Caspases metabolism, Cell Count methods, Cell Nucleus drug effects, Cell Nucleus radiation effects, Cell Nucleus ultrastructure, Cells, Cultured, DNA, Single-Stranded metabolism, Densitometry methods, Dose-Response Relationship, Drug, Enzyme Inhibitors pharmacology, Immunohistochemistry methods, Light, Microscopy, Electron, Transmission methods, Neurons ultrastructure, Proto-Oncogene Proteins c-bcl-2 metabolism, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species metabolism, bcl-2-Associated X Protein metabolism, Apoptosis drug effects, Cyanides pharmacology, Neurons drug effects, Neurons radiation effects, Phototherapy methods, Visual Cortex cytology
- Abstract
Near-infrared light via light-emitting diode treatment has documented therapeutic effects on neurons functionally inactivated by tetrodotoxin or methanol intoxication. Light-emitting diode pretreatment also reduced potassium cyanide-induced cell death, but the mode of death via the apoptotic or necrotic pathway was unclear. The current study tested our hypothesis that light-emitting diode rescues neurons from apoptotic cell death. Primary neuronal cultures from postnatal rat visual cortex were pretreated with light-emitting diode for 10 min at a total energy density of 30 J/cm2 before exposing to potassium cyanide for 28 h. With 100 or 300 microM potassium cyanide, neurons died mainly via the apoptotic pathway, as confirmed by electron microscopy, Hoechst 33258, single-stranded DNA, Bax, and active caspase-3. In the presence of caspase inhibitor I, the percentage of apoptotic cells in 300microM potassium cyanide was significantly decreased. Light-emitting diode pretreatment reduced apoptosis from 36% to 17.9% (100 microM potassium cyanide) and from 58.9% to 39.6% (300 microM potassium cyanide), representing a 50.3% and 32.8% reduction, respectively. Light-emitting diode pretreatment significantly decreased the expression of caspase-3 elicited by potassium cyanide. It also reversed the potassium cyanide-induced increased expression of Bax and decreased expression of Bcl-2 to control levels. Moreover, light-emitting diode decreased the intensity of 5-(and -6) chloromethy-2', 7-dichlorodihydrofluorescein diacetate acetyl ester, a marker of reactive oxygen species, in neurons exposed to 300 microM potassium cyanide. These results indicate that light-emitting diode pretreatment partially protects neurons against cyanide-induced caspase-mediated apoptosis, most likely by decreasing reactive oxygen species production, down-regulating pro-apoptotic proteins and activating anti-apoptotic proteins, as well as increasing energy metabolism in neurons as reported previously.
- Published
- 2006
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119. Nurr1-null heterozygous mice have reduced mesolimbic and mesocortical dopamine levels and increased stress-induced locomotor activity.
- Author
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Eells JB, Lipska BK, Yeung SK, Misler JA, and Nikodem VM
- Subjects
- Amphetamine pharmacology, Animals, Brain Chemistry genetics, Brain Chemistry physiology, Catecholamines metabolism, Central Nervous System Stimulants pharmacology, DNA-Binding Proteins physiology, Heterozygote, Mice, Mice, Knockout, Nuclear Receptor Subfamily 4, Group A, Member 2, Reverse Transcriptase Polymerase Chain Reaction, Stress, Psychological metabolism, Transcription Factors physiology, Cerebral Cortex metabolism, DNA-Binding Proteins genetics, Dopamine metabolism, Limbic System metabolism, Motor Activity physiology, Stress, Psychological psychology, Transcription Factors genetics
- Abstract
Nurr1, an orphan nuclear receptor, is essential for the differentiation of the midbrain dopamine (DA) neurons; however, its function in adult midbrain DA neurons has not been determined. The present study compared regional brain levels of catecholamines and spontaneous and pharmacologically induced locomotor behaviors between mice heterozygous for the Nurr1-null allele (+/-) and wild type (+/+) littermates. The Nurr1 +/- mice had significantly lower levels of DA in whole brain, midbrain, prefrontal cortex and nucleus accumbens, although no significant differences were observed in the striatum, olfactory bulb or hippocampus. Nurr1 +/- mice displayed significantly greater locomotor activity in a novel open field and after saline injection with no significant difference in activity after treatment with amphetamine (2.5 or 5.0 mg/kg) or MK 801 (0.2 or 0.4 mg/kg). A similar elevation in locomotor activity was observed in Nurr1 +/- mice at 35 days old as was found in 70 days old adults. These data demonstrate that the loss of a single Nurr1 allele results in reduced DA levels in mesolimbic and mesocortical pathways and increased locomotor activity in response to mild stress. The involvement of Nurr1 in DA neurotransmission and the implications for schizophrenia are discussed.
- Published
- 2002
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120. PKC-delta inhibition does not block preconditioning-induced preservation in mitochondrial ATP synthesis and infarct size reduction in rats.
- Author
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Fryer RM, Hsu AK, Wang Y, Henry M, Eells J, and Gross GJ
- Subjects
- Acetophenones pharmacology, Alkaloids, Animals, Benzophenanthridines, Benzopyrans pharmacology, Enzyme Inhibitors pharmacology, Hemodynamics, Immunohistochemistry, Isoenzymes metabolism, Male, Mitochondria, Heart drug effects, Mitochondria, Heart enzymology, Myocardial Infarction enzymology, Phenanthridines pharmacology, Protein Kinase C metabolism, Protein Kinase C-delta, Rats, Rats, Wistar, Adenosine Triphosphate biosynthesis, Ischemic Preconditioning, Myocardial, Isoenzymes antagonists & inhibitors, Mitochondria, Heart metabolism, Myocardial Infarction metabolism, Myocardial Infarction pathology, Protein Kinase C antagonists & inhibitors
- Abstract
We have previously demonstrated that cardioprotection induced by the infusion of a selective delta1-opioid agonist is mediated by the specific translocation of PKC-delta to the mitochondria in in vivo rat hearts and via opening of the mitochondrial KATP channel. Ischemic preconditioning (IPC) is also thought to involve the translocation of specific isoforms of PKC and KATP channel activation. Therefore, we utilized the PKC-delta selective antagonist, rottlerin, to assess the effect of inhibition of this isozyme on cardioprotection induced by one-cycle of IPC prior to 30 minutes of ischemia and 2 hours of reperfusion. Infarct size (IS) was determined by tetrazolium chloride staining and expressed as a percent of the area at risk (AAR). Non-preconditioned control animals had an IS/AAR of 59.7 +/- 1.6. IPC significantly reduced the extent of myocardial infarction (6.3 +/- 1.4). Rottlerin, 0.3 mg/kg, did not alter IS/AAR in control animals (55.0 +/- 5.6), and had no significant effect on IS/AAR in preconditioned animals (14.4 +/- 3.8). Additionally, we demonstrated, using a luciferase-based assay to determine the rate of ATP synthesis and state of mitochondrial bioenergetics, that IPC preserves ATP synthesis in the ischemic myocardium and that this preservation is attenuated by the isoform non-selective PKC inhibitor, chelerythrine, but not by the delta-selective antagonist, rottlerin. These data suggest that PKC-delta does not play an important role in IPC and that differences in isoform importance are evident during pharmacological versus ischemia-induced preconditioning.
- Published
- 2002
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121. In vitro regulated expression of tyrosine hydroxylase in ventral midbrain neurons from Nurr1-null mouse pups.
- Author
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Eells JB, Rives JE, Yeung SK, and Nikodem VM
- Subjects
- Animals, Animals, Newborn, Astrocytes drug effects, Astrocytes metabolism, Cardiotonic Agents pharmacology, Cells, Cultured, Glial Cell Line-Derived Neurotrophic Factor, Mesencephalon drug effects, Mesencephalon metabolism, Mice, Mice, Mutant Strains, Microtubule-Associated Proteins metabolism, Nerve Tissue Proteins pharmacology, Neurons metabolism, Nuclear Receptor Subfamily 4, Group A, Member 2, Transcription Factors genetics, Tyrosine 3-Monooxygenase metabolism, Brain-Derived Neurotrophic Factor pharmacology, Colforsin pharmacology, DNA-Binding Proteins, Dopamine pharmacology, Nerve Growth Factors, Neurons drug effects, Neuroprotective Agents pharmacology, Transcription Factors deficiency, Tyrosine 3-Monooxygenase drug effects
- Abstract
The transcription factor Nurr1, an orphan member of the steroid-thyroid hormone nuclear receptor superfamily, is essential for the proper terminal differentiation of ventral midbrain dopaminergic neurons. Disruption of the Nurr1 gene in mice by homologous recombination abolishes synthesis of dopamine (DA) and expression of DA biosynthetic enzymes, including tyrosine hydroxylase (TH), in the ventral midbrain without affecting the synthesis of DA in other areas of the brain. At birth, however, dopaminergic neuron precursors in Nurr1 null (-/-) pups remain as shown by continued expression of residual, untranslated Nurr1 mRNA not altered by homologous recombination. Since Nurr1 disruption is lethal shortly after birth, to further investigate the developmental properties of these neurons, dissociated ventral midbrain neurons from newborn pups were grown for 5 days on an astrocyte feeder layer, subjected to various treatments and then evaluated for expression of TH by fluorescent immunocytochemistry. Initially, a small percentage of neurons (0.26% +/- 0.07%) from the ventral midbrain of Nurr1 -/- pups were TH-immunoreactive (TH-IR). No change in TH expression was observed in the presence of glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), or DA alone or in combination. Treatment with forskolin (Fsk), however, significantly increased the percentage of TH-IR neurons (1.36% +/- 0.15%). Combination of Fsk, BNDF, and DA further increased the percentage of TH-IR neurons (2.58% +/- 0.50%). Therefore, these data suggest that dopaminergic neuron precursors, which develop in vivo without Nurr1, remain in an undifferentiated condition that is permissive to the induction of TH in vitro. J. Neurosci. Res. 64:322-330, 2001. Published 2001 Wiley-Liss, Inc.
- Published
- 2001
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122. Differential recovery of retinal function after mitochondrial inhibition by methanol intoxication.
- Author
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Seme MT, Summerfelt P, Neitz J, Eells JT, and Henry MM
- Subjects
- Adenosine Diphosphate metabolism, Adenosine Triphosphate metabolism, Animals, Electroretinography, Formates metabolism, Glutathione metabolism, Male, Mitochondria metabolism, Rats, Rats, Long-Evans, Retina drug effects, Retina metabolism, Retina pathology, Methanol toxicity, Mitochondria drug effects, Retina physiology
- Abstract
Purpose: The authors' laboratory has previously documented formate-induced retinal toxicity in a rodent model of methanol intoxication. These studies determined functional, bioenergetic, and structural recovery of the retina after methanol intoxication., Methods: Rats were intoxicated with methanol, and retinal function was assessed by electroretinography 72 hours after the initial dose of methanol and after a 72-hour recovery period. Retinal energy metabolites, glutathione (GSH) concentrations, and histology were determined at the same time points., Results: Both rod-dominated and UV-cone-mediated electroretinogram responses were profoundly attenuated in methanol-intoxicated rats. In rats allowed to recover from methanol intoxication, there was significant, although incomplete, recovery of rod-dominated retinal function. However, there was no demonstrable improvement in UV-cone-mediated responses. Retinal adenosine triphosphate (ATP), adenosine diphosphate (ADP), and GSH concentrations were significantly reduced after intoxication. Although retinal energy metabolites returned to control values after the recovery period, retinal GSH remained significantly depleted. Histopathologic changes were apparent in the photoreceptors after methanol intoxication, with evidence of inner segment swelling and mitochondrial disruption. In animals allowed to recover from methanol intoxication, there was no evidence of histopathology at the light microscopic level; however, ultrastructural studies revealed subtle photoreceptor mitochondrial alterations., Conclusions: These findings support the hypothesis that formate inhibits retinal mitochondrial function and increases oxidative stress. They also provide evidence for a differential sensitivity of photoreceptors to the cytotoxic actions of formic acid, with a partial recovery of rod-dominated responses and no recovery of UV-cone-mediated responses.
- Published
- 2001
123. Increased mitochondrial K(ATP) channel activity during chronic myocardial hypoxia: is cardioprotection mediated by improved bioenergetics?
- Author
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Eells JT, Henry MM, Gross GJ, and Baker JE
- Subjects
- Adaptation, Physiological drug effects, Adenosine Triphosphate metabolism, Animals, Animals, Newborn, Benzopyrans pharmacology, Cell Hypoxia physiology, Chronic Disease, Cytoprotection physiology, Decanoic Acids pharmacology, Dihydropyridines pharmacology, Energy Metabolism drug effects, Energy Metabolism physiology, Glyburide pharmacology, Heart Ventricles metabolism, Hemodynamics drug effects, Hydroxy Acids pharmacology, In Vitro Techniques, Membrane Potentials drug effects, Mitochondria, Heart drug effects, Potassium Channel Blockers, Potassium Channels agonists, Rabbits, Hypoxia metabolism, Mitochondria, Heart metabolism, Myocardial Ischemia metabolism, Myocardium metabolism, Potassium Channels metabolism
- Abstract
Increased resistance to myocardial ischemia in chronically hypoxic immature rabbit hearts is associated with activation of ATP-sensitive K(+) (K(ATP)) channels. We determined whether chronic hypoxia from birth alters the function of the mitochondrial K(ATP) channel. The K(ATP) channel opener bimakalim (1 micromol/L) increased postischemic recovery of left ventricular developed pressure in isolated normoxic (FIO(2)=0.21) hearts to values (42+/-4% to 67+/-5% ) not different from those of hypoxic controls but did not alter postischemic recovery of developed pressure in isolated chronically hypoxic (FIO(2)=0.12) hearts (69+/-5% to 72+/-5%). Conversely, the K(ATP) channel blockers glibenclamide (1 micromol/L) and 5-hydroxydecanoate (5-HD, 300 micromol/L) attenuated the cardioprotective effect of hypoxia but had no effect on postischemic recovery of function in normoxic hearts. ATP synthesis rates in hypoxic heart mitochondria (3.92+/-0.23 micromol ATP. min(-1). mg mitochondrial protein(-1)) were significantly greater than rates in normoxic hearts (2.95+/-0.08 micromol ATP. min(-1). mg mitochondrial protein(-1)). Bimakalim (1 micromol/L) decreased the rate of ATP synthesis in normoxic heart mitochondria consistent with mitochondrial K(ATP) channel activation and mitochondrial depolarization. The effect of bimakalim on ATP synthesis was antagonized by the K(ATP) channel blockers glibenclamide (1 micromol/L) and 5-HD (300 micromol/L) in normoxic heart mitochondria, whereas glibenclamide and 5-HD alone had no effect. In hypoxic heart mitochondria, the rate of ATP synthesis was not affected by bimakalim but was attenuated by glibenclamide and 5-HD. We conclude that mitochondrial K(ATP) channels are activated in chronically hypoxic rabbit hearts and implicate activation of this channel in the improved mitochondrial bioenergetics and cardioprotection observed.
- Published
- 2000
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124. Development and characterization of a rodent model of methanol-induced retinal and optic nerve toxicity.
- Author
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Eells JT, Henry MM, Lewandowski MF, Seme MT, and Murray TG
- Subjects
- Animals, Folic Acid metabolism, Formates metabolism, Humans, Optic Nerve drug effects, Optic Nerve pathology, Rats, Retina drug effects, Retina pathology, Disease Models, Animal, Methanol toxicity, Optic Nerve Diseases chemically induced, Retinal Diseases chemically induced, Solvents toxicity
- Abstract
Methanol is an important public health and environmental concern because of the selective actions of its neurotoxic metabolite, formic acid, on the retina, optic nerve and central nervous system. Humans and non-human primates are uniquely sensitive to methanol-induced neurotoxicity as a consequence of the limited capacity of primate species to oxidize and thus detoxify formic acid. The toxic syndrome in primates is characterized by formic acidemia, metabolic acidosis and blindness or serious visual impairment. Nonprimate species are normally resistant to the accumulation of formate and associated metabolic and visual toxicity. We have characterized retinal and optic nerve toxicity in a nonprimate model of methanol toxicity using rats in which folate-dependent formate oxidation has been selectively inhibited, allowing formate to accumulate to toxic concentrations following methanol administration. Methanol-intoxicated rats developed formic acidemia, metabolic acidosis and visual toxicity analogous to the human methanol poisoning syndrome. Visual dysfunction was manifested as reductions in the electroretinogram and the flash-evoked cortical potential which occurred coincident with blood formate accumulation. Histological studies revealed mitochondrial disruption and vacuolation in the retinal pigment epithelium, photoreceptor inner segments and optic nerve. The temporal relationship between methanol administration and the onset and development of ocular toxicity, as well as, the degree of metabolic acidosis and extent of formic acidemia in this rodent model are remarkably similar to that documented in human methanol intoxication. Moreover, the functional and morphologic findings in methanol-intoxicated rats are consistent with the hypothesis that formate acts as a mitochondrial toxin in the retina and optic nerve. The establishment and characterization of this nonprimate animal model of methanol intoxication will facilitate research into the mechanistic aspects of methanol toxicity and the development and testing of treatments for human methanol poisoning.
- Published
- 2000
125. Ischemic preconditioning in rats: role of mitochondrial K(ATP) channel in preservation of mitochondrial function.
- Author
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Fryer RM, Eells JT, Hsu AK, Henry MM, and Gross GJ
- Subjects
- Adenosine Triphosphate biosynthesis, Adenosine Triphosphate metabolism, Animals, Decanoic Acids pharmacology, Diazoxide pharmacology, Hemodynamics drug effects, Hydroxy Acids pharmacology, Male, Membrane Proteins antagonists & inhibitors, Mitochondria, Heart metabolism, Myocardial Infarction pathology, Myocardium metabolism, Osmolar Concentration, Potassium Channels, Rats, Rats, Wistar, Ischemic Preconditioning, Myocardial, Membrane Proteins physiology, Mitochondria, Heart physiology
- Abstract
We examined the role of the sarcolemmal and mitochondrial K(ATP) channels in a rat model of ischemic preconditioning (IPC). Infarct size was expressed as a percentage of the area at risk (IS/AAR). IPC significantly reduced infarct size (7 +/- 1%) versus control (56 +/- 1%). The sarcolemmal K(ATP) channel-selective antagonist HMR-1098 administered before IPC did not significantly attenuate cardioprotection. However, pretreatment with the mitochondrial K(ATP) channel-selective antagonist 5-hydroxydecanoic acid (5-HD) 5 min before IPC partially abolished cardioprotection (40 +/- 1%). Diazoxide (10 mg/kg iv) also reduced IS/AAR (36.2 +/- 4.8%), but this effect was abolished by 5-HD. As an index of mitochondrial bioenergetic function, the rate of ATP synthesis in the AAR was examined. Untreated animals synthesized ATP at 2.12 +/- 0.30 micromol x min(-1) x mg mitochondrial protein(-1). Rats subjected to ischemia-reperfusion synthesized ATP at 0.67 +/- 0.06 micromol x min(-1) x mg mitochondrial protein(-1). IPC significantly increased ATP synthesis to 1.86 +/- 0.23 micromol x min(-1) x mg mitochondrial protein(-1). However, when 5-HD was administered before IPC, the preservation of ATP synthesis was attenuated (1.18 +/- 0.15 micromol x min(-1) x mg mitochondrial protein(-1)). These data are consistent with the notion that inhibition of mitochondrial K(ATP) channels attenuates IPC by reducing IPC-induced protection of mitochondrial function.
- Published
- 2000
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126. [Folic acid deficiency and increased concentrations of formate in serum and cerebrospinal fluid of patients with epidemic optical neuropathy].
- Author
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Eells JT, González-Quevedo A, Santiesteban Freixas R, McMartin KE, and Sadun AA
- Subjects
- Alcohol Drinking, Female, Humans, Male, Methanol adverse effects, Middle Aged, Optic Nerve Diseases blood, Optic Nerve Diseases cerebrospinal fluid, Optic Nerve Diseases chemically induced, Risk Factors, Solvents adverse effects, Disease Outbreaks, Folic Acid blood, Folic Acid cerebrospinal fluid, Folic Acid Deficiency complications, Formates blood, Formates cerebrospinal fluid, Optic Nerve Diseases epidemiology
- Abstract
We studied 62 patients aged 48 years as an average and diagnosed with bilateral optical neuropathy during an epidemics in Pinar del Río province. Of these patients, 42 showed the optical form whereas 20 had the mixed form of optical neuropathy. We researched into the levels of formate and folate in serum and cerebrospinal fluid samples and we found a marked deficiency of folates in more than 50% of samples and high formate concentration levels in almost 25% of samples. We concluded that nutritional shortages that lead to a reduction of folates, and the intake of small amounts of methanol in alcoholic drinks could lead to lacking energetic states which would facilitate that the optical nerve be affected and the epidemic optical neuropathy appear.
- Published
- 2000
127. Opioid-induced second window of cardioprotection: potential role of mitochondrial KATP channels.
- Author
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Fryer RM, Hsu AK, Eells JT, Nagase H, and Gross GJ
- Subjects
- Analgesics pharmacology, Animals, Benzylidene Compounds pharmacology, Blood Pressure, Coronary Circulation, Glyburide pharmacology, Hypoglycemic Agents pharmacology, Ischemic Preconditioning, Myocardial, Male, Myocardial Infarction drug therapy, Myocardial Infarction physiopathology, Myocardial Ischemia drug therapy, Myocardial Reperfusion Injury drug therapy, Myocardium chemistry, Naltrexone analogs & derivatives, Naltrexone pharmacology, Narcotic Antagonists pharmacology, Quinolines pharmacology, Rats, Rats, Wistar, Mitochondria chemistry, Myocardial Ischemia physiopathology, Myocardial Reperfusion Injury physiopathology, Potassium Channels physiology, Receptors, Opioid, delta physiology
- Abstract
Opioids have been previously shown to confer short-term cardioprotection against a prolonged ischemic insult. Therefore, the present study was designed to determine whether opioids can induce a delayed or "second window" of cardioprotection and to assess the potential involvement of the mitochondrial KATP channel. All rats were subjected to 30 minutes of ischemia and 2 hours of reperfusion (I/R). Control animals, injected with saline 24 hours before I/R, elicited an infarct size/area at risk (IS/AAR) of 62.9+/-3.4. TAN-67, a delta1-opioid receptor agonist, was administered 10 or 30 mg/kg IP 12, 24, 48, or 72 hours before I/R. TAN-67 (10 mg/kg) 12- or 24-hour pretreatment did not significantly reduce IS/AAR (62.1+/-6.3 and 43.3+/-7.3, respectively). Similarly, 12-hour pretreatment with TAN-67 (30 mg/kg) did not reduce IS/AAR (60.0+/-5.6); however, 24-hour pretreatment significantly reduced IS/AAR (34.5+/-5.9). Forty-eight-hour pretreatment with TAN-67 maximally reduced IS/AAR (29.2+/-7.0), and opioid-induced cardioprotection was lost after 72-hour pretreatment (61.7+/-3.8). TAN-67-induced cardioprotection could be abolished by pretreatment with the selective delta1-opioid receptor antagonist 7-benzylidenenaltrexone, BNTX, administered either 30 minutes before TAN-67 given 48 hours before I/R or 10 minutes before I/R in rats previously treated for 48 hours with TAN-67 (59.6+/-3.1 and 58.7+/-3.5, respectively). The involvement of the KATP channel was investigated with 2 inhibitors: glibenclamide, a nonselective KATP channel inhibitor, and 5-hydroxydecanoic acid, selective for the mitochondrial KATP channel in rabbits. Glibenclamide, administered 30 minutes before I/R in 48-hour TAN-67-pretreated rats, completely abolished cardioprotection (60. 4+/-3.2). Similarly, 5-hydroxydecanoic acid, administered 5 minutes before I/R in rats pretreated 48 hours previously with TAN-67, completely abolished cardioprotection (57.8+/-2.5). These results suggest that delta1-opioid receptor stimulation, 24 to 48 hours before an ischemic insult, produces a delayed cardioprotective effect that is possibly the result of mitochondrial KATP channel activation.
- Published
- 1999
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128. Formate-induced inhibition of photoreceptor function in methanol intoxication.
- Author
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Seme MT, Summerfelt P, Henry MM, Neitz J, and Eells JT
- Subjects
- Animals, Electroretinography drug effects, Energy Metabolism drug effects, Formates blood, Light, Male, Methanol metabolism, Mitochondria drug effects, Photoreceptor Cells, Vertebrate radiation effects, Photoreceptor Cells, Vertebrate ultrastructure, Rats, Rats, Long-Evans, Retina drug effects, Retina pathology, Retina ultrastructure, Retinal Cone Photoreceptor Cells drug effects, Retinal Cone Photoreceptor Cells radiation effects, Retinal Cone Photoreceptor Cells ultrastructure, Retinal Rod Photoreceptor Cells drug effects, Retinal Rod Photoreceptor Cells radiation effects, Retinal Rod Photoreceptor Cells ultrastructure, Solvents metabolism, Ultraviolet Rays, Formates metabolism, Methanol toxicity, Photoreceptor Cells, Vertebrate drug effects, Solvents toxicity
- Abstract
Formic acid is the toxic metabolite responsible for the retinal and optic nerve toxicity produced in methanol intoxication. Previous studies in our laboratory have documented formate-induced retinal dysfunction and histopathology in a rodent model of methanol intoxication. The present studies define the time and concentration dependence of formate-induced retinal toxicity in methanol-intoxicated rats. Retinal function was assessed 24, 48, and 72 h after the initial dose of methanol by flicker electroretinographic measurements. Retinal histopathology was assessed at the same time intervals. Rod- and cone-mediated electroretinogram (ERG) responses were attenuated in a formate concentration- and time-dependent manner, and both retinal sensitivity and maximal responsiveness to light were diminished. Attenuation of UV-cone-mediated responses was temporally delayed in comparison to the functional deficits observed in the 15 Hz/510 nm responses, which have a rod-mediated component and occurred at significantly higher formate concentrations. Both 15 Hz/510 nm and UV-cone-mediated ERG responses were undetectable by 72 h; however, if light intensity was increased, a retinal ERG response could be recorded, indicating that photoreceptor function was profoundly attenuated, but not abolished, under these intoxication conditions. Functional changes preceded structural alterations. Histopathological changes were most pronounced in the outer retina with evidence of inner segment swelling, photoreceptor mitochondrial disruption, and the appearance of fragmented photoreceptor nuclei in the outer nuclear layer. The nature of both the functional and structural alterations observed are consistent with formate-induced inhibition of mitochondrial energy production, resulting in photoreceptor dysfunction and pathology.
- Published
- 1999
129. Seizures and proto-oncogene expression of fos in the brain of adult genetically epilepsy-prone rats.
- Author
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Clough RW, Eells JB, Browning RA, and Jobe PC
- Subjects
- Acoustic Stimulation, Animals, Female, Genetic Predisposition to Disease, Immunochemistry, Rats, Rats, Mutant Strains, Rats, Sprague-Dawley, Brain physiopathology, Epilepsy genetics, Gene Expression, Genes, fos
- Abstract
The mechanisms and brain circuitry that render genetically epilepsy-prone rats (GEPRs) susceptible to acoustically induced seizures are not completely known. The present study explores the neuroanatomy of acoustically induced seizures by immunohistochemical analysis of the proto-oncoprotein fos after intense acoustic stimulation (AS) with and without seizures. Acoustic stimulation induced tonic convulsions in GEPR-9s, but not in control rats. Locations of brain nuclei showing fos-like immunoreactive (FLI) neurons following AS with and without seizures were mapped. Semiquantitative methods were used to compare FLI neuron numerical densities in AS control rats and GEPRs. Many brain areas exhibited profound FLI in AS control rats and GEPRs. Unexpectedly, the cochlear nuclei and the central nucleus of the inferior colliculi (ICc), both of which are requisite for AGS initiation, exhibited a diminished fos expression in animals having seizures compared to AS controls. In contrast, GEPRs displayed a significant increase in FLI neurons within the dorsal cortex of the IC (ICd) compared to AS controls. This finding may suggest a seizure-related amplification of the auditory signal between the ICc and the ICd. Other nuclei, known to be involved in auditory transmission (i.e., superior olivary complex; trapezoid nucleus; dorsal nucleus of the lateral lemniscus, DNLL), did not show differential FLI densities between seizure and AS control animals. In contrast, seizure-induced FLI was observed in many nonauditory brain nuclei. Of particular interest was the identification of an intensely labeled nucleus in the GEPR. This nucleus resides in the most posterior and dorsal-lateral part of the pedunculopontine tegmental nucleus-pars compacta (PPTn-pc) immediately adjacent to the DNLL and extends posteriorly into the superior lateral subnucleus of the lateral parabrachial area (SLPBn). Therefore, we have tentatively termed this nucleus the PPSLPBn. The PPSLPBn lies in a region previously described as a mesencephalic locomotor region and a suspected functional involvement of this nucleus in display of seizure activity is under investigation. Other brain stem nuclei showing differential fos expression between GEPRs and AS control rats are also described.
- Published
- 1997
- Full Text
- View/download PDF
130. Fetal raphe transplants reduce seizure severity in serotonin-depleted GEPRs.
- Author
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Clough R, Statnick M, Maring-Smith M, Wang C, Eells J, Browning R, Dailey J, and Jobe P
- Subjects
- 5,7-Dihydroxytryptamine pharmacology, Acoustic Stimulation, Animals, Brain Chemistry drug effects, Brain Chemistry physiology, Epilepsy metabolism, Male, Norepinephrine metabolism, Rats, Rats, Inbred Strains, Serotonin metabolism, Serotonin Agents pharmacology, Brain Tissue Transplantation physiology, Epilepsy genetics, Epilepsy physiopathology, Raphe Nuclei physiology, Serotonin physiology
- Abstract
This study investigated whether transplantation of fetal raphe tissue into genetically epilepsy-prone rats (GEPR-3s) would reduce the severity of seizures previously exacerbated by depletion of brain serotonin. Mild-seizure GEPR-3s were depleted of brain serotonin by 5,7-dihydroxytryptamine (DHT) and evaluated for seizure severity. Rats then received 15-day fetal raphe tissue, fetal neocortical tissue or were sham grafted. GEPR-3s treated with 5,7-DHT showed increased seizure severity following depletion of serotonin and subsequent reductions in severity as a result of fetal raphe transplantation. Sham- or neocortex-grafted rats maintained elevated seizure severity scores throughout the study. Prominent raphe or cortical grafts were observed within the third ventricle of GEPRs at autopsy. These findings show that transplantation of fetal raphe tissue promotes lasting reductions in increased seizure severity resulting from depletion of serotonin in the GEPR brain.
- Published
- 1996
- Full Text
- View/download PDF
131. Formate-induced alterations in retinal function in methanol-intoxicated rats.
- Author
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Eells JT, Salzman MM, Lewandowski MF, and Murray TG
- Subjects
- Animals, Bicarbonates blood, Dose-Response Relationship, Drug, Electrophysiology, Formates metabolism, Formates pharmacokinetics, Male, Methanol metabolism, Rats, Retina pathology, Retina physiology, Tissue Distribution, Formates toxicity, Methanol poisoning, Retina drug effects
- Abstract
Formic acid is the toxic metabolite in methanol poisoning. Permanent visual damage in methanol-intoxicated humans and non-human primates has been associated with prolonged exposures (> 24 hr) to blood formate concentrations in excess of 7 mM; however, little information is available on the toxicity associated with chronic low-level or repeated exposure to methanol. The present studies compared the effects on retinal function and structure of rapidly increasing formate concentrations typical of acute methanol intoxication with low-level plateau formate concentrations more likely to be generated by subacute or chronic methanol exposure. Rats that accumulated formate concentrations of 8-15 mM developed metabolic acidosis, retinal dysfunction, and retinal histopathologic changes. Retinal dysfunction was measured as reductions in the a- and b-waves of the electroretinogram that occurred coincident with blood formate accumulation. Histopathologic studies revealed vacuolation in the retinal pigment epithelium and photoreceptor inner segments. Rats exposed to formate concentrations ranging from 4 to 6 mM for 48 hr showed evidence of retinal dysfunction in the absence of metabolic acidosis and retinal histopathology. These data indicate that formic acid generated from methanol oxidation acts as a direct retinal toxin. Formate-induced retinal dysfunction in methanol-intoxicated rats can be produced by steadily increasing concentrations of formate and importantly can also be produced by prolonged exposure to lower concentrations of formate. Our findings substantiate evidence based on clinical case reports and a small number of epidemiological studies and support the hypothesis that the visual system toxicity produced by acute, subacute, or chronic methanol poisoning share a common mechanism.
- Published
- 1996
- Full Text
- View/download PDF
132. Differences in the neuroexcitatory actions of pyrethroid insecticides and sodium channel-specific neurotoxins in rat and trout brain synaptosomes.
- Author
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Eells JT, Rasmussen JL, Bandettini PA, and Propp JM
- Subjects
- Alkaloids toxicity, Animals, Male, Membrane Potentials drug effects, Rats, Rats, Sprague-Dawley, Scorpion Venoms toxicity, Species Specificity, Synaptosomes physiology, Temperature, Tetrodotoxin toxicity, Trout, Brain drug effects, Neurotoxins toxicity, Pyrethrins toxicity, Sodium Channels drug effects, Synaptosomes drug effects
- Abstract
The effects of pyrethroid insecticides and other sodium channel-specific neurotoxins on synaptosomal membrane potential were investigated in rat and trout brain synaptosomes using the membrane-permeant lipophilic cation [3H]tetraphenylphosphonium (TPP+). Concentration-dependent and tetrodotoxin-sensitive decreases in TPP+ accumulation, indicative of membrane depolarization, were produced by veratridine, aconitine, scorpion (Leiurus quinquestriatus) venom, and type I and type II pyrethroids, in both species. Veratridine, aconitine, and Leiurus venom were more potent and efficacious membrane-depolarizing agents in rat synaptosomes than in trout synaptosomes. Type II (deltamethrin, cypermethrin) pyrethroids produced similar depolarizing responses in rat and trout synaptosomes; however, the 1R-cis-alpha R isomer of deltamethrin, which had no effect on membrane potential in rat synaptosomes, depolarized trout synaptosomes. This isomer of deltamethrin was also shown to produce toxicity in trout, but not in rats. The type I pyrethroids, permethrin and NRDC 157, exhibited significantly greater intrinsic activity in trout brain synaptosomes, producing maximal membrane depolarizations that were three times greater than those observed in rat brain synaptosomes. These results provide evidence of species-specific differences in the membrane-depolarizing properties of pyrethroid insecticides and sodium channel-specific neurotoxins. They also suggest that some of the neurotoxin binding domains of the voltage-sensitive sodium channel in trout brain differ from those in mammalian brain. The hypersensitivity of fish to the neurotoxic actions of pyrethroid insecticides may be related to these differences.
- Published
- 1993
- Full Text
- View/download PDF
133. The dcc mutation affects ciliary length in Tetrahymena thermophila.
- Author
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Gitz DL, Eells JB, and Pennock DG
- Subjects
- Animals, Cell Division, Culture Media pharmacology, Dinitrobenzenes pharmacology, Protozoan Proteins biosynthesis, RNA, Messenger biosynthesis, Temperature, Tetrahymena thermophila drug effects, Tetrahymena thermophila growth & development, Tetrahymena thermophila ultrastructure, Cilia ultrastructure, Mutation, Sulfanilamides, Tetrahymena thermophila genetics
- Abstract
We have characterized ciliogenesis in a mutant Tetrahymena thermophila that both fails to regain motility following deciliation and that fails to complete cytokinesis. Scanning electron microscopic (SEM) observations revealed that starved deciliated cells regenerated fewer, shorter cilia at the restrictive temperature than similarly treated cells incubated at the permissive temperature. Transmission electron microscopic evaluation of isolated, regenerated cilia revealed no structural abnormalities. Incorporation of S-35 methionine was similar during ciliary regeneration at both the restrictive and permissive temperatures, indicating the mutant phenotype was not due to a simple failure in translation or transcription. Mutant cells incubated in growth medium at the restrictive temperature arrested in cytokinesis and assembled a large number of abnormally short cilia. These cells also developed irregular surface projections that were not visible on wild-type cells. These observations suggest that ciliogenesis can be initiated in growing cells as well as in starved deciliated cells but that elongation is inhibited before cilia reach full length. The mutation was named dcc for defective in ciliogenesis and cytokinesis.
- Published
- 1993
- Full Text
- View/download PDF
134. Methanol poisoning. A rodent model with structural and functional evidence for retinal involvement.
- Author
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Murray TG, Burton TC, Rajani C, Lewandowski MF, Burke JM, and Eells JT
- Subjects
- Animals, Disease Models, Animal, Electroretinography drug effects, Formates blood, Male, Optic Nerve drug effects, Photoreceptor Cells drug effects, Photoreceptor Cells ultrastructure, Pigment Epithelium of Eye drug effects, Pigment Epithelium of Eye ultrastructure, Rats, Rats, Inbred Strains, Retina drug effects, Retina ultrastructure, Vision Disorders chemically induced, Methanol poisoning, Retina physiopathology
- Abstract
Methanol ingestion can lead to visual impairment, central nervous system dysfunction, or death. The extent of ocular involvement has been difficult to determine because the toxicity is restricted to humans and nonhuman primates due to species differences in methanol metabolism. A rodent model of methanol toxicity recently developed by us was used to evaluate retinal dysfunction in methanol poisoning. Formic acidemia and visual toxic reactions developed in methanol-intoxicated rats. Electroretinographic analysis indicated a significant early deficit in b-wave amplitude followed by a temporally delayed, lesser reduction in a-wave amplitude. Histologic evaluation of the eyes 60 hours after methanol administration revealed generalized retinal edema and vacuolation in the photoreceptors and retinal pigment epithelium. Ultrastructural examination showed swelling and disruption of the mitochondria in photoreceptor inner segments, optic nerve, and the retinal pigment epithelium. These studies document direct retinal involvement in this nonprimate model of methanol toxicity.
- Published
- 1991
- Full Text
- View/download PDF
135. Effects of N6, O2'-dibutyryl adenosine 3':5'-cyclic monophosphate on the actions of pentobarbital.
- Author
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Isom GE, Eells JT, and Wimer ER
- Subjects
- Animals, Blood Pressure drug effects, Body Temperature drug effects, Lethal Dose 50, Male, Oxygen Consumption drug effects, Pentobarbital toxicity, Postural Balance drug effects, Rats, Reflex drug effects, Sleep drug effects, Time Factors, Bucladesine pharmacology, Pentobarbital antagonists & inhibitors
- Published
- 1976
136. In time of grief.
- Author
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Eells J
- Published
- 1977
- Full Text
- View/download PDF
137. Purine and pyrimidine base and nucleoside concentrations in human cerebrospinal fluid and plasma.
- Author
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Eells JT and Spector R
- Subjects
- Chromatography, High Pressure Liquid, Humans, Purine Nucleosides analysis, Pyrimidine Nucleosides analysis
- Abstract
Purine and pyrimidine base and nucleoside levels were determined in adult human lumbar (CSF) and plasma by reversed-phase high performance liquid chromatography (HPLC). Guanine, thymine, cytosine and uracil were not detectable (less than 0.1 microM) in human CSF or plasma. Adenine was detectable in plasma (0.3 microM) but was not found in CSF (less than 0.2 microM). Hypoxanthine and xanthine levels in CSF were each approximately 2.5 microM. Plasma levels of hypoxanthine and xanthine were considerably lower (0.4-0.6 microM). Purine and pyrimidine ribonucleosides in human CSF were less than or equal to 0.2 microM with the exception of uridine which was present at concentrations of 2-3 microM. Although low concentrations of thymidine and deoxyuridine (0.2 microM) were present in human plasma, purine and pyrimidine deoxyribonucleosides were less than 0.1 microM in human lumbar CSF.
- Published
- 1983
- Full Text
- View/download PDF
138. Effects of intraocular mescaline and LSD on visual-evoked responses in the rat.
- Author
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Eells JT and Wilkison DM
- Subjects
- Administration, Topical, Animals, Atropine administration & dosage, Atropine pharmacology, Cyproheptadine pharmacology, Electrodes, Implanted, Eye, Injections, Lysergic Acid Diethylamide administration & dosage, Mescaline administration & dosage, Methysergide pharmacology, Phenylephrine administration & dosage, Phenylephrine pharmacology, Rats, Rats, Inbred Strains, Evoked Potentials, Visual drug effects, Lysergic Acid Diethylamide pharmacology, Mescaline pharmacology
- Abstract
The effects of mescaline and LSD on the flash-evoked cortical potential (FEP) were determined in unrestrained rats with chronically-implanted electrodes. Systemic administration of mescaline or LSD significantly attenuated the primary component of the FEP at three stimulus intensities with the greatest effect observed 60-90 minutes following drug administration. The magnitude and specificity of the effects of these agents on the primary response suggest that they produce deficits in conduction through the retino-geniculato-cortical system. The serotonin receptor antagonists, cyproheptadine and methysergide, antagonized the mescaline-induced depression of the FEP in accordance with neurochemical and behavioral evidence that mescaline acts as a partial agonist on serotonin receptors. Topical or intraocular administration of atropine antagonized the actions of systemically-administered mescaline. In addition, intraocular administration of mescaline or LSD attenuated the FEP indicative of an action of these hallucinogens on visual processing in the retina which is modulated by muscarinic receptor activity.
- Published
- 1989
- Full Text
- View/download PDF
139. Identification, development, and regional distribution of ribonucleotide reductase in adult rat brain.
- Author
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Eells JT and Spector R
- Subjects
- Aging, Animals, Animals, Newborn, Brain growth & development, Organ Specificity, Rabbits, Rats, Brain enzymology, Ribonucleotide Reductases metabolism
- Abstract
The development and regional distribution of ribonucleotide reductase (EC 1.17.4.1) were determined in rat brain. Ribonucleotide reductase was partially purified by ammonium sulfate fractionation (20-40% saturation). Enzyme activity was measured by a specific radiochemical assay. This method involved the reduction of [14C]cytidine diphosphate (CDP) to [14C]deoxycytidine diphosphate with subsequent hydrolysis and separation of the product ([14C]deoxycytidine) from substrate ([14C]cytidine) by Dowex-1-borate ion-exchange chromatography. The specific activity of ribonucleotide reductase in whole brain of newborn rats was 3.78 +/- 0.55 units (pmol/h)/mg protein (SEM; n = 6) and declined to 0.17 +/- 0.01 units/mg protein (n = 7) at 10-12 weeks of age, with a further decline to 0.11 +/- 0.01 units/mg protein (n = 3) at 1 year. Ribonucleotide reductase activity in rat liver decreased from 4.58 +/- 0.62 units/mg protein (n = 3) in newborn animals to 0.06 +/- 0.01 units/mg protein (n = 7) at 10-12 weeks and was present at trace levels at 6 months of age. The decline in specific activity with age was not due to a change in the Km for CDP. The Km for CDP in brain of newborn and adult rats was 80-90 microM. In 10- to 12-week-old rats, the specific activity of ribonucleotide reductase was similar in the various regions of the brain tested except for the brainstem, which had 50% lower specific activity than the whole brain. These results indicate that ribonucleotide reductase activity is present and widely distributed in adult rat brain.
- Published
- 1983
- Full Text
- View/download PDF
140. The regulation of one-carbon oxidation in the rat by nitrous oxide and methionine.
- Author
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Eells JT, Black KA, Makar AB, Tedford CE, and Tephly TR
- Subjects
- Animals, Carbon Radioisotopes, Folic Acid metabolism, Kinetics, Liver metabolism, Male, Oxidation-Reduction, Rats, Rats, Inbred Strains, Formates metabolism, Methionine pharmacology, Nitrous Oxide pharmacology
- Published
- 1982
- Full Text
- View/download PDF
141. Nucleoside and oxypurine homeostasis in adult rabbit cerebrospinal fluid and plasma.
- Author
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Eells JT, Spector R, and Huntoon S
- Subjects
- Animals, Chromatography, High Pressure Liquid methods, Fasting, Male, Nucleosides blood, Purines blood, Rabbits, Thymidine metabolism, Uridine metabolism, Homeostasis, Nucleosides cerebrospinal fluid, Purines cerebrospinal fluid
- Abstract
In adult New Zealand white rabbits, the effects of food deprivation and of massive elevations of plasma uridine or thymidine concentrations on CSF and plasma nucleoside and oxypurine concentrations were studied. Nucleoside and oxypurine levels were determined by high performance liquid chromatography using unequivocal methods of compound identification. After 48 and 96 h of food deprivation, the concentrations of uridine, cytidine, inosine, thymidine, deoxycytidine, deoxyuridine, hypoxanthine, xanthine, and uric acid in CSF and plasma were not different than in controls, except at 96 h, when the plasma uridine concentration was 35% lower (p less than 0.05). After elevation of the plasma and CSF thymidine concentrations to approximately 200 and 100 microM, respectively, with intravenous thymidine for 5 h, there was a large increase in CSF and plasma thymidine to approximately 100 microM and a smaller increase in plasma and CSF deoxyuridine concentrations. After elevation of the plasma and CSF uridine concentrations to 0.6 and 0.2 mM, respectively, there was a large increase in CSF and plasma uracil and a smaller increase in plasma and CSF deoxyuridine concentrations. Elevated plasma concentration of thymidine and uridine significantly decreased the CSF to plasma ratios of deoxyuridine and thymidine; however, only elevated plasma uridine concentrations decreased the CSF to plasma ratio of uridine. These results document the powerful homeostatic mechanisms that regulate the concentrations of the principal nucleosides and oxypurine bases in CSF.
- Published
- 1984
- Full Text
- View/download PDF
142. Deoxynucleoside and vitamin transport into the central nervous system.
- Author
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Spector R and Eells J
- Subjects
- Animals, Ascorbic Acid metabolism, Brain metabolism, Folic Acid metabolism, Rabbits, Blood-Brain Barrier, Cerebrospinal Fluid physiology, Choroid Plexus metabolism, Deoxyribonucleosides metabolism, Vitamins metabolism
- Abstract
Several essential substances for the mammalian brain including certain vitamins and deoxynucleosides do not enter the brain in appreciable amounts directly through the cerebral capillaries, the blood-brain barrier; rather these substances are transported from blood into cerebrospinal fluid (CSF) by specific, carrier-mediated transport systems in the choroid plexus, the anatomic locus of the blood-CSF barrier. From the CSF, these substances then enter the brain. The evidence supporting the notion that the choroid plexus is important in the transfer of ascorbic acid, folates, and pyrimidine deoxynucleosides from blood into CSF is summarized. This evidence provides strong support for the theory that the CSF is, in fact, a nourishing liquor, although an incomplete one, for developing and adult mammalian brain.
- Published
- 1984
143. Influence of intracerebroventricular injections of N6, O2'-dibutyryl adenosine 3':5'-cyclic monophosphate on sodium pentobarbital-induced narcosis in rats.
- Author
-
Isom GE, McCarthy TA, Eells JT, and Wimer ER
- Subjects
- Animals, Blood Pressure drug effects, Body Temperature drug effects, Bucladesine administration & dosage, Drug Interactions, Injections, Intraventricular, Male, Pentobarbital toxicity, Rats, Time Factors, Bucladesine pharmacology, Pentobarbital pharmacology, Sleep drug effects
- Published
- 1978
- Full Text
- View/download PDF
144. The effects of bleomycin on Ehrlich ascites carcinoma in suspension culture.
- Author
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Eells JT, Farrell LD, and Fontenelle LJ
- Subjects
- Animals, Carcinoma, Ehrlich Tumor metabolism, Cell Division drug effects, Cells, Cultured, Centrifugation, Density Gradient, DNA, Neoplasm biosynthesis, In Vitro Techniques, Mice, Nucleic Acid Denaturation drug effects, Temperature, Time Factors, Bleomycin pharmacology, Carcinoma, Ehrlich Tumor physiopathology
- Published
- 1977
145. Determination of ribonucleosides, deoxyribonucleosides, and purine and pyrimidine bases in adult rabbit cerebrospinal fluid and plasma.
- Author
-
Eells JT and Spector R
- Subjects
- Adenine analysis, Animals, Chromatography, High Pressure Liquid methods, Cytosine analysis, Deoxyribonucleosides blood, Deoxyuridine analysis, Purines blood, Pyrimidines blood, Rabbits, Ribonucleosides blood, Deoxyribonucleosides cerebrospinal fluid, Purines cerebrospinal fluid, Pyrimidines cerebrospinal fluid, Ribonucleosides cerebrospinal fluid
- Abstract
Purine and pyrimidine base and nucleoside levels were measured in adult rabbit cisternal CSF and plasma by reversed-phase high-performance liquid chromatography. The concentrations of bases, nucleosides, and nucleoside phosphates were similar in plasma and CSF except for the adenosine phosphates and uracil which were higher in the plasma. In plasma and CSF, adenosine levels were low (0.12 microM) and guanosine, deoxyadenosine, deoxyguanosine, and deoxyinosine were not detectable (less than 0.1 microM); inosine and xanthine concentrations were 1-2 microM and hypoxanthine concentrations were approximately 5 microM; uridine (approximately 8 microM), cytidine (2-3 microM), and thymidine, deoxyuridine, and deoxycytidine (0.5-1.4 microM) were easily detectable. In both plasma and CSF, guanine, and thymine were undetectable (less than 0.1 microM), adenine and cytosine were less than 0.2 microM, but uracil was present (greater than 1 microM). Adenosine, inosine, and guanosine phosphates were also detectable at low concentrations in CSF and plasma. These results are consistent with the hypothesis that purine deoxyribonucleosides are synthesized in situ in the adult rabbit brain. In contrast, pyrimidine deoxyribonucleosides and ribonucleosides, and purine and pyrimidine bases are available in the CSF for use by the brain.
- Published
- 1983
- Full Text
- View/download PDF
146. Inconsistency of early handling and its effect upon emotionality in the rat.
- Author
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EELLS JF
- Subjects
- Animals, Rats, Behavior
- Published
- 1961
- Full Text
- View/download PDF
147. A VARIATIONAL METHOD IN THE THEORY OF HARMONIC INTEGRALS.
- Author
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Morrey CB and Eells J
- Published
- 1955
- Full Text
- View/download PDF
148. Patients and therapists assess the same psychotherapy.
- Author
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FEIFEL H and EELLS J
- Subjects
- Humans, Health Personnel, Psychotherapy
- Published
- 1963
- Full Text
- View/download PDF
149. ON SUBMANIFOLDS OF CERTAIN FUNCTION SPACES.
- Author
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Eells J
- Published
- 1959
- Full Text
- View/download PDF
150. GEOMETRIC ASPECTS OF CURRENTS AND DISTRIBUTIONS.
- Author
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Eells J
- Published
- 1955
- Full Text
- View/download PDF
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