Takahiro Tadokoro

Usefulness of stroke volume variation to assess blood volume during blood removal for autologous blood transfusion in pediatric patients

Dynamic variables based on the heart–lung interaction induced by positive pressure ventilation have not been shown to be useful in assessing cardiac preload in pediatric patients.

Erratum to: Guidewire advancement is interrupted by an internal jugular vein valve with a restricted opening: an ultrasound image

To the Editor, Anesthesiologists have generally paid relatively little attention to the internal jugular vein valve (IJVV) during central venous catheter insertion. Interruption of guidewire insertion by the IJVV is known to occur; however, very few related images appear in the published literature. Recently, a 73-yr-old male with a bicuspid aortic valve and a history of hypertension presented to our hospital for aortic valve replacement. Following induction of anesthesia, we attempted an ultrasound-guided placement of the Sheath Introducer (Multi-lumen access catheter, ARROW ) into the patient’s right internal jugular vein (IJV). We rotated the patient’s head to the left while slightly extending his neck, and we then confirmed that the IJV was lying parallel to the right carotid artery which had no evidence of stenosis. Ultrasound imaging was used to confirm the location of the needle tip within the vessel and backflow of blood. Next, we attempted to introduce a guidewire into the right IJV; however, we were unable to advance the guidewire more than 8 cm due to resistance. During ultrasound-guided indwelling of the guidewire, a large membranous structure was detected protruding from the posterior wall of the IJV. Although we attempted to advance the guidewire with the assistance of ultrasound imaging, the wire could only push the bottom of membranous structure (Figure, Panel A). The guidewire was caught by the membranous structure, and we could not advance the wire further. After several failed attempts, we placed the Sheathe Introducer into the left IJV instead. Internal jugular vein valves are the only barrier between the brain and the heart that prevent retrograde venous blood flow when the intrathoracic pressure increases. Malfunction of the IJVV may include restriction of the opening and valve incompetence. As was the case here, a restricted opening may impede insertion of the catheter or guidewire during central venous catheterization, while valve incompetence may be a complication of catheterization. A guidewire is introduced along the posterior wall of the IJV. In this case, the patient’s IJVV was a bicuspid valve which consisted of a large posterior leaflet and a small anterior leaflet. Advancement of the guidewire was obstructed by the bottom of the posterior leaflet with a restricted opening. Based on our experience, we suggest assessing any malfunctioning opening movement of the IJVV with a preprocedural ultrasound scan. Macchi et al. reported that IJVV incompetence may be considered a normal finding; however, a pressure gradient develops in this valve during coughing. Catheterization of the IJV involves a risk of injury to the IJVV. Wu et al. reported that IJVV incompetence is more commonly caused by cannulation and catheterization at the proximal site of the IJV than at the distal site. Internal jugular vein valve incompetence causes an increase in retrograde

Survival of syngeneic and allogeneic iPSC–derived neural precursors after spinal grafting in minipigs

Syngeneic iPSC–derived neurons survive and mature without immunosuppression after grafting into the spinal cord of adult pigs. Stem cell transplants in pigs with spinal cord injury Neural precursor cells (NPCs) hold promise for treating spinal cord injury (SCI). Testing viability and engraftment properties of NPC transplants in large-animal models is necessary for understanding the clinical potential of this approach. In a new study, Strnadel et al. transplanted syngeneic and allogeneic induced pluripotent stem cell–derived NPCs (iPSC-NPCs) into the spinal cords of naïve pigs and animals with SCI. The transplanted cells showed a good safety profile, long-term survival, and differentiation into mature neurons and glial cells. Successful engraftment of allogeneic iPSC-NPCs required only temporary immunosuppression, an important consideration for the future clinical evaluation of iPSC-NPCs for treating SCI. The use of autologous (or syngeneic) cells derived from induced pluripotent stem cells (iPSCs) holds great promise for future clinical use in a wide range of diseases and injuries. It is expected that cell replacement therapies using autologous cells would forego the need for immunosuppression, otherwise required in allogeneic transplantations. However, recent studies have shown the unexpected immune rejection of undifferentiated autologous mouse iPSCs after transplantation. Whether similar immunogenic properties are maintained in iPSC-derived lineage-committed cells (such as neural precursors) is relatively unknown. We demonstrate that syngeneic porcine iPSC-derived neural precursor cell (NPC) transplantation to the spinal cord in the absence of immunosuppression is associated with long-term survival and neuronal and glial differentiation. No tumor formation was noted. Similar cell engraftment and differentiation were shown in spinally injured transiently immunosuppressed swine leukocyte antigen (SLA)–mismatched allogeneic pigs. These data demonstrate that iPSC-NPCs can be grafted into syngeneic recipients in the absence of immunosuppression and that temporary immunosuppression is sufficient to induce long-term immune tolerance after NPC engraftment into spinally injured allogeneic recipients. Collectively, our results show that iPSC-NPCs represent an alternative source of transplantable NPCs for the treatment of a variety of disorders affecting the spinal cord, including trauma, ischemia, or amyotrophic lateral sclerosis.

ALS/FTD-Linked Mutation in FUS Suppresses Intra-axonal Protein Synthesis and Drives Disease Without Nuclear Loss-of-Function of FUS

Summary Through the generation of humanized FUS mice expressing full-length human FUS, we identify that when expressed at near endogenous murine FUS levels, both wild-type and ALS-causing and frontotemporal dementia (FTD)-causing mutations complement the essential function(s) of murine FUS. Replacement of murine FUS with mutant, but not wild-type, human FUS causes stress-mediated induction of chaperones, decreased expression of ion channels and transporters essential for synaptic function, and reduced synaptic activity without loss of nuclear FUS or its cytoplasmic aggregation. Most strikingly, accumulation of mutant human FUS is shown to activate an integrated stress response and to inhibit local, intra-axonal protein synthesis in hippocampal neurons and sciatic nerves. Collectively, our evidence demonstrates that human ALS/FTD-linked mutations in FUS induce a gain of toxicity that includes stress-mediated suppression in intra-axonal translation, synaptic dysfunction, and progressive age-dependent motor and cognitive disease without cytoplasmic aggregation, altered nuclear localization, or aberrant splicing of FUS-bound pre-mRNAs. Video Abstract

Subpial Adeno-associated Virus 9 (AAV9) Vector Delivery in Adult Mice.

The successful development of a subpial adeno-associated virus 9 (AAV9) vector delivery technique in adult rats and pigs has been reported on previously. Using subpially-placed polyethylene catheters (PE-10 or PE-5) for AAV9 delivery, potent transgene expression through the spinal parenchyma (white and gray matter) in subpially-injected spinal segments has been demonstrated. Because of the wide range of transgenic mouse models of neurodegenerative diseases, there is a strong desire for the development of a potent central nervous system (CNS)-targeted vector delivery technique in adult mice. Accordingly, the present study describes the development of a spinal subpial vector delivery device and technique to permit safe and effective spinal AAV9 delivery in adult C57BL/6J mice. In spinally immobilized and anesthetized mice, the pia mater (cervical 1 and lumbar 1-2 spinal segmental level) was incised with a sharp 34 G needle using an XYZ manipulator. A second XYZ manipulator was then used to advance a blunt 36G needle into the lumbar and/or cervical subpial space. The AAV9 vector (3-5 µL; 1.2 x 1013 genome copies (gc)) encoding green fluorescent protein (GFP) was then injected subpially. After injections, neurological function (motor and sensory) was assessed periodically, and animals were perfusion-fixed 14 days after AAV9 delivery with 4% paraformaldehyde. Analysis of horizontal or transverse spinal cord sections showed transgene expression throughout the entire spinal cord, in both gray and white matter. In addition, intense retrogradely-mediated GFP expression was seen in the descending motor axons and neurons in the motor cortex, nucleus ruber, and formatio reticularis. No neurological dysfunction was noted in any animals. These data show that the subpial vector delivery technique can successfully be used in adult mice, without causing procedure-related spinal cord injury, and is associated with highly potent transgene expression throughout the spinal neuraxis.