19 research outputs found
Tonic endocannabinoid-mediated modulation of GABA release is independent of the CB1 content of axon terminals
Fast- or Slow-inactivated State Preference of Na+ Channel Inhibitors: A Simulation and Experimental Study
Sodium channels are one of the most intensively studied drug targets. Sodium channel inhibitors (e.g., local anesthetics, anticonvulsants, antiarrhythmics and analgesics) exert their effect by stabilizing an inactivated conformation of the channels. Besides the fast-inactivated conformation, sodium channels have several distinct slow-inactivated conformational states. Stabilization of a slow-inactivated state has been proposed to be advantageous for certain therapeutic applications. Special voltage protocols are used to evoke slow inactivation of sodium channels. It is assumed that efficacy of a drug in these protocols indicates slow-inactivated state preference. We tested this assumption in simulations using four prototypical drug inhibitory mechanisms (fast or slow-inactivated state preference, with either fast or slow binding kinetics) and a kinetic model for sodium channels. Unexpectedly, we found that efficacy in these protocols (e.g., a shift of the “steady-state slow inactivation curve”), was not a reliable indicator of slow-inactivated state preference. Slowly associating fast-inactivated state-preferring drugs were indistinguishable from slow-inactivated state-preferring drugs. On the other hand, fast- and slow-inactivated state-preferring drugs tended to preferentially affect onset and recovery, respectively. The robustness of these observations was verified: i) by performing a Monte Carlo study on the effects of randomly modifying model parameters, ii) by testing the same drugs in a fundamentally different model and iii) by an analysis of the effect of systematically changing drug-specific parameters. In patch clamp electrophysiology experiments we tested five sodium channel inhibitor drugs on native sodium channels of cultured hippocampal neurons. For lidocaine, phenytoin and carbamazepine our data indicate a preference for the fast-inactivated state, while the results for fluoxetine and desipramine are inconclusive. We suggest that conclusions based on voltage protocols that are used to detect slow-inactivated state preference are unreliable and should be re-evaluated
Effectiveness and safety of anti-ischemic trimetazidine in patients with stable angina pectoris and Type 2 diabetes
Infarct density distribution by MRI in the porcine model of acute and chronic myocardial infarction as a potential method transferable to the clinic
Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas
Age-independent myocardial infarct quantification by signal intensity percent infarct mapping in swine
Cardiovascular Aspects of Radiolog
РЕФЕРЕНТНЫЕ ЗНАЧЕНИЯ СКОРОСТИ РАСПРОСТРАНЕНИЯ ПУЛЬСОВОЙ ВОЛНЫ ПО АОРТЕ У ЗДОРОВЫХ ДЕТЕЙ В ВОЗРАСТЕ ОТ 3 ДО 18 ЛЕТ
Objective: The measurement of aortic pulse wave velocity (PWVao) is an accepted marker in stratifying individual cardiovascular risk in adults. There is an increasing volume of evidence concerning impaired vascular function in different diseases in paediatric populations, but, unfortunately, only a few studies are available on the measurement of normal PWVao values in children. The aim of our study was to determine the reference values of PWVao in a large healthy population using a newly developed technique. Methods: Three thousand, three hundred and seventyfour healthy individuals (1802 boys) aged 3–18 years were examined by an invasively validated, occlusive, oscillometric device. Results: The mean PWVao values increased from 5.5_0.3 to 6.5_0.3 m/s (P<0.05) in boys and from 5.6_0.3 to 6.4_0.3 m/s (P<0.05) in girls. The increase, however, was not constant, and the values exhibited a flat period between the ages of 3 and 8 years in both sexes. The first pronounced increase occurred at the age of 12.1 years in boys and 10.4 years in girls. Moreover, between the ages of 3 and 8 years, the brachial SBP and mean blood pressures increased continuously and gradually, whereas the PWVao remained unchanged. By contrast, beyond the age of 9 years, blood pressure and aortic stiffness trends basically moved together. Conclusion: Our study provides the largest database to date concerning arterial stiffness in healthy children and adolescents between the ages of 3 and 18 years, and the technology adopted proved easy to use in large paediatric populations, even at a very young age. Цель. Измерение скорости распространения пульсовой волны (СРПВ) по аорте является маркером стратификации риска развития сердечно-сосудистых заболеваний у взрослых. Доказано, что у детей с различными заболеваниями отмечается ухудшение сосудистой функции, но, к сожалению, только в нескольких исследованиях определены нормальные значения скорости распространения пульсовой волны у детей. Цель нашего исследования ― определить референтные значения СРПВ у здоровых детей, используя новейшие технологии. Пациенты и методы. С помощью неинвазивного окклюзионного осциллометрического аппарата обследовано 3374 здоровых ребенка (из них 1802 мальчики) в возрасте от 3 до 18 лет. Результаты. Средние значения СРПВ увеличиваются от 5,5±0,3 до 6,5±03 м/с (р<0,05) у мальчиков и с 5,6±0,3 до 6,4±03 м/с (р<0,05) у девочек. Тем не менее данное повышение не постоянное. У детей обоих полов в возрасте от 3 до 8 лет увеличения СРПВ не отмечается. Первое отчетливое повышение СРПВ происходит в возрасте 12,1 лет у мальчиков и в 10,4 года у девочек. В возрасте от 3 до 8 лет отмечалось непрерывное постепенное нарастание систолического артериального давления, измеренного на плече, и среднего артериального давления, при этом показатели СРПВ оставались неизменными. С 9 лет показатели артериального давления и ригидности аорты изменялись одновременно. Заключение. В проведенном исследовании представлена самая большая на сегодняшний день база данных по артериальной ригидности, полученная у здоровых детей и подростков в возрасте от 3 до 18 лет с помощью простого исследования, адаптированного для широкого применения в педиатрической практике, даже у детей раннего возраста
Double-difference relocation of the 29 January 2011 ML 4.5 Oroszlány earthquake and its aftershocks and its relevance to the rheology of the lithosphere and geothermal prospectivity
Effect of inversion time on the precision of myocardial late gadolinium enhancement quantification evaluated with synthetic inversion recovery MR imaging.
OBJECTIVES: To evaluate the influence of inversion time (TI) on the precision of myocardial late gadolinium enhancement (LGE) quantification using synthetic inversion recovery (IR) imaging in patients with myocardial infarction (MI). METHODS: Fifty-three patients with suspected prior MI underwent 1.5-T cardiac MRI with conventional magnitude (MagIR) and phase-sensitive IR (PSIR) LGE imaging and T1 mapping at 15 min post-contrast. T1-based synthetic MagIR and PSIR images were calculated with a TI ranging from -100 to +150 ms at 5-ms intervals relative to the optimal TI (TI0). LGE was quantified using a five standard deviation (5SD) and full width at half-maximum (FWHM) thresholds. Measurements were compared using one-way analysis of variance. RESULTS: The MagIRsy technique provided precise assessment of LGE area at TIs >/= TI0, while precision was decreased below TI0. The LGE area showed significant differences at </= -25 ms compared to TI0 using 5SD (P < 0.001) and at </= -65 ms using the FWHM approach (P < 0.001). LGE measurements did not show significant difference over the analysed TI range in the PSIRsy images using either of the quantification methods. CONCLUSIONS: T1 map-based PSIRsy images provide precise quantification of MI independent of TI at the investigated time point post-contrast. MagIRsy-based MI quantification is precise at TI0 and at longer TIs while showing decreased precision at TI values below TI0. KEY POINTS: * Synthetic IR imaging retrospectively generates LGE images at any theoretical TI * Synthetic IR imaging can simulate the effect of TI on LGE quantification * Fifteen minutes post-contrast MagIR sy accurately quantifies infarcts from TI 0 to TI 0 + 150 ms * Fifteen minutes post-contrast PSIR sy provides precise infarct size independent of TI * Synthetic IR imaging has further advantages in reducing operator dependence