Inhibition of Advanced Glycation End Products Formation Attenuates Cardiac Electrical and Mechanical Remodeling and Vulnerability to Tachyarrhythmias in Diabetic Rats.

Diabetic patients with cardiomyopathy show a higher incidence of arrhythmias and sudden death. Chronic hyperglycemia induces the formation of advanced glycation end products (AGEs), which contribute to the pathogenesis of diabetic cardiomyopathy. This study investigated whether inhibition of AGEs formation by aminoguanidine (AG) could prevent cardiac electromechanical and arrhythmogenic remodeling in diabetes mellitus. Streptozotocin-induced diabetic rats received AG (100 mg/kg daily, i.p.) or vehicle (normal saline, i.p.) for 5 weeks. The rats underwent hemodynamic recording to evaluate cardiac function, and heart preparations were used to determine the electrical, mechanical, and biochemical functions. In vitro high glucose-induced AGEs formation, reactive oxygen species (ROS) generation, and action potential changes were examined in HL-1 atrial cells. AG treatment improved the diabetes-induced depression in left ventricular pressure and the relaxation rate, and normalized the prolongation of QTc intervals in anesthetized rats. AG reduced the vulnerabilities to atrial and ventricular tachyarrhythmias in perfused diabetic hearts. AG normalized the prolonged action potential duration in diabetic atrial and ventricular muscles, which was correlated with the restoration of both transient outward (I to) and steady-state outward (I SS) K+ current densities in cardiomyocytes. The abnormal kinetics of Ca2+ transients and contraction were reversed in cardiomyocytes from AG-treated diabetic rats, along with parallel preservation of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a) expression. Furthermore, ex vivo and in vitro studies showed AG attenuated AGEs and ROS formation. Thus, long-term administration of AG ameliorated cardiac electromechanical remodeling and arrhythmogenicity in diabetic rats and may present an effective strategy for the prevention of diabetes-associated arrhythmias.

Measurement of Interhemispheric Correlation Coefficient in Rodent Model of Middle Cerebral Artery Occlusion Using Near Infrared Spectroscopy.

Near-infrared spectroscopy (NIRS) is a noninvasive brain imaging technique that measures hemodynamics by determining the optical properties of tissue. Clinical potential of NIRS for monitoring cerebral hemodynamics in cerebrovascular diseases, such as stroke, has been studied. However, inconsistencies in measurements among studies, which are believed to be partly due to anatomical variance and diversity in disease presentation, limit the clinical feasibility of NIRS for stroke monitoring. In the present study, bihemispheric frequency-domain NIRS measurements on middle cerebral artery occlusion rats were performed. The discrepancy in interhemispheric synchronicity in hemodynamic oscillation appeared during the early reperfusion stage is related to the size of infarct that developed three days later. These NIRS parameters may have the potential to be early prognostic biomarkers for long-term stroke monitoring in the future translational investigation.

Swallowing Training Combined With Game-Based Biofeedback in Poststroke Dysphagia.

BACKGROUND: For patients with dysphagia due to stroke, in addition to compensatory strategies, exercises are used to help improve motor function. Biofeedback is used in neuromuscular training and is promising for swallowing training. OBJECTIVE: To evaluate the functional value of game-based biofeedback in swallowing therapy for patients with poststroke dysphagia. DESIGN: A case-control study. SETTING: Academic tertiary hospital. PARTICIPANTS: Subjects with poststroke dysphagia (n = 20) were individually matched to 2 separate groups, a game-based biofeedback group (n = 10) or a control group (n = 10), for age, gender, duration of dysphagia, and dysphagia grades. INTERVENTIONS: Each participant underwent 1-hour sessions 3 times per week for a total of 16 treatment sessions. Each session included a 30-minute session of traditional swallow treatment and a 30-minute session of laryngeal elevation exercises. In the experimental group, laryngeal elevation exercises were combined with additional game-based biofeedback. MAIN OUTCOME MEASURES: Outcomes assessed before and after interventions included hyoid bone displacement, Functional Oral Intake Scale (FOIS) scores, and nasogastric (NG) tube removal rate. RESULTS: Intergroup analyses showed larger differences in hyoid bone displacement and FOIS scores (before and after treatment) in the experimental group than in the control group, with statistical significance (P = .007 and P = .014, respectively). Intergroup analyses showed that the hyoid bone displacement change and FOIS scores before and after treatment exhibited statistically significant improvement only in the experimental group (P = .002 and P = .004, respectively). In all, 8 of 10 patients (80%) in the experimental group and 2 of 10 patients (20%) in the control group discontinued NG tube insertion after therapy. Participation in the experimental group was associated with an increased probability of tube removal (odds ratio = 6.00; 95% confidence interval = 1.08-33.27, P = .009). CONCLUSIONS: Laryngeal elevation training combined with game-based biofeedback augments the change in hyoid bone displacement and FOIS scores, and increases the NG tube removal rate in patients with poststroke dysphagia.

Nonacog alfa: an analysis of safety data from six prospective clinical studies in different patient populations with haemophilia B treated with different therapeutic modalities.

Nonacog alfa is a recombinant factor IX (FIX) product indicated for treatment and prevention of bleeding episodes in patients with haemophilia B. This posthoc analysis evaluated the safety of nonacog alfa in key clinical studies across 15 years. Data were pooled from six prospective studies that utilized on-demand, prophylactic and preventive nonacog alfa regimens: three open-label, nonrandomized studies that assessed efficacy and safety; a bioequivalence study of original and reformulated nonacog alfa; an open-label, randomized study that compared on-demand and prophylactic treatment; and a noninterventional observational registry study that evaluated safety. Safety assessments included adverse events, serious adverse events (SAEs) and events of special interest. In total, 412 patients received nonacog alfa treatment. Adverse events occurred in 220 patients (53.4%), the most common being pyrexia (n = 63), nasopharyngitis (n = 53) and cough (n = 52). Forty-eight patients (11.7%) experienced treatment-related adverse events; the most common were hypersensitivity (n = 6), urticaria (n = 6), FIX inhibition (n = 5) and pyrexia (n = 4). Seventy-four patients (18.0%) developed SAEs. Thirty-seven events of special interest occurred in 31 (7.5%) patients. Events of special interest included allergic-type manifestations (n = 15), inhibitor development (n = 5), lack of effect (n = 8), red blood cell agglutination in tubing or syringe (n = 7), and thrombogenicity (n = 2). Six patients (1.5%) withdrew due to seven adverse events: hypersensitivity (n = 3), drug eruption, pruritic rash, urticaria and decreased therapeutic response (n = 1 each). Four patients died during the study; no deaths were related to study medication. This pooled safety analysis in haemophilia B patients confirmed the safety of nonacog alfa across various patient populations.

Electrophysiological and mechanical effects of caffeic acid phenethyl ester, a novel cardioprotective agent with antiarrhythmic activity, in guinea-pig heart.

Caffeic acid phenethyl ester (CAPE) is an active component of propolis that exhibits cardioprotective and antiarrhythmic effects. The detailed mechanisms underlying these effects, however, are not entirely understood. The aim of this study was to elucidate the electromechanical effects of CAPE in guinea-pig cardiac preparations. Intracardiac electrograms, left ventricular (LV) pressure, and the anti-arrhythmic efficacy were determined using isolated hearts. Action potentials of papillary muscles were assessed with microelectrodes, Ca(2+) transients were measured by fluorescence, and ion fluxes were measured by patch-clamp techniques. In a perfused heart model, CAPE prolonged the atrio-ventricular conduction interval, the Wenckebach cycle length, and the refractory periods of the AV node and His-Purkinje system, while shortening the QT interval. CAPE reduced the occurrence of reperfusion-induced ventricular fibrillation and decreased LV pressure in isolated hearts. In papillary muscles, CAPE shortened the action potential duration and reduced both the maximum upstroke velocity and contractile force. In fura-2-loaded single ventricular myocytes, CAPE decreased cell shortening and the Ca(2+) transient amplitude. Patch-clamp experiments revealed that CAPE produced a use-dependent decrease in L-type Ca(2+) current (ICa,L) (IC50=1.1 µM) and Na(+) current (INa) (IC50=0.43 µM), caused a negative-shift of the voltage-dependent inactivation and a delay of recovery from inactivation. CAPE decreased the delayed outward K(+) current (IK) slightly, without affecting the inward rectifier K(+) current (IK1). These results suggest that the preferential inhibition of Ca(2+) inward and Na(+) inward currents by CAPE may induce major electromechanical alterations in guinea-pig cardiac preparations, which may underlie its antiarrhythmic action.

Quantitative video-based gait pattern analysis for hemiparkinsonian rats.

Gait disturbances are common in the rat model of Parkinson's disease (PD) by administrating 6-hydroxydopamine. However, few studies have simultaneously assessed spatiotemporal gait indices and the kinematic information of PD rats during overground locomotion. This study utilized a simple, accurate, and reproducible method for quantifying the spatiotemporal and kinematic changes of gait patterns in hemiparkinsonian rats. A transparent walkway with a tilted mirror was set to capture underview footprints and lateral joint ankle images using a high-speed and high-resolution digital camera. The footprint images were semi-automatically processed with a threshold setting to identify the boundaries of soles and the critical points of each hindlimb for deriving the spatiotemporal and kinematic indices of gait. Following PD lesion, asymmetrical gait patterns including a significant decrease in the step/stride length and increases in the base of support and ankle joint angle were found. The increased footprint length, toe spread, and intermediary toe spread were found, indicating a compensatory gait pattern for impaired locomotor function. The temporal indices showed a significant decrease in the walking speed with increased durations of the stance/swing phase and double support time, which was more evident in the affected hindlimb. Furthermore, the ankle kinematic data showed that the joint angle decreased at the toe contact stage. We conclude that the proposed gait analysis method can be used to precisely detect locomotor function changes in PD rats, which is useful for objective assessments of investigating novel treatments for PD animal model.

Time-course gait analysis of hemiparkinsonian rats following 6-hydroxydopamine lesion.

Gait disturbances similar to those of human Parkinson's disease (PD) can be observed in animals after administration of neurotoxin 6-hydroxydopamine (6-OHDA) to induce unilateral nigrostriatal dopamine depletion. However, the relationship between gait disturbances and dopamine depletion following 6-OHDA infusion has not been determined. The present study investigated the longitudinal changes of spatiotemporal gait patterns using a walkway system to acquire footprints and lateral limb images over a 6-week period following unilateral 6-OHDA injection into the medial forebrain bundle of rats. Our results indicated that hemiparkinsonian rats exhibited changes in gait patterns, as compared to normal controls, and pre-lesion levels, including a significantly decreased walking speed and step/stride length as well as an increased base of support and foot angle. The relative percentage of the gait cycle was also altered, showing an increase in the stance to swing ratio, which was more evident in the affected hindlimb. Time-course observations showed that these gait disturbances occurred as early as 4 days post-lesion and gradually increased up to 42 days post-injury. The extents of gait disturbances were compared with conventional apomorphine-induced turning behavior and akinesia bar tests, which were also apparent at 4 days post-lesion but remained relatively unchanged after 28 days. Our time-course gait analysis of a unilateral 6-OHDA rodent model provides insight into the compensatory changes of motor functions during the 6-week development of a nigrostriatal lesion, which might be useful for future objective assessment of novel treatments for human PD subjects.

Comparing the effects of light alcohol consumption on human response to auditory and visual stimuli.

The purpose of this study is to examine the effects of various levels of alcohol consumption on human response to auditory and visual stimuli in terms of reaction time, movement time, total reaction time, and error rate. Placebo level and three low-level alcohol doses were randomly assigned to 20 male university student volunteers. 30 min. after consuming the alcohol or placebo, participants responded to either auditory or visual stimuli. Total reaction time increased significantly at the mid-low dose of alcohol (0.3 g/kg). For alcohol doses less than .5 g/kg, the change in total reaction time was confined to reaction time, i.e., the processing time between onset of stimulus and onset of movement. Effects of alcohol were significantly more pronounced in the choice-type tests. Notably, the effects of alcohol on total reaction time and error rate were significant for auditory but not visual stimuli.

Measurement and modeling of stimulus-evoked electromyography in lengthened and shortened muscles for spinal cord injured subjects during an electrically-elicited fatigue process.

This study compares the amplitude and temporal features of stimulus-evoked electromyography (EMG) of paralyzed muscle, rectus femoris (RF), in both lengthened and shortened positions of six spinal cord injured (SCI) subjects during an electrically elicited fatigue process. The torque output and evoked EMG were fitted by hyperbolic tangent functions from which their amplitude residual levels and temporal inflection times can be extracted. Furthermore, a structural EMG model of Fuglevand et al (1992 Biol. Cybern. 67 143-53) was modified to include type I (slow twitch) and type II (fast twitch) of motor unit (MU) fibers with viable parameters obtained from paralyzed muscles to observe their amplitude and temporal changes. Our results showed that the amplitude of stimulus-evoked EMG decreased earlier in the lengthened muscle with a shorter inflection time (48.53 +/- 8.7 s versus 55.13 +/- 4.03 s) than that of the shortened position during 120 s of stimulation time (p < 0.05). Similarly, the peak-to-peak duration (PTPd) of the evoked EMG increased faster at an earlier time to a higher asymptotical value in lengthened muscle (2.23 +/- 0.74 versus 1.77 +/- 0.54), compared to that of a shortened one (p < 0.05). These observations coincided with the higher rising rate and larger final value of the temporal coefficients, i.e., longer duration, in both type I and II MUs of lengthened muscles. From the observation of all parameters, the fatigue process in lengthened muscle proceeds faster than that in shortened muscle.

Development of a quantitative assessment system for correlation analysis of footprint parameters to postural control in children.

It is known that neurological impairments impact postural stability, but few studies have observed the biomechanical influence of foot structure on balance. The aim of this study was to develop an integrated device for investigating the relationship between static balance and the foot structure, derived from a footprint image, under clinical tests of sensory interactions. Quantitative analysis of the footprint image acquired during balanced standing was developed as an indirect measure of the longitudinal arch, an important structural component of the foot. A data pool was collected from 64 children, 32 children from each of two age groups (4-5 years old versus 8-10 years old). Six common footprint parameters derived from the footprint angle or contact area were used to investigate the relationship between footprint parameters and postural stability. Postural balance ability was evaluated by analyzing sway area in posturography under visual or somatosensory confliction conditions. The footprint parameters, derived from the footprint image, inter-correlated well with each other (p < 0.01). The relationships between footprint parameters and sway area were correlated only for younger children under visually deprived (eye close) and cutaneous unreliable (standing on compliant foam) conditions. This implies that the correlations between footprint parameters and sway area are very subtle which can only be observed in unreliable visual and somatosensory conditions of younger children. In addition, younger children with a lower arch height would have a smaller sway area and better posture control which might result from more cutaneous somatosensation or a flexible biomechanical structure in low arch feet during conditioned static standing.

Development of a virtual reality environment for somatosensory and perceptual stimulation in the balance assessment of children.

In this study, we developed a balance assessment system in which the visual stimulus was generated by a virtual reality (VR) technique and somatosensation was obtained from a movable platform. By standing on the movable platform, the center of pressure (COP) was measured to express the subject's postural control in response to varied visual stimuli. From the COP data, a singular value decomposition technique was used to derive the sway area and direction, represented in a polar form. Our system demonstrated the feasibility of using a VR environment in postural control trials and provided more realistic somatosensory and visual inputs.

Image analysis system for acquiring three-dimensional contour of foot arch during balanced standing.

Compared to the X-ray approach, footprint analysis is a non-radiation and more viable method for clinical assessment of the medial longitudinal arch of the foot. In this study, we have designed an optical footprint acquisition system that consists of a digital camera and two pieces of glass, each with four load cells under each corner. When the subject stands on the transparent force plates, the digital camera is triggered, photographing the soles of the feet at the moment when both feet bear approximately at the same weight. A blue gel is placed between the foot and the force plate to enhance the contrast between sole and background. Based on the relationship between the brightness of the image and the thickness of the gel, the three-dimensional (3D) structure of the arch can be reconstructed which can provide more representative information than a conventional footprint image, with its low resolution and easy smearing.