Isobolographic characterization of interactions of retigabine with carbamazepine, lamotrigine, and valproate in the mouse maximal electroshock-induced seizure model

The aim of this study was to characterize the pharmacodynamic, pharmacokinetic, and adverse-effect profiles of retigabine (RTG) in combination with carbamazepine (CBZ), lamotrigine (LTG), and valproate (VPA). The isobolographic analysis for parallel and nonparallel dose–response effects was used in the mouse maximal electroshock seizure (MES) model for evaluation of pharmacodynamic interaction. Potential adverse-effect profiles of interactions of RTG with CBZ, LTG, and VPA at the fixed ratio of 1:1 in the MES test were evaluated in the chimney (motor performance), passive avoidance (long-term memory), and grip strength (muscular strength) tests. Free plasma and total brain concentrations of CBZ, LTG, and VPA were determined by immunofluorescence and chromatography to assess pharmacokinetic interaction. In the MES model, RTG administered singly had its dose–response relationship curve (DRRC) parallel to that for VPA and nonparallel to that for CBZ and LTG. With isobolography for parallel DRRCs, the combination of RTG with VPA at fixed ratios of 1:3, 1:1, and 3:1 exerted supraadditive (synergistic) interaction. Isobolography for nonparallel DRRCs revealed that the combinations of RTG with CBZ and LTG at the fixed ratio of 1:1 produced additive interaction. In all combinations, neither motor coordination, long-term memory, nor muscular strength were affected. Only the combination of RTG with VPA at the fixed ratio of 3:1 was complicated by a pharmacokinetic increase in both free plasma and total brain VPA concentrations. All remaining combinations of RTG with VPA, CBZ, and LTG were pharmacodynamic in nature. RTG synergistically interacted with VPA and exerted additive interaction with CBZ and LTG in the mouse MES model.     

Characterization of interaction and the effect of carbamazepine on the structure of human serum albumin

The binding of carbamazepine (CBZ) to human serum albumin (HSA) was investigated under simulative physiological conditions. In this study, intrinsic fluorescence of tryptophan-214 in HSA was monitored upon the addition of CBZ. Binding constant of CBZ–HSA was calculated by the remarkable static quenching effect of CBZ and found to be (2.081 ± 0.023) × 10⁴ M⁻¹. The fluorimetric results revealed that the hydrophobic interaction was a predominant intermolecular force for stabilizing the complex, which is also in agreement with the results obtained from voltammetric approach. Three site probes, warfarin, ibuprofen and digitoxin, were employed in fluorescence displacement experiments to locate the exact binding site for CBZ in HSA. The alteration in secondary structure of protein in the presence of CBZ was confirmed by the evidences from circular dichroism and FT-IR spectroscopy. Further, the distance r between donor (Trp-214) and acceptor (CBZ) was obtained according to fluorescence resonance energy transfer (FRET).     

MiR-34b Protects Against Focal Cerebral Ischemia-Reperfusion (I/R) Injury in Rat by Targeting Keap1

Ischemic stroke is one of the leading causes of death and disability globally and has been regarded as a major public health problem. Understanding the mechanism of ischemia/reperfusion (I/R)-induced oxidative stress injury may provide new treatment for ischemic stroke. Kelch-like ECH-associated protein 1 (Keap1)/ NF-E2-related factor 2 (Nrf2)/ antioxidant response elements (ARE) signaling pathway has been considered to be the major cellular defense against oxidative stress. In the present study, our objective is to evaluate the molecular mechanism of miR-34b/Keap1 in modulating focal cerebral I/R induced oxidative injury. miR-34b was predicted to target the 3′-UTR of the rat Keap1. After focal cerebral I/R, miR-34b expression was downregulated in a time-dependent manner; miR-34b overexpression ameliorated I/R-induced oxidative stress injury in middle cerebral artery occlusion (MCAO) rats by reducing the infarction volume, the neurological severity scores, the levels of nitric oxide (NO) and (3-nitrotyrosine) 3-NT while increasing total (superoxide dismutases) SOD and manganese SOD (MnSOD). Through direct targeting, miR-34b could suppress the protein levels of Keap1 and increase the protein levels of Nrf2 and heme oxygenase (HO-1). Regarding the molecular mechanism, Keap1 overexpression exacerbated, while miR-34b improved H2O2-induced oxidative stress injury; the effect of miR-34b could be partially attenuated by Keap1 overexpression, suggesting that miR-34b modulated oxidative stress injury in vitro and in vivo through targeting Keap1. Taken together, we demonstrate that miR-34b protects against focal cerebral I/R-induced oxidative stress injury in MCAO rats and H2O2-induced oxidative stress injury in rat neuroblast B35 cells through targeting Keap1 and downstream Keap1/Nrf2 signaling pathway. We provided a novel mechanism of focal cerebral I/R injury from the perspective of miRNA regulation.     

Combination of Exoskeletal Upper Limb Robot and Occupational Therapy Improve Activities of Daily Living Function in Acute Stroke Patients

Purpose: Previous studies have suggested that upper limb rehabilitation using therapeutic robots improves motor function of stroke patients. However, the effect of upper limb robotic rehabilitation on improving functioning in activities of daily living (ADL) remains unclear. The present study aimed to determine whether upper limb rehabilitation using single joint Hybrid Assistive Limb (HAL-SJ) affects ADL function and the use of a hemiparetic arm in ADLs of acute stroke patients. Materials and Methods: Twelve acute stroke patients participated in the study and were randomly divided into group A or group B. The patients in group A followed an A-B-A-B design and those in group B followed a B-A-B-A design. The patients received combination HAL-SJ and occupational therapy during A and conventional occupational therapy during B. Results: Upper limb motor function and ADLs, in particular, dressing the upper body, were improved during combination HAL-SJ and occupational therapy. Interestingly, the use of a hemiparetic arm in daily life evaluated using the motor activity log was also significantly improved during A in group A. Conclusions: Combination HAL-SJ and occupational therapy affects ADL function and real use of a hemiparetic arm in the daily life of acute stroke patients.     

Pure Cortical Stroke Causing Hemichorea-Hemiballismus

Background: Movement disorders including hemichorea-hemiballism as the initial presentation of an acute ischemic stroke are uncommon. Structures outside of the deep subcortical areas such as the subthalamic nucleus or basal ganglia are rarely involved. Case Report: We report a case of a 72-year-old man with vascular risk factors who presented with acute onset right-sided hemichorea-hemiballism. Metabolic-, infectious-, and toxic-related conditions were ruled out, his EEG was without epileptiform changes. An MRI confirmed an acute ischemic stroke in the parieto-occipital region without any subcortical structures involved. Atrial Fibrillation was later discovered during his hospitalization and was treated appropriately. Conclusions: Although rare, strokes outside of the subthalamic nucleus can result in hemichorea-hemiballism.     

Is Artery Web Seen in Vertebral Artery?

Carotid artery web has been frequently reported. However, the vertebral artery web has been less reported. It is difficult and seldom to diagnose vertebral artery web with noninvasive examinations. Here, we present a case of asymptomatic vertebral artery web diagnosed by ultrasound and confirmed by digital subtraction angiography.     

Romanian Laypeople’s and Health Professionals’ Views Regarding Living Organ Donation

BackgroundRomanian laypeople’s and health professionals’ views on living organ donation were examined.MethodsFrom July 2015 to May 2016, 263 adults (among them 31 physicians and 20 nurses) judged the acceptability of living organ donation in 42 realistic scenarios composed of varying levels of 6 factors: 1. type of organ, 2. whether it could have been obtained from a cadaver, 3. donor-recipient relationship, 4. donor’s level of autonomy, 5. financial compensation, and 6. patients’ level of responsibility for their illness. In all scenarios, the patients were in need of either a kidney or liver transplantation.ResultsThe ratings were subjected to cluster analysis and analyses of variance. Seven qualitatively different positions were found that were termed never acceptable (12%), free market (44%), compensation (12%), altruism (6%), always acceptable (16%), responsibility (4%), and undetermined (6%). Physicians were more frequently in the free market or in the compensation clusters (81%) than laypeople (51%).ConclusionOnly a few participants held the altruism model, even though this model has been promoted as the normative model by the World Health Organization and by most national legislations, including the legislation in Romania. Instead, the free market position and its variant—the compensation position—can be considered the majority positions (66%) in Romania.