Chikara Kubota

Filamin A-interacting protein (FILIP) regulates cortical cell migration out of the ventricular zone

Precisely regulated radial migration out of the ventricular zone is essential for corticogenesis. Here, we identify a mechanism that can tether ventricular zone cells in situ. FILIP interacts with Filamin A, an indispensable actin-binding protein that is required for cell motility, and induces its degradation in COS-7 cells. Degradation of Filamin A is identified in the cortical ventricular zone, where filip mRNA is localized. Furthermore, most ventricular zone cells that overexpress FILIP fail to migrate in explants. These results demonstrate that FILIP functions through a Filamin A–F-actin axis to control the start of neocortical cell migration from the ventricular zone.

Effect of mechanical compression on the lumbar nerve root: localization and changes of intraradicular inflammatory cytokines, nitric oxide, and cyclooxygenase.

Study Design. Investigation of intraradicular inflammation induced by mechanical compression. Objective. To investigate the mechanism of nerve root pain, this study used a lumbar nerve root compression model. Summary of Background Data. The manifestation of pain at sites of inflammation has a close relationship with the release of mediators from macrophages. However, the mediators involved in inflammation of nerve roots as a result of mechanical compression remain almost unknown. Methods. In this study, the seventh lumbar nerve root of dogs was compressed with a clip for 3 weeks to observe the changes caused by compression. Immunohistochemistry was performed using the avidin-biotin-peroxidase complex method to observe the changes of T cells (CD45) and macrophages (Mac-1) after compression. Antibodies against as interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (i-NOS), and cyclooxygenase (COX)-1 and 2 were used to examine the localization and changes of these mediators caused by nerve root compression. Results. In control animals, resident T cells were detected, but there were no macrophages. IL-1β and COX-2 were positive in the Schwann cells and vascular endothelial cells, while COX-1 was detected in the vascular endothelial cells. However, no cells showed TNF-α or i-NOS positively. After nerve root compression, numerous T cells and macrophages appeared among the demyelinized nerve fibers. The macrophages were positive for IL-1β, TNF-α, i-NOS, and COX-2. Conclusion. Inflammatory cytokines, NO, and COX-2 may be deeply involved in radiculitis caused by mechanical compression, and these mediators seem to be important in the manifestation of root pain.

Progressive changes in neurofilament proteins and growth-associated protein-43 immunoreactivities at the site of cervical spinal cord compression in spinal hyperostotic mice.

Study Design. Immunohistochemical examination of the expression and localization of neurofilament (NF) proteins and growth-associated protein (GAP)-43 in spinal hyperostotic (twy/twy) mice with progressive compression of the cervical spinal cord. Objective. To determine the biologic functions of NF proteins and GAP-43 in the mouse cervical spinal cord during chronic mechanical compression. Summary of Background Data. The pathologic and repair process in the chronically compressed spinal cord are understood poorly. The present authors hypothesized that there existed an increased expression of NF proteins and GAP-43 in twy/twy mice during the lengthy period of spinal cord compression, which resembles compressive myelopathy. Methods. The cervical spinal cords of 54 twy mice (aged 8 weeks [n = 18], 14 weeks [n = 18], and 20 weeks [n = 18]) and 18 control animals were examined histologically. Using appropriate antibodies, sections were also stained immunohistochemically for NF proteins and GAP-43. Results. Separation of the myelin sheath from the axon and axonal swelling with deformation were detected in the anterior and lateral funiculi of the spinalcords of 20-week-old twy/twy mice. No such changes were noted in 8-week-old twy mice. In twy/twy mice aged 8 and 14 weeks with mild-to-moderate compression, weak immunoreactivities (mainly in the white matter) for NF proteins and GAP-43 were noted; however, in 20-week-old twy/twy mice, these axons stained strongly positive and immunoreactive swollen axons were present. The relative area of GAP-43 immunoreactive axons gradually increased between 8 and 20 weeks in each column, particularly in the anterior and lateral funiculi in the contralateral side of compression. Conclusions. The results showed that the expression of NF proteins and GAP-43 in the white matter increased proportionally with the magnitude of spinal cord compression, and indicated the possible involvement of GAP-43 in both axonal degeneration and repair processes in the chronically compressed spinal cord.

Ligamentum flavum hematoma in the thoracic spine.

We report a case of a hematoma of ligamentum flavum at T11-12 in a 66-year-old man who presented with progressive weakness of the right foot and numbness of both legs. Past history was negative and no precipitating episode of lower back sprain or trauma. The resected T11 and T12 laminas showed old hematoma with degenerative changes in the ligamentum flavum. Hematoma occurring in the thoracic spine has never been reported previously.

Spontaneous remission of a solitary intraspinal synovial cyst of the lumbar spine

Abstract We report on a 15-year-old boy in whom a spontaneous remission of a symptomatic synovial cyst, possibly emanating from the L4-5 facet joint, was noted. The medical history suggested that sport-related overactivity and/or minor trauma was the underlying cause. Conservative treatment for several months may be one treatment option if the cyst wall is not calcified and the symptoms and signs related to radiculopathy show a gradual decrease.

LL5β Directs the Translocation of Filamin A and SHIP2 to Sites of Phosphatidylinositol 3,4,5-Triphosphate (PtdIns(3,4,5)P3) Accumulation, and PtdIns(3,4,5)P3 Localization Is Mutually Modified by Co-recruited SHIP2

Phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) accumulates at the leading edge of migrating cells and works, at least partially, as both a compass to indicate directionality and a hub for subsequent intracellular events. However, how PtdIns(3,4,5)P3 regulates the migratory machinery has not been fully elucidated. Here, we demonstrate a novel mechanism for efficient lamellipodium formation that depends on PtdIns(3,4,5)P3 and the reciprocal regulation of PtdIns(3,4,5)P3 itself. LL5β, whose subcellular localization is directed by membrane PtdIns(3,4,5)P3, recruits the actin-cross-linking protein Filamin A to the plasma membrane, where PtdIns(3,4,5)P3 accumulates, with the Filamin A-binding Src homology 2 domain-containing inositol polyphosphate 5-phosphatase 2 (SHIP2). A large and dynamic lamellipodium was formed in the presence of Filamin A and LL5β by the application of epidermal growth factor. Conversely, depletion of either Filamin A or LL5β or the overexpression of either an F-actin-cross-linking mutant of Filamin A or a mutant of LL5β without its PtdIns(3,4,5)P3-interacting region inhibited such events in COS-7 cells. Because F-actin initially polymerizes near the plasma membrane, it is likely that membrane-recruited Filamin A efficiently cross-links newly polymerized F-actin, leading to enhanced lamellipodium formation at the site of PtdIns(3,4,5)P3 accumulation. Moreover, we demonstrate that co-recruited SHIP2 dephosphorylates PtdIns(3,4,5)P3 at the same location.

Netrin-1 is crucial for the establishment of the dorsal column-medial lemniscal system

The dorsal column‐medial lemniscal system is a significant sensory pathway that mediates touch and limb position sense. In this system, axons from the second‐order neurons in the dorsal column nuclei form the internal arcuate fibers, cross the ventral midline (floor plate) within the medulla oblongata, and then project to the thalamus as the medial lemniscus. Here we demonstrate that Netrin‐1, which is secreted from the floor plate in the medulla oblongata, is indispensable to the formation of the dorsal column‐medial lemniscal system. Axons from the dorsal column nuclei cross the midline at around embryonic day 11 in mice. Concurrently, Netrin‐1 mRNA and its receptor DCC (deleted in colorectal cancer) were expressed in the floor plate and commissural axons there, respectively. In our explant culture experiments, the floor plates of the embryonic 11‐day‐old mutant Netrin‐1 homozygous mice did not attract axons from the dorsal column nuclei of ICR mice, while those from the wild type littermates did. Moreover, we observed that although the dorsal column nuclei developed in situ in mutant mice, their axons were not attracted toward the floor plate: they did not cross midline and remained ipsilaterally, without forming the internal arcuate fibers, in embryonic 17‐day‐old mutant Netrin‐1 homozygous mice.

Second lumbrical-interossei nerve test predicts clinical severity and surgical outcome of carpal tunnel syndrome

The purpose of this study was to examine the utility of the second lumbrical-interossei nerve (2L-IN) test in the diagnosis of carpal tunnel syndrome (CTS). We examined 65 patients with suspected unilateral CTS using the 2L-IN test, in addition to the standard electrophysiological test. The operative cases were divided into three classes of severity based on Paduas neurophysiological classification: extreme CTS (absence of median motor and sensory response); severe CTS (absence of sensory response, abnormal distal motor latency [DML]); and moderate CTS (abnormal sensory nerve conduction velocity, abnormal DML). With the 2L-IN test, the extreme CTS group could be further subdivided into extreme CTS-A (both abductor pollicis brevis [APB]- compound muscle action potential [CMAP] and 2L-CMAP not recordable) and extreme CTS-B (2L-CMAP recordable, APB-CMAP not recordable). Patients with extreme CTS and severe CTS were older, had chronic symptoms, and poorer outcome compared with the moderate CTS patients. Patients of the moderate CTS group were almost all satisfied with the results of surgery. The electrodiagnostic severity correlated with the clinical outcome. Severe strangulation of the thenar muscle branch was identified in patients in the extreme CTS-B group, requiring decompression of the thenar muscle branch rather than conventional simple transverse ligament detachment.

Microsurgical Excision of Ganglioneuroma Arising from the C8 Nerve Root within the Neuroforamen

Ganglioneuromas are benign, slow-growing tumors originating from sympathetic nerves or peripheral nerves, often associated with multiple tumor syndromes. They occasionally occur as spinal lesions and grow within the spinal canal or as paraspinal lesions. In this report, we describe a rare solitary ganglioneuroma arising from the cervical nerve root (C8) within the intervertebral foramen in adults. The tumor could be detected as a mass limited to the neuroforamen at an early stage by MR images. Unilateral microsurgical foraminotomy and EN BLOC resection of the tumor resulted in disappearance of the symptoms. Microsurgical resection of the relevant nerve root through limited medial foraminotomy at an intricate anatomical region of the cervico-thoracic junction was appropriate in the current case for complete resection of the tumor as well as to prevent postoperative structural weakness that could result in late segmental instability.

Additional method for diagnosis of carpal tunnel syndrome: value of the second lumbrical-interossei test (2L-INT).

We examined 57 hands referred with suspected carpal tunnel syndrome (CTS) using the second lumbrical-interossei nerve test (2L-INT) as well as standard test. Sensory nerve conduction velocity (SCV) was detectible in 67% of patients (38/57), the abductor pollicis brevis-compound muscle action potential (APB-CMAP) in 84% (48/57), 2L-CMAP in 96% (55/57) and the first interossei palmares muscle (INT-CMAP) in 100% (57/57). ABP-CMAP was not recorded in patients in whom severe atrophy of the abductor pollicis brevis muscle was evident. As 2L-CMAP is maintained even in the most severe cases of CTS, the 2L-INT method is a valuable test for improving the accuracy of preoperative diagnosis in the electrophysiological diagnosis of CTS.