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| 2. |
- Vos, Theo, et al.
(författare)
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Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013
- 2015
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Ingår i: The Lancet. - 1474-547X .- 0140-6736. ; 386:9995, s. 743-800
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Tidskriftsartikel (refereegranskat)abstract
- Background Up-to-date evidence about levels and trends in disease and injury incidence, prevalence, and years lived with disability (YLDs) is an essential input into global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013), we estimated these quantities for acute and chronic diseases and injuries for 188 countries between 1990 and 2013. Methods Estimates were calculated for disease and injury incidence, prevalence, and YLDs using GBD 2010 methods with some important refinements. Results for incidence of acute disorders and prevalence of chronic disorders are new additions to the analysis. Key improvements include expansion to the cause and sequelae list, updated systematic reviews, use of detailed injury codes, improvements to the Bayesian meta-regression method (DisMod-MR), and use of severity splits for various causes. An index of data representativeness, showing data availability, was calculated for each cause and impairment during three periods globally and at the country level for 2013. In total, 35 620 distinct sources of data were used and documented to calculated estimates for 301 diseases and injuries and 2337 sequelae. The comorbidity simulation provides estimates for the number of sequelae, concurrently, by individuals by country, year, age, and sex. Disability weights were updated with the addition of new population-based survey data from four countries. Findings Disease and injury were highly prevalent; only a small fraction of individuals had no sequelae. Comorbidity rose substantially with age and in absolute terms from 1990 to 2013. Incidence of acute sequelae were predominantly infectious diseases and short-term injuries, with over 2 billion cases of upper respiratory infections and diarrhoeal disease episodes in 2013, with the notable exception of tooth pain due to permanent caries with more than 200 million incident cases in 2013. Conversely, leading chronic sequelae were largely attributable to non-communicable diseases, with prevalence estimates for asymptomatic permanent caries and tension-type headache of 2.4 billion and 1.6 billion, respectively. The distribution of the number of sequelae in populations varied widely across regions, with an expected relation between age and disease prevalence. YLDs for both sexes increased from 537.6 million in 1990 to 764.8 million in 2013 due to population growth and ageing, whereas the age-standardised rate decreased little from 114.87 per 1000 people to 110.31 per 1000 people between 1990 and 2013. Leading causes of YLDs included low back pain and major depressive disorder among the top ten causes of YLDs in every country. YLD rates per person, by major cause groups, indicated the main drivers of increases were due to musculoskeletal, mental, and substance use disorders, neurological disorders, and chronic respiratory diseases; however HIV/AIDS was a notable driver of increasing YLDs in sub-Saharan Africa. Also, the proportion of disability-adjusted life years due to YLDs increased globally from 21.1% in 1990 to 31.2% in 2013. Interpretation Ageing of the world's population is leading to a substantial increase in the numbers of individuals with sequelae of diseases and injuries. Rates of YLDs are declining much more slowly than mortality rates. The non-fatal dimensions of disease and injury will require more and more attention from health systems. The transition to non-fatal outcomes as the dominant source of burden of disease is occurring rapidly outside of sub-Saharan Africa. Our results can guide future health initiatives through examination of epidemiological trends and a better understanding of variation across countries.
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| 3. |
- Alomaja, Oladunni, et al.
(författare)
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Alteration in Cerebral Metabolism in a Rodent Model of Acute Sub-lethal Cyanide Poisoning
- 2023
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Ingår i: Journal of Medical Toxicology. - : Springer Science and Business Media LLC. - 1556-9039 .- 1937-6995. ; 19:2, s. 196-204
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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.
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| 4. |
- Ehinger, Johannes K., et al.
(författare)
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Cell-permeable succinate prodrugs bypass mitochondrial complex i deficiency
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial complex I (CI) deficiency is the most prevalent defect in the respiratory chain in paediatric mitochondrial disease. This heterogeneous group of diseases includes serious or fatal neurological presentations such as Leigh syndrome and there are very limited evidence-based treatment options available. Here we describe that cell membrane-permeable prodrugs of the complex II substrate succinate increase ATP-linked mitochondrial respiration in CI-deficient human blood cells, fibroblasts and heart fibres. Lactate accumulation in platelets due to rotenone-induced CI inhibition is reversed and rotenone-induced increase in lactate:pyruvate ratio in white blood cells is alleviated. Metabolomic analyses demonstrate delivery and metabolism of [ 13 C]succinate. In Leigh syndrome patient fibroblasts, with a recessive NDUFS2 mutation, respiration and spare respiratory capacity are increased by prodrug administration. We conclude that prodrug-delivered succinate bypasses CI and supports electron transport, membrane potential and ATP production. This strategy offers a potential future therapy for metabolic decompensation due to mitochondrial CI dysfunction.
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| 5. |
- Elihn, Karine, et al.
(författare)
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Air quality impacts of a large waste fire in Stockholm, Sweden
- 2023
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Ingår i: Atmospheric Environment. - : Elsevier BV. - 1352-2310 .- 1873-2844. ; 315
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Tidskriftsartikel (refereegranskat)abstract
- Fires in waste facilities are a common occurrence. Since many waste facilities are located adjacent to densely populated areas, these fires could potentially expose large populations to the emitted pollutants. However, at the moment there are only few field studies investigating the impact of waste fire emissions on air quality since the unpredictable nature of these events makes them challenging to capture. This study investigated the impact of a large and persistent un-prescribed fire in a waste storage facility in Stockholm county, Sweden, on the local air quality of two residential areas in close proximity to the fire. In-situ measurements of particulate matter, black carbon and nitrogen oxide concentrations were conducted both during open burning and after the fire was fully covered. In addition, filter samples were collected for offline analysis of organic composition, metal content and toxicity. Strongly increased concentrations of PM10, PM2.5 and black carbon were found during the open burning period, especially when the wind was coming from the direction of the fire. In addition, elevated concentrations of particulate heavy metals and polycyclic aromatic hydrocarbons were observed in the air during the open burning period. These results show that waste fires can have a strong impact on the air quality of nearby residential areas.
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| 6. |
- Gnaiger, Erich, et al.
(författare)
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Mitochondrial respiratory states and rates
- 2019
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Ingår i: MitoFit Preprint Arch.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- As the knowledge base and importance of mitochondrial physiology to human health expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow guidelines of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of databases of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery.
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| 7. |
- Jang, David H., et al.
(författare)
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Alterations in cerebral and cardiac mitochondrial function in a porcine model of acute carbon monoxide poisoning
- 2021
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Ingår i: Clinical Toxicology. - : Informa UK Limited. - 1556-3650 .- 1556-9519. ; 59:9, s. 801-809
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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.
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| 8. |
- Jang, David H., et al.
(författare)
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Emerging cellular-based therapies in carbon monoxide poisoning
- 2021
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Ingår i: American Journal of Physiology - Cell Physiology. - : American Physiological Society. - 0363-6143 .- 1522-1563. ; 321:2, s. 269-275
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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.
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| 9. |
- Janowska, Joanna I., et al.
(författare)
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Mitochondrial respiratory chain complex I dysfunction induced by N-methyl carbamate ex vivo can be alleviated with a cell-permeable succinate prodrug
- 2020
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Ingår i: Toxicology in Vitro. - : Elsevier BV. - 0887-2333. ; 65
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Tidskriftsartikel (refereegranskat)abstract
- Human exposure to carbamates and organophosphates poses a serious threat to society and current pharmacological treatment is solely targeting the compounds' inhibitory effect on acetylcholinesterase. This toxicological pathway, responsible for acute symptom presentation, can be counteracted with currently available therapies such as atropine and oximes. However, there is still significant long-term morbidity and mortality. We propose mitochondrial dysfunction as an additional cellular mechanism of carbamate toxicity and suggest pharmacological targeting of mitochondria to overcome acute metabolic decompensation. Here, we investigated the effects on mitochondrial respiratory function of N-succinimidyl N-methylcarbamate (NSNM), a surrogate for carbamate insecticides, ex vivo in human platelets. Characterization of the mitochondrial toxicity of NSNM in platelets revealed a dose-dependent decrease in mitochondral oxygen consumption linked to respiratory chain complex I while the pathway through complex II was unaffected. In intact platelets, an increase in lactate production was seen, due to a compensatory shift towards anaerobic metabolism. Treatment with a cell-permeable succinate prodrug restored the NSNM-induced (100 μM) decrease in mitochondrial oxygen consumption and normalized lactate production to the level of control. We have demonstrated that carbamate-induced mitochondrial complex I dysfunction can be alleviated with a mitochondrial targeted countermeasure: a cell-permeable prodrug of the mitochondrial complex II substrate succinate.
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| 10. |
- Kao, Shih Han, et al.
(författare)
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Cell-Free DNA as a Biomarker in a Rodent Model of Chlorpyrifos Poisoning Causing Mitochondrial Dysfunction
- 2023
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Ingår i: Journal of Medical Toxicology. - 1556-9039. ; 19:4, s. 352-361
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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.
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