Development of glial restricted human neural stem cells for oligodendrocyte differentiation in vitro and in vivo.

In this study, we have developed highly expandable neural stem cells (NSCs) from HESCs and iPSCs that artificially express the oligodendrocyte (OL) specific transcription factor gene Zfp488. This is enough to restrict them to an exclusive oligodendrocyte progenitor cell (OPC) fate during differentiation in vitro and in vivo. During CNS development, Zfp488 is induced during the early stages of OL generation, and then again during terminal differentiation of OLs. Interestingly, the human ortholog Znf488, crucial for OL development in human, has been recently identified to function as a dorsoventral pattering regulator in the ventral spinal cord for the generation of P1, P2/pMN, and P2 neural progenitor domains. Forced expression of Zfp488 gene in human NSCs led to the robust generation of OLs and suppression of neuronal and astrocyte fate in vitro and in vivo. Zfp488 expressing NSC derived oligodendrocytes are functional and can myelinate rat dorsal root ganglion neurons in vitro, and form myelin in Shiverer mice brain in vivo. After transplantation near a site of demyelination, Zfp488 expressing hNSCs migrated to the lesion and differentiated into premyelinating OLs. A certain fraction also homed in the subventricular zone (SVZ). Zfp488-ZsGreen1-hNSC derived OLs formed compact myelin in Shiverer mice brain seen under the electron microscope. Transplanted human neural stem cells (NSC) that have the potential to differentiate into functional oligodendrocytes in response to remyelinating signals can be a powerful therapeutic intervention for disorders where oligodendrocyte (OL) replacement is beneficial

Zac1 plays a key role in the development of specific neuronal subsets in the mouse cerebellum

<p>Abstract</p> <p>Background</p> <p>The cerebellum is composed of a diverse array of neuronal subtypes. Here we have used a candidate approach to identify <it>Zac1</it>, a tumor suppressor gene encoding a zinc finger transcription factor, as a new player in the transcriptional network required for the development of a specific subset of cerebellar nuclei and a population of Golgi cells in the cerebellar cortex.</p> <p>Results</p> <p>We found that Zac1 has a complex expression profile in the developing cerebellum, including in two proliferating progenitor populations; the cerebellar ventricular zone and the external granular layer overlying posterior cerebellar lobules IX and X. Zac1 is also expressed in some postmitotic cerebellar neurons, including a subset of GABAergic interneurons in the medial cerebellar nuclei. Notably, GABAergic interneurons in the cerebellar nuclei are derived from the cerebellar ventricular zone, where Zac1 is also expressed, consistent with a lineage relationship between these two Zac1⁺populations. Zac1 is also expressed in a small subset of cells in the posterior vermis, including some neurogranin-immunoreactive (NG⁺) Golgi cells, which, based on short-term birthdating, are derived from the EGL, where Zac1 is also expressed. However, Zac1⁺cells and NG⁺Golgi cells in the cerebellar cortex also display unique properties, as they are generated within different, albeit overlapping, time windows. Finally, consistent with the expression profile of Zac1, two conspicuous abnormalities were found in the cerebellum of <it>Zac1 </it>null mice: the medial cerebellar nuclei, and not the others, were significantly reduced in size; and the number of Golgi cells in cerebellar lobule IX was reduced by approximately 60% compared to wild-type littermates.</p> <p>Conclusions</p> <p>The data presented here indicate that the tumor suppressor gene <it>Zac1 </it>is expressed in a complex fashion in the developing cerebellum, including in two dividing progenitor populations and in specific subsets of postmitotic neurons, including Golgi cells and GABAergic neurons in the medial nuclei, which require Zac1 for their differentiation. We thus conclude that Zac1 is a critical regulator of normal cerebellar development, adding a new transcriptional regulator to the growing list of factors involved in generating neuronal diversity in the developing cerebellum.</p

Concomitant Laparoendoscopic Single-Site Surgery for Vesicolithotomy and Finger-Assisted Single-Port Transvesical Enucleation of the Prostate

Transurethral resection of the prostate is the most common surgery for benign prostatic hyperplasia. However, it doesn't work best for men with very large prostate and bladder stones. Herein we report our initial experience with concomitant laparoendoscopic single-site surgery and finger-assisted single-port transvesical enucleation of the prostate for the treatment of the condition

The origin of proinflammatory cytokines in patients with idiopathic dilated cardiomyopathy.

Proinflammatory cytokines and their receptors are increased in the peripheral blood of patients with heart failure. We measured cytokines and their receptors in systemic artery (SA), coronary sinus (CS) and infra-renal inferior vena cava (IVC), in order to investigate their origin and influential factors. Thirty patients with idiopathic dilated cardiomyopathy were performed echocardiography at admission, and right heart catheterization after stabilization. Blood was drawn from 3 sites for measurement of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and soluble tumor necrosis factor-alpha receptor (sTNFR) I, II. TNF-alpha at CS (3.25 +/- 0.34 pg/mL) was higher than those of SA (1.81 +/- 0.39 pg/mL) and IVC (1.88 +/- 0.38 pg/mL, p<0.05). IL-6 at CS (18.3 +/- 3.8 pg/mL) was higher than that of SA (5.8 +/- 1.2 pg/mL, p<0.01). The levels of sTNFR I, II showed increasing tendency in sequence of SA, IVC and CS. TNF-alpha and sTNFR I, II from all sites were proportional to worsening of functional classes at admission (p<0.05). E/Ea by Doppler study at admission, which reflects left ventricular end-diastolic pressure (LVEDP) was positively correlated with TNF-alpha from SA (R=0.71, p<0.01), CS (R=0.52, p<0.05) and IVC (R=0.46, p<0.05). Thus, elevated LVEDP during decompensation might cause cytokine release from myocardium in patients with idiopathic dilated cardiomyopathy

Femoral anteversion and tibial torsion only explain 25% of variance in regression analysis of foot progression angle in children with diplegic cerebral palsy

Background : The relationship between torsional bony deformities and rotational gait parameters has not been sufficiently investigated. This study was to investigate the degree of contribution of torsional bony deformities to rotational gait parameters in patients with diplegic cerebral palsy (CP). Methods : Thirty three legs from 33 consecutive ambulatory patients (average age 9.5 years, SD 6.9 years; 20 males and 13 females) with diplegic CP who underwent preoperative three dimensional gait analysis, foot radiographs, and computed tomography (CT) were included. Adjusted foot progression angle (FPA) was retrieved from gait analysis by correcting pelvic rotation from conventional FPA, which represented the rotational gait deviation of the lower extremity from the tip of the femoral head to the foot. Correlations between rotational gait parameters (FPA, adjusted FPA, average pelvic rotation, average hip rotation, and average knee rotation) and radiologic measurements (acetabular version, femoral anteversion, knee torsion, tibial torsion, and anteroposteriortalo-first metatarsal angle) were analyzed. Multiple regression analysis was performed to identify significant contributing radiographic measurements to adjusted FPA. Results : Adjusted FPA was significantly correlated with FPA (r=0.837, p<0.001), contralateral FPA (r=0.492, p=0.004), pelvic rotation during gait (r=−0.489, p=0.004), knee rotation during gait (r=0.376, p=0.031), and femoral anteversion (r=0.350, p=0.046). In multiple regression analysis, femoral anteversion (p=0.026) and tibial torsion (p=0.034) were found to be the significant contributing structural deformities to the adjusted FPA (R2=0.247). Conclusions : Femoral anteversion and tibial torsion were found to be the significant structural deformities that could affect adjusted FPA in patients with diplegic CP. Femoral anteversion and tibial torsion could explain only 24.7% of adjusted FPA.This study was supported by research funding (grant no. 02-2011-045) from Seoul National University Bundang Hospital, Republic of Korea.Peer Reviewe

Influence of surgery involving tendons around the knee joint on ankle motion during gait in patients with cerebral palsy

Background Simultaneous motion of the knee and ankle joints is required for many activities including gait. We aimed to evaluate the influence of surgery involving tendons around the knee on ankle motion during gait in the sagittal plane in cerebral palsy patients. Methods We included data from 55 limbs in 34 patients with spastic cerebral palsy. Patients were followed up after undergoing only distal hamstring lengthening with or without additional rectus femoris transfer. The patients mean age at the time of knee surgery was 11.2 ± 4.7 years, and the mean follow-up duration was 2.2 ± 1.5 years (range, 0.9–6.0 years). Pre- and postoperative kinematic variables that were extracted from three-dimensional gait analyses were then compared to assess changes in ankle motion after knee surgery. Outcome measures included ankle dorsiflexion at initial contact, peak ankle dorsiflexion during stance, peak ankle dorsiflexion during swing, and dynamic range of motion of the ankle. Various sagittal plane knee kinematics were also measured and used to predict ankle kinematics. A linear mixed model was constructed to estimate changes in ankle motion after adjusting for multiple factors. Results Improvement in total range of motion of the knee resulted in improved motion of the ankle joint. We estimated that after knee surgery, ankle dorsiflexion at initial contact, peak ankle dorsiflexion during stance, peak ankle dorsiflexion during swing, and dynamic range of motion of the ankle decreased, respectively, by 0.4° (p = 0.016), 0.6° (p < 0.001), 0.2° (p = 0.038), and 0.5° (p = 0.006) per degree increase in total range of motion of the knee after either knee surgery. Furthermore, dynamic range of motion of the ankle increased by 0.4° per degree increase in postoperative peak knee flexion during swing. Conclusions Improvement in total knee range of motion was found to be correlated with improvement in ankle kinematics after surgery involving tendons around the knee. As motion of the knee and ankle joints is cross-linked, surgeons should be aware of potential changes in the ankle joint after knee surgery.This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2016R1C1B2008557), and was partly supported by the Technology Innovation Program funded By the Ministry of Trade, Industry and Energy (MOTIE) of Korea (10049785) and SNUBH research fund (grant no. 02-2012-018). No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article