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- Oldgren, Jonas, et al.
(författare)
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Variations in Cause and Management of Atrial Fibrillation in a Prospective Registry of 15 400 Emergency Department Patients in 46 Countries The RE-LY Atrial Fibrillation Registry
- 2014
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 129:15, s. 1568-1576
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Tidskriftsartikel (refereegranskat)abstract
- Background Atrial fibrillation (AF) is the most common sustained arrhythmia; however, little is known about patients in a primary care setting from high-, middle-, and low-income countries. Methods and Results This prospective registry enrolled patients presenting to an emergency department with AF at 164 sites in 46 countries representing all inhabited continents. Patient characteristics were compared among 9 major geographic regions. Between September 2008 and April 2011, 15 400 patients were enrolled. The average age was 65.9, standard deviation 14.8 years, ranging from 57.2, standard deviation 18.8 years in Africa, to 70.1, standard deviation 13.4 years in North America, P<0.001. Hypertension was globally the most common risk factor for AF, ranging in prevalence from 41.6% in India to 80.7% in Eastern Europe, P<0.001. Rheumatic heart disease was present in only 2.2% of North American patients, in comparison with 21.5% in Africa and 31.5% in India, P<0.001. The use of oral anticoagulation among patients with a CHADS(2) score of 2 was greatest in North America (65.7%) but was only 11.2% in China, P<0.001. The mean time in the therapeutic range was 62.4% in Western Europe, 50.9% in North America, but only between 32% and 40% in India, China, Southeast Asia, and Africa, P<0.001. Conclusions There is a large global variation in age, risk factors, concomitant diseases, and treatment of AF among regions. Improving outcomes globally requires an understanding of this variation and the conduct of research focused on AF associated with different underlying conditions and treatment of AF and predisposing conditions in different socioeconomic settings.
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| 4. |
- Sakurai, Eiko, et al.
(författare)
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Evidence for the presence of histamine uptake into the synaptosomes of rat brain
- 2006
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Ingår i: Pharmacology. - : S. Karger AG. - 0031-7012 .- 1423-0313. ; 78:2, s. 72-80
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Tidskriftsartikel (refereegranskat)abstract
- Histamine has many physiological roles in the brain and periphery. Neuronal histamine is metabolized almost exclusively by histamine N-methyltransferase. Although several neurotransmitter systems such as dopamine and 5-hydroxytryptamine have their specific reuptake system in their neurons and glial cells, a specific histamine reuptake system into the corresponding nerve terminals or glial cells has not yet been clearly elucidated. We characterized the uptake of histamine into the P2 fractions of rat brain homogenized in 0.32 mol/l sucrose using in vitro uptake techniques. [3H]histamine uptake increased with the increment of added protein amount and elapsed time. [3H]histamine uptake was also temperature-dependent. The uptake of [3H]histamine into the P2 fractions occurs by two saturable processes, a high-affinity and a low-affinity, characterized by K(m) values of 0.16 and 1.2 micromol/l, respectively. Na(+), Cl(-) and HCO(3)(-) ions were essential for the uptake of histamine in P2 fractions. [3H]histamine uptake was inhibited in the presence of several tricyclic antidepressants. In accordance with this, the endogenous release of histamine from brain slices evoked by 100 mmol/l K(+) was augmented in the presence of 20 micromol/l imipramine. These results further support the existence of a specific histamine uptake system in the brain, although the precise molecular entities have not been identified until now.
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| 5. |
- Tokuda, Eiichi, et al.
(författare)
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Dysregulation of intracellular copper homeostasis is common to transgenic mice expressing human mutant superoxide dismutase-1s regardless of their copper-binding abilities
- 2013
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 54, s. 308-319
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Tidskriftsartikel (refereegranskat)abstract
- Over 170 mutations in superoxide dismutase-1 (SOD1) have been linked to amyotrophic lateral sclerosis (ALS). The properties of SOD1 mutants differ considerably including copper-binding abilities. Nevertheless, they cause the same disease phenotype, suggesting a common neurotoxic pathway. We have previously reported that copper homeostasis is disturbed in spinal cords of SOD1(G93A) mice. However, it is unknown whether copper dyshomeostasis is induced by other SOD1 mutants. Using the additional mouse strains SOD1(G127insTGGG), SOD1(G85R), and SOD1(D90A), which express SOD1 mutants with different copper-binding abilities, we show that copper dyshomeostasis is common to SOD1 mutants. The SOD1 mutants shifted the copper trafficking systems toward copper accumulation in spinal cords of the mice. Copper contents bound to the SOD1 active site varied considerably between SOD1 mutants. Still, copper bound to other ligands in the spinal cord were markedly increased in all. Zinc was also increased, whereas there were no changes in magnesium, calcium, aluminum, manganese and iron. Further support for a role of copper dyshomeostasis in ALS was gained from results of pharmacological intervention. Ammonium tetrathiomolybdate (TTM), a copper chelating agent, prolonged survival and slowed the disease progression of SOD1(G93A) mice, even when the treatment was started after the disease onset. TTM markedly attenuated pathology, including the loss of motor neurons and axons, and atrophy of skeletal muscles. Additionally, TTM decreased amounts of SOD1 aggregates. We propose that pharmacological agents that are capable of modulating copper dyshomeostasis, such as TTM, might be beneficial for the treatment of ALS caused by SOD1 mutations.
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| 6. |
- Tokuda, Eiichi, et al.
(författare)
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Regulation of Intracellular Copper by Induction of Endogenous Metallothioneins Improves the Disease Course in a Mouse Model of Amyotrophic Lateral Sclerosis
- 2015
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Ingår i: Neurotherapeutics. - : Springer Science and Business Media LLC. - 1933-7213 .- 1878-7479. ; 12:2, s. 461-476
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), an incurable motor neuron disease. The pathogenesis of the disease is poorly understood, but intracellular copper dyshomeostasis has been implicated as a key process in the disease. We recently observed that metallothioneins (MTs) are an excellent target for the modification of copper dyshomeostasis in a mouse model of ALS (SOD1(G93A)). Here, we offer a therapeutic strategy designed to increase the level of endogenous MTs. The upregulation of endogenous MTs by dexamethasone, a synthetic glucocorticoid, significantly improved the disease course and rescued motor neurons in SOD1(G93A) mice, even if the induction was initiated when peak body weight had decreased by 10 %. Neuroprotection was associated with the normalization of copper dyshomeostasis, as well as with decreased levels of SOD1(G93A) aggregates. Importantly, these benefits were clearly mediated in a MT-dependent manner, as dexamethasone did not provide any protection when endogenous MTs were abolished from SOD1(G93A) mice. In conclusion, the upregulation of endogenous MTs represents a promising strategy for the treatment of ALS linked to mutant SOD1.
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