Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome

The functional relevance of brain-derived neurotrophic factor (BDNF) is beginning to be well appreciated not only in mice, but also in humans. Because reduced levels typically correlate with impaired neuronal function, increasing BDNF levels with well-tolerated drugs diffusing into the central nervous system may help in ameliorating functional deficits. With this objective in mind, we used the sphingosine-1 phosphate receptor agonist fingolimod, a drug that crosses the blood-brain barrier. In addition, fingolimod has recently been introduced as the first oral treatment for multiple sclerosis. In cultured neurons, fingolimod increases BDNF levels and counteracts NMDA-induced neuronal death in a BDNF-dependent manner. Ongoing synaptic activity and MAPK signaling is required for fingolimod-induced BDNF increase, a pathway that can also be activated in vivo by systemic fingolimod administration. Mice lacking Mecp2, a gene frequently mutated in Rett syndrome, show decreased levels of BDNF, and fingolimod administration was found to partially rescue these levels as well as the size of the striatum, a volumetric sensor of BDNF signaling in rodents. These changes correlate with increased locomotor activity of the Mecp2-deficient animals, suggesting that fingolimod may improve the functional output of the nervous system, in addition to its well-documented effects on lymphocyte egress from lymph nodes.     

Visual impairment in children with spastic cerebral palsy measured by psychophysical and electrophysiological grating acuity tests

Background: This study measured grating visual acuity in 173 children between 6–48 months of age who had different types of spastic cerebral palsy (CP).

Method: Behavioural acuity was measured with the Teller Acuity Cards (TAC) using a staircase psychophysical procedure. Electrophysiological visual acuity was estimated using the sweep VEP (sVEP).

Results: The percentage of children outside the superior tolerance limits was 44 of 63 (69%) and 50 of 55 (91%) of tetraplegic, 36 of 56 (64%) and 42 of 53 (79%) of diplegic, 10 of 48 (21%) and 12 of 40 (30%) of hemiplegic for sVEP and TAC, respectively. For the sVEP, the greater visual acuity deficit found in the tetraplegic group was significantly different from that of the hemiplegic group (p?<?0.001). In the TAC procedure the mean visual acuity deficits of the tetraplegic and diplegic groups were significantly different from that of hemiplegic group (p?<?0.001). The differences between sVEP and TAC means of visual acuity difference were statistically significant for the tetraplegic (p?<?0.001), diplegic (p?<?0.001), and hemiplegic group (p?=?0.004).

Discussion: Better visual acuities were obtained in both procedures for hemiplegic children compared to diplegic or tetraplegic. Tetraplegic and diplegic children showed greater discrepancies between the TAC and sVEP results. Inter-ocular acuity difference was more frequent in sVEP measurements.

Conclusions: Electrophysiologically measured visual acuity is better than behavioural visual acuity in children with CP.     

特发性室性心律失常的发生基质研究进展

心律失常的发生基质是目前电生理领域研究的热点问题。近期研究提示:心肌组织、心肌细胞间的缝隙连接、心脏传导系统以及自主神经系统等在特发性室性心律失常的发生和维持中起着重要作用。深入研究特发性室性心律失常的发生基质将会为一些难治性室性心律失常提供新的治疗方法,有助于从根源上治疗特发性室性心律失常。     

Atrial Burst Pacing with Biphasic and Monophasic Waveforms for Atrial Fibrillation

Background: Biphasic pacing is a novel mode of pacing that was suggested to increase cardiac conduction velocity as compared with cathodal monophasic pacing. We aimed to evaluate the safety and efficacy of rapid atrial pacing to convert atrial fibrillation (AF) to normal sinus rhythm. Methods: Multiple biphasic (anodal/cathodal), reverse biphasic (cathodal/anodal), and monophasic (cathodal) atrial pacing therapies were performed among 12 patients undergoing left atrial catheter ablation for AF. The efficacy end point was successful conversion of AF to sinus rhythm, and safety end point no induction of ventricular arrhythmias. Patients were paced at three cycle lengths (100, 200, and 333 msec) for 60 seconds at three locations (right and left atrial appendages and coronary sinus). Results: Among the 66 biphasic (anodal/cathodal) pacing procedures one procedure in a patient with chronic AF, which involved pacing at the left atrial appendage with a cycle length of 200 msec, led to conversion of AF to sinus rhythm. None of the 66 monophasic pacing procedures or the 66 reverse biphasic (cathodal/anodal) pacing procedures was associated with AF termination. None of the biphasic pacing procedures was associated with induction of ventricular arrhythmias. Conclusions: Rapid atrial pacing using a variety of waveforms at the cycle length and output used in the current study was found to be safe. There was a single success in converting a chronic AF to sinus rhythm. Ann Noninvasive Electrocardiol 2012;17(1):22–27     

A Technique for Conducting Noninvasive Cardiac Electrophysiology Studies in Conscious Swine

A noninvasive method was developed in swine for conducting cardiac electrophysiology (EP) studies without the potential confounding effects of sedatives or anesthetics. Following a 1-week conditioning regimen in the EP laboratory, 3-month-old Hanford miniature swine underwent transvenous pacemaker (PM) implantation under isoflurane anesthesia. Two bipolar screw-in pacing leads were inserted into the left external jugular vein, with one positioned in the right atrial appendage and one in the myocardium at the right ventricular apex. The leads were attached to a multiprogrammable pulse generator, and the pacing system was placed in a subcutaneous pocket. At weekly intervals following implantation, conscious, unsedated swine were restrained in a sling for noninvasive programmed stimulation (NIPS) using a programmable telemetry system. A NIPS protocol to induce arrhythmias was performed separately for the atrium and ventricle. Data for this model are reported. Complications occurred in 6 of 26 animals studied and included one infection of the PM pocket, three cases of dislodgement of the atrial lead, and rotation of the generator within the pocket in two animals, preventing communication with the PM. This technique has been used to perform EP studies successfully in swine and has been utilized in a variety of studies of the cardiac conduction system.     

Electrophysiological subtypes and prognosis of Guillain–Barré syndrome in Northeastern China

Introduction: The dystrophic features in hindlimb skeletal muscles of female mdx mice are unclear. Methods: We analyzed force‐generating capacity and force decline after lengthening contraction‐induced damage (fragility). Results: Young (6‐month‐old) female mdx mice displayed reduced force‐generating capacity (?18%) and higher fragility (23% force decline) compared with female age‐matched wild‐type mice. These 2 dystrophic features were less accentuated in young female than in young male mdx mice (?32% and 42% force drop). With advancing age, force‐generating capacity decreased and fragility increased in old (20 month) female mdx mice (?21% and 57% force decline), but they were unchanged in old male mdx mice. Moreover, estradiol treatment had no effect in old female mdx mice. Conclusions: Female gender–related factors mitigate dystrophic features in young but not old mdx mice. Further studies are warranted to identify the beneficial gender‐related factor in dystrophic muscle. Muscle Nerve, 2013