| 1. |
- Alomaja, Oladunni, et al.
(författare)
-
Alteration in Cerebral Metabolism in a Rodent Model of Acute Sub-lethal Cyanide Poisoning
- 2023
-
Ingår i: Journal of Medical Toxicology. - : Springer Science and Business Media LLC. - 1556-9039 .- 1937-6995. ; 19:2, s. 196-204
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Cyanide exposure can occur in various settings such as industry and metallurgy. The primary mechanism of injury is cellular hypoxia from Complex IV (CIV) inhibition. This leads to decreased ATP production and increased reactive oxygen species production. The brain and the heart are the organs most affected due to their high metabolic demand. While the cardiac effects of cyanide are well known, the cerebral effects on cellular function are less well described. We investigated cerebral metabolism with a combination of brain respirometry, microdialysis, and western blotting using a rodent model of sub-lethal cyanide poisoning. Methods: Twenty rodents were divided into two groups: control (n = 10) and sub-lethal cyanide (n = 10). Cerebral microdialysis was performed during a 2 mg/kg/h cyanide exposure to obtain real-time measurements of cerebral metabolic status. At the end of the exposure (90 min), brain-isolated mitochondria were measured for mitochondrial respiration. Brain tissue ATP concentrations, acyl-Coenzyme A thioesters, and mitochondrial content were also measured. Results: The cyanide group showed significantly increased lactate and decreased hypotension with decreased cerebral CIV-linked mitochondrial respiration. There was also a significant decrease in cerebral ATP concentration in the cyanide group and a significantly higher cerebral lactate-to-pyruvate ratio (LPR). In addition, we also found decreased expression of Complex III and IV protein expression in brain tissue from the cyanide group. Finally, there was no change in acyl-coenzyme A thioesters between the two groups. Conclusions: The key finding demonstrates mitochondrial dysfunction in brain tissue that corresponds with a decrease in mitochondrial function, ATP concentrations, and an elevated LPR indicating brain dysfunction at a sub-lethal dose of cyanide.
|
|
| 2. |
- Douglas, Pamela S, et al.
(författare)
-
Comparison of an Initial Risk-Based Testing Strategy vs Usual Testing in Stable Symptomatic Patients With Suspected Coronary Artery Disease: The PRECISE Randomized Clinical Trial.
- 2023
-
Ingår i: JAMA cardiology. - 2380-6591.
-
Tidskriftsartikel (refereegranskat)abstract
- Trials showing equivalent or better outcomes with initial evaluation using coronary computed tomography angiography (cCTA) compared with stress testing in patients with stable chest pain have informed guidelines but raise questions about overtesting and excess catheterization.To test a modified initial cCTA strategy designed to improve clinical efficiency vs usual testing (UT).This was a pragmatic randomized clinical trial enrolling participants from December 3, 2018, to May 18, 2021, with a median of 11.8 months of follow-up. Patients from 65 North American and European sites with stable symptoms of suspected coronary artery disease (CAD) and no prior testing were randomly assigned 1:1 to precision strategy (PS) or UT.PS incorporated the Prospective Multicenter Imaging Study for the Evaluation of Chest Pain (PROMISE) minimal risk score to quantitatively select minimal-risk participants for deferred testing, assigning all others to cCTA with selective CT-derived fractional flow reserve (FFR-CT). UT included site-selected stress testing or catheterization. Site clinicians determined subsequent care.Outcomes were clinical efficiency (invasive catheterization without obstructive CAD) and safety (death or nonfatal myocardial infarction [MI]) combined into a composite primary end point. Secondary end points included safety components of the primary outcome and medication use.A total of 2103 participants (mean [SD] age, 58.4 [11.5] years; 1056 male [50.2%]) were included in the study, and 422 [20.1%] were classified as minimal risk. The primary end point occurred in 44 of 1057 participants (4.2%) in the PS group and in 118 of 1046 participants (11.3%) in the UT group (hazard ratio [HR], 0.35; 95% CI, 0.25-0.50). Clinical efficiency was higher with PS, with lower rates of catheterization without obstructive disease (27 [2.6%]) vs UT participants (107 [10.2%]; HR, 0.24; 95% CI, 0.16-0.36). The safety composite of death/MI was similar (HR, 1.52; 95% CI, 0.73-3.15). Death occurred in 5 individuals (0.5%) in the PS group vs 7 (0.7%) in the UT group (HR, 0.71; 95% CI, 0.23-2.23), and nonfatal MI occurred in 13 individuals (1.2%) in the PS group vs 5 (0.5%) in the UT group (HR, 2.65; 95% CI, 0.96-7.36). Use of lipid-lowering (450 of 900 [50.0%] vs 365 of 873 [41.8%]) and antiplatelet (321 of 900 [35.7%] vs 237 of 873 [27.1%]) medications at 1 year was higher in the PS group compared with the UT group (both P < .001).An initial diagnostic approach to stable chest pain starting with quantitative risk stratification and deferred testing for minimal-risk patients and cCTA with selective FFR-CT in all others increased clinical efficiency relative to UT at 1 year. Additional randomized clinical trials are needed to verify these findings, including safety.ClinicalTrials.gov Identifier: NCT03702244.
|
|
| 3. |
- Jang, David H., et al.
(författare)
-
Alterations in cerebral and cardiac mitochondrial function in a porcine model of acute carbon monoxide poisoning
- 2021
-
Ingår i: Clinical Toxicology. - : Informa UK Limited. - 1556-3650 .- 1556-9519. ; 59:9, s. 801-809
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: The purpose of this study is the development of a porcine model of carbon monoxide (CO) poisoning to investigate alterations in brain and heart mitochondrial function. Design: Two group large animal model of CO poisoning. Setting: Laboratory. Subjects: Ten swine were divided into two groups: Control (n = 4) and CO (n = 6). Interventions: Administration of a low dose of CO at 200 ppm to the CO group over 90 min followed by 30 min of re-oxygenation at room air. The Control group received room air for 120 min. Measurements: Non-invasive optical monitoring was used to measure cerebral blood flow and oxygenation. Cerebral microdialysis was performed to obtain semi real time measurements of cerebral metabolic status. At the end of the exposure, both fresh brain (cortical and hippocampal tissue) and heart (apical tissue) were immediately harvested to measure mitochondrial respiration and reactive oxygen species (ROS) generation and blood was collected to assess plasma cytokine concentrations. Main results: Animals in the CO group showed significantly decreased Complex IV-linked mitochondrial respiration in hippocampal and apical heart tissue but not cortical tissue. There also was a significant increase in mitochondrial ROS generation across all measured tissue types. The CO group showed a significantly higher cerebral lactate-to-pyruvate ratio. Both IL-8 and TNFα were significantly increased in the CO group compared with the Control group obtained from plasma. While not significant there was a trend to an increase in optically measured cerebral blood flow and hemoglobin concentration in the CO group. Conclusions: Low-dose CO poisoning is associated with early mitochondrial disruption prior to an observable phenotype highlighting the important role of mitochondrial function in the pathology of CO poisoning. This may represent an important intervenable pathway for therapy and intervention.
|
|
| 4. |
- Jang, David H., et al.
(författare)
-
Emerging cellular-based therapies in carbon monoxide poisoning
- 2021
-
Ingår i: American Journal of Physiology - Cell Physiology. - : American Physiological Society. - 0363-6143 .- 1522-1563. ; 321:2, s. 269-275
-
Forskningsöversikt (refereegranskat)abstract
- Carbon monoxide (CO) is an odorless and colorless gas with multiple sources that include engine exhaust, faulty furnaces, and other sources of incomplete combustion of carbon compounds such as house fires. The most serious complications for survivors of consequential CO exposure are persistent neurological sequelae occurring in up to 50% of patients. CO inhibits mitochondrial respiration by specifically binding to the heme a3 in the active site of CIV-like hydrogen sulfide, cyanide, and phosphides. Although hyperbaric oxygen remains the cornerstone for treatment, it has variable efficacy requiring new approaches to treatment. There is a paucity of cellular-based therapies in the area of CO poisoning, and there have been recent advancements that include antioxidants and a mitochondrial substrate prodrug. The succinate prodrugs derived from chemical modification of succinate are endeavored to enhance delivery of succinate to cells, increasing uptake of succinate into the mitochondria, and providing metabolic support for cells. The therapeutic intervention of succinate prodrugs is thus potentially applicable to patients with CO poisoning via metabolic support for fuel oxidation and possibly improving efficacy of HBO therapy.
|
|
| 5. |
- Kao, Shih Han, et al.
(författare)
-
Cell-Free DNA as a Biomarker in a Rodent Model of Chlorpyrifos Poisoning Causing Mitochondrial Dysfunction
- 2023
-
Ingår i: Journal of Medical Toxicology. - 1556-9039. ; 19:4, s. 352-361
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Organophosphates (OPs) are a major public health problem worldwide due to ease of access and high toxicity lacking effective biomarkers and treatment. Cholinergic agents such as OPs and carbamates are responsible for many pesticide-related deaths. While the inhibition of AChE is thought to be the main mechanism of injury, there are other important pathways that contribute to the overall toxicity of OPs such as mitochondrial dysfunction. An existing gap in OP poisoning are biomarkers to gauge severity and prognosis. Cell-free DNA (cfDNA) are novel biomarkers that have gained increased attention as a sensitive biomarker of disease with novel use in acute poisoning. This study investigates alterations in cerebral mitochondrial function in a rodent model of chlorpyrifos poisoning with the use of cfDNA as a potential biomarker. Methods: Twenty rodents were divided into two groups: Control (n = 10) and Chlorpyrifos (n = 10). Chlorpyrifos was administered through the venous femoral line with a Harvard Apparatus 11 Elite Syringe pump (Holliston, MA, USA) at 2 mg/kg. Animals were randomized to receive chlorpyrifos versus the vehicle (10% DMSO) for 60 min which would realistically present an acute exposure with continued absorption. At the end of the exposure (60 min), isolated mitochondria were measured for mitochondrial respiration along with measures of acetylcholinesterase activity, cfDNA, cytokines and western blot. Results: The Chlorpyrifos group showed a significant decrease in heart rate but no change in the blood pressure. There was a significant increase in bulk cfDNA concentrations and overall decrease in mitochondrial respiration from brain tissue obtained from animals in the Chlorpyrifos group when compared to the Control group with no difference in acetylcholinesterase activity. In addition, there was a significant increase in both IL-2 and IL-12 in the Chlorpyrifos group. Conclusions: In our study, we found that the total cfDNA concentration may serve as a more accurate biomarker of OP exposure compared to acetylcholinesterase activity. In addition, there was an overall decrease in cerebral mitochondrial function in the Chlorpyrifos group when compared to the Control group.
|
|
| 6. |
|
|
| 7. |
- Lewis, Alistair T., et al.
(författare)
-
Preliminary Research : Application of Non-Invasive Measure of Cytochrome c Oxidase Redox States and Mitochondrial Function in a Porcine Model of Carbon Monoxide Poisoning
- 2022
-
Ingår i: Journal of Medical Toxicology. - : Springer Science and Business Media LLC. - 1556-9039 .- 1937-6995. ; 18:3, s. 214-222
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Carbon monoxide (CO) is a colorless and odorless gas that is a leading cause of environmental poisoning in the USA with substantial mortality and morbidity. The mechanism of CO poisoning is complex and includes hypoxia, inflammation, and leukocyte sequestration in brain microvessel segments leading to increased reactive oxygen species. Another important pathway is the effects of CO on the mitochondria, specifically at cytochrome c oxidase, also known as Complex IV (CIV). The purpose of this ongoing study is the preliminary development of a porcine model of CO poisoning for investigation of alterations in brain mitochondrial physiology. Methods: Four pigs (10 kg) were divided into two groups: Sham (n = 2) and CO (n = 2). Administration of a dose of CO at 2000 ppm to the CO group over 120 minutes followed by 30 minutes of re-oxygenation at room air. The control group received room air for 150 minutes. Non-invasive optical monitoring was used to measure CIV redox states. Cerebral microdialysis was performed to obtain semi real-time measurements of cerebral metabolic status. At the end of the exposure, fresh brain tissue (cortical and hippocampal) was immediately harvested to measure mitochondrial respiration. Snap frozen cortical tissue was also used for ATP concentrations and western blotting. Results: While a preliminary ongoing study, animals in the CO group showed possible early decreases in brain mitochondrial respiration, citrate synthase density, CIV redox changes measured with optics, and an increase in the lactate-to-pyruvate ratio. Conclusions: There is a possible observable phenotype highlighting the important role of mitochondrial function in the injury of CO poisoning.
|
|
| 8. |
- Mavroudis, Constantine D., et al.
(författare)
-
Investigation of Cerebral Mitochondrial Injury in a Porcine Survivor Model of Carbon Monoxide Poisoning
- 2024
-
Ingår i: Journal of Medical Toxicology. - 1556-9039. ; 20:1, s. 39-48
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Carbon monoxide (CO) is a colorless and odorless gas that is a leading cause of environmental poisoning in the USA with substantial mortality and morbidity. The mechanism of CO poisoning is complex and includes hypoxia, inflammation, and leukocyte sequestration in brain microvessel segments leading to increased reactive oxygen species. Another important pathway is the effects of CO on the mitochondria, specifically at cytochrome c oxidase, also known as Complex IV (CIV). One of the glaring gaps is the lack of rigorous experimental models that may recapitulate survivors of acute CO poisoning in the early phase. The primary objective of this preliminary study is to use our advanced swine platform of acute CO poisoning to develop a clinically relevant survivor model to perform behavioral assessment and MRI imaging that will allow future development of biomarkers and therapeutics. Methods: Four swine (10 kg) were divided into two groups: control (n = 2) and CO (n = 2). The CO group received CO at 2000 ppm for over 120 min followed by 30 min of re-oxygenation at room air for one swine and 150 min followed by 30 min of re-oxygenation for another swine. The two swine in the sham group received room air for 150 min. Cerebral microdialysis was performed to obtain semi real-time measurements of cerebral metabolic status. Following exposures, all surviving animals were observed for a 24-h period with neurobehavioral assessment and imaging. At the end of the 24-h period, fresh brain tissue (cortical and hippocampal) was immediately harvested to measure mitochondrial respiration. Results: While a preliminary ongoing study, animals in the CO group showed alterations in cerebral metabolism and cellular function in the acute exposure phase with possible sustained mitochondrial changes 24 h after the CO exposure ended. Conclusions: This preliminary research further establishes a large animal swine model investigating survivors of CO poisoning to measure translational metrics relevant to clinical medicine that includes a basic neurobehavioral assessment and post exposure cellular measures.
|
|
| 9. |
- Regnéll, Joachim, 1956-, et al.
(författare)
-
Ice-dammed lakes of Scandinavia : A key to the pattern and chronology of the final decay of the Scandinavian ice-sheet
- 2021
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Here we present the use of ice-dammed lake-related landforms and sediments for reconstructing the final phases of decay of the Scandinavian Ice Sheet.In the late stages of the deglaciation, extensive glacial lakes were dammed between the easterly retreating Scandinavian Ice Sheet and the water divide within the mountains to the west. Using high-resolution airborne LiDAR-data, shorelines and other landforms relating to these ice-dammed lakes have now been discovered over larger areas and in greater numbers than previously known, opening a treasure trove of palaeoglaciological information of vast potential for reconstructing the final decay phase of the Scandinavian Ice Sheet.The geomorphological imprint of the ice-dammed lakes is of particular importance in northern Scandinavia, as geological evidence pertaining unequivocally to the final ice sheet decay is sparse. Its interpretation is complicated since the ice sheet is thought to have mainly been cold-based during final decay, inhibiting sliding at the ice-bed interface and limiting the construction (or destruction) of landforms indicative of the changing shape and flow of the ice sheet. Furthermore, dated sediment sequences marking the onset of ice-free conditions are woefully few in northern Scandinavia. Likewise, available cosmogenic nuclide exposure dates provide high age uncertainty and inadequate geographical cover, leaving the timing and location of final ice sheet decay still elusive.Using examples from northern and central Scandinavia, we show that ice-dammed lakes are an intricate part of the deglacial dynamics and show how mapping and dating them offer a solution to these problems. Even with a frozen ice-bed interface, surface melting and meltwater drainage creates landforms unequivocally associated with ice sheet decay: drainage channels, dammed lake shorelines, and deltas. Meltwater drainage routes and ice-dammed lakes are therefore powerful tools for reconstructing a disintegrating ice sheet; a ponded lake reveals the location of its requisite ice-dam, and drainage pathways reveal ice-free conditions. A dated sequence of ice-dammed lake sediments can therefore constrain both ice and lake coverage at that time for a much larger area than the dated site itself. Furthermore, the extent of different ice-dammed lake stages and their requisite ice-damming positions enables the pattern of ice margin change to be traced, and the relative age of ice-marginal positions determined using cross-cutting relations. The shorelines’ present-day tilts are also used to inform patterns and magnitudes of postglacial isostatic uplift, information otherwise lacking from the continental interior but of particular importance for modelling former ice sheet volumes and understanding the crustal response to ice sheet loading. Reconstructing the extents and timing of ice-dammed lakes and the study of related landforms and deposits can therefore greatly improve our understanding of the final decay of the Scandinavian Ice Sheet and provide potential analogues for the predicted future behaviours of modern ice sheets.
|
|
| 10. |
- Regnéll, Joachim, et al.
(författare)
-
Ice-dammed lakes of Scandinavia : A key to the pattern and chronology of the final decay of the Scandinavian ice-sheet
- 2021
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Here we present the use of ice-dammed lake-related landforms and sediments for reconstructing the final phases of decay of the Scandinavian Ice Sheet. In the late stages of the deglaciation, extensive glacial lakes were dammed between the easterly retreating Scandinavian Ice Sheet and the water divide within the mountains to the west. Using high-resolution airborne LiDAR-data, shorelines and other landforms relating to these ice-dammed lakes have now been discovered over larger areas and in greater numbers than previously known, opening a treasure trove of palaeoglaciological information of vast potential for reconstructing the final decay phase of the Scandinavian Ice Sheet. The geomorphological imprint of the ice-dammed lakes is of particular importance in northern Scandinavia, as geological evidence pertaining unequivocally to the final ice sheet decay is sparse. Its interpretation is complicated since the ice sheet is thought to have mainly been cold-based during final decay, inhibiting sliding at the ice-bed interface and limiting the construction (or destruction) of landforms indicative of the changing shape and flow of the ice sheet. Furthermore, dated sediment sequences marking the onset of ice-free conditions are woefully few in northern Scandinavia. Likewise, available cosmogenic nuclide exposure dates provide high age uncertainty and inadequate geographical cover, leaving the timing and location of final ice sheet decay still elusive. Using examples from northern and central Scandinavia, we show that ice-dammed lakes are an intricate part of the deglacial dynamics and show how mapping and dating them offer a solution to these problems. Even with a frozen ice-bed interface, surface melting and meltwater drainage creates landforms unequivocally associated with ice sheet decay: drainage channels, dammed lake shorelines, and deltas. Meltwater drainage routes and ice-dammed lakes are therefore powerful tools for reconstructing a disintegrating ice sheet; a ponded lake reveals the location of its requisite ice-dam, and drainage pathways reveal ice-free conditions. A dated sequence of ice-dammed lake sediments can therefore constrain both ice and lake coverage at that time for a much larger area than the dated site itself. Furthermore, the extent of different ice-dammed lake stages and their requisite ice-damming positions enables the pattern of ice margin change to be traced, and the relative age of ice-marginal positions determined using cross-cutting relations. The shorelines’ present-day tilts are also used to inform patterns and magnitudes of postglacial isostatic uplift, information otherwise lacking from the continental interior but of particular importance for modelling former ice sheet volumes and understanding the crustal response to ice sheet loading. Reconstructing the extents and timing of ice-dammed lakes and the study of related landforms and deposits can therefore greatly improve our understanding of the final decay of the Scandinavian Ice Sheet and provide potential analogues for the predictedfuture behaviours of modern ice sheets.
|
|
