Characteristics of successful termination of atrial fibrillation by atrial antitachycardia pacing in patients with cardiac implantable electronic devices.

Asymptomatic paroxysmal atrial fibrillation (AF) is often found in patients implanted with cardiac implantable electronic devices (CIEDs). Second-generation atrial antitachycardia pacing (A-ATP) is effective in managing AF in patients implanted with CIEDs. The purpose of this study was to evaluate the efficacy and safety of A-ATP in patients implanted with CIEDs. This was a single-center retrospective study involving 91 patients (male 46 patients, mean age 74 ± 9 years) implanted with Reactive A-ATP equipped devices (84 patients with pacemakers, 6 with ICDs, and 1 with a CRT-D). The AF burden, rate of AF termination, and details of the activation of the A-ATP were analyzed in each patient. During a mean follow-up period of 21 ± 13 months, A-ATP was activated in 45 of 91 patients (49.5%). No patients had adverse events. Although the efficacy of the A-ATP varied among the patients, the median rate of AF termination was 44%. In comparison to the A-ATP start time, "0 min" had a higher AF termination rate by the A-ATP (39.4% vs. 24.4%, P = 0.011). The rate of termination by the A-ATP was high for AF with a long cycle length and a relatively regular rhythm. A-ATP successfully terminated AF episodes in some patients implanted with CIEDs. The optimal settings of the A-ATP will be determined in future studies.

Myelinating cocultures of rodent stem cell line-derived neurons and immortalized Schwann cells.

Myelination is one of the most remarkable biological events in the neuron-glia interactions for the development of the mammalian nervous system. To elucidate molecular mechanisms of cell-to-cell interactions in myelin synthesis in vitro, establishment of the myelinating system in cocultures of continuous neuronal and glial cell lines are desirable. In the present study, we performed co-culture experiments using rat neural stem cell-derived neurons or mouse embryonic stem (ES) cell-derived motoneurons with immortalized rat IFRS1 Schwann cells to establish myelinating cultures between these cell lines. Differentiated neurons derived from an adult rat neural stem cell line 1464R or motoneurons derived from a mouse ES cell line NCH4.3, were mixed with IFRS1 Schwann cells, plated, and maintained in serum-free F12 medium with B27 supplement, ascorbic acid, and glial cell line-derived neurotrophic factor. Myelin formation was demonstrated by electron microscopy at 4 weeks in cocultures of 1464R-derived neurons or NCH4.3-derived motoneurons with IFRS1 Schwann cells. These in vitro coculture systems utilizing the rodent stable stem and Schwann cell lines can be useful in studies of peripheral nerve development and regeneration.

Involvement of oxidative stress and impaired lysosomal degradation in amiodarone-induced schwannopathy.

Amiodarone hydrochloride (AMD), an anti-arrhythmic agent, has been shown to cause peripheral neuropathy; however, its pathogenesis remains unknown. We examined the toxic effects of AMD on an immortalized adult rat Schwann cell line, IFRS1, and cocultures of IFRS1 cells and adult rat dorsal root ganglion neurons or nerve growth factor-primed PC12 cells. Treatment with AMD (1, 5, and 10 µm) induced time- and dose-dependent cell death, accumulation of phospholipids and neutral lipids, upregulation of the expression of gangliosides, and oxidative stress (increased nuclear factor E2-related factor in nuclear extracts and reduced GSH/GSSG ratios) in IFRS1 cells. It also induced the upregulation of LC3-II and p62 expression, with phosphorylation of p62, suggesting that deficient autolysosomal degradation is involved in AMD-induced IFRS1 cell death. Furthermore, treatment of the cocultures with AMD induced detachment of IFRS1 cells from neurite networks in a time- and dose-dependent manner. These findings suggest that AMD-induced lysosomal storage accompanied by enhanced oxidative stress and impaired lysosomal degradation in Schwann cells might be a cause of demyelination in the peripheral nervous system.

Adenoviral expression of TDP-43 and FUS genes and shRNAs for protein degradation pathways in rodent motoneurons in vitro and in vivo.

Formation of cytoplasmic aggregates in neuronal and glial cells is one of the pathological hallmarks of amyotrophic lateral sclerosis (ALS). Mutations in two genes encoding transactivation response (TAR) DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS), both of which are main constituents of cytoplasmic aggregates, have been identified in patients with familial and sporadic ALS. Impairment of protein degradation machineries has also been recognized to participate in motoneuron degeneration in ALS. In the present study, we produced recombinant adenovirus vectors encoding wild type and mutant TDP-43 and FUS, and those encoding short hairpin RNAs (shRNAs) for proteasome (PSMC1), autophagy (ATG5), and endosome (VPS24) systems to investigate whether the coupled gene transductions in motoneurons by these adenoviruses elicit ALS pathology. Cultured neurons, astrocytes and oligodendrocytes differentiated from adult rat neural stem cells and motoneurons derived from mouse embryonic stem cells were successfully infected with these adenoviruses showing cytoplasmic aggregate formation. When these adenoviruses were injected into the facial nerves of adult rats, exogenous TDP-43 and FUS proteins were strongly expressed in facial motoneurons by a retrograde axonal transport of the adenoviruses. Co-infections of adenovirus encoding shRNA for PSMC1, ATG5 or VPS24 with TDP-43 or FUS adenovirus enhanced cytoplasmic aggregate formation in facial motoneurons, suggesting that impairment of protein degradation pathways accelerates formation of TDP-43 and FUS-positive aggregates in ALS.

Myelination in coculture of established neuronal and Schwann cell lines.

Establishing stable coculture systems with neuronal and Schwann cell lines has been considered difficult, presumably because of their high proliferative activity and phenotypic differences from primary cultured cells. The present study is aimed at developing methods for myelin formation under coculture of the neural crest-derived pheochromocytoma cell line PC12 and the immortalized adult rat Schwann cell line IFRS1. Prior to coculture, PC12 cells were seeded at low density (3 × 10(2)/cm(2)) and maintained in serum-free medium with N2 supplement, ascorbic acid (50 µg/ml), and nerve growth factor (NGF) (50 ng/ml) for a week. Exposure to such a NGF-rich environment with minimum nutrients accelerated differentiation and neurite extension, but not proliferation, of PC12 cells. When IFRS1 cells were added to NGF-primed PC12 cells, the cell density ratio of PC12 cells to IFRS1 cells was adjusted from 1:50 to 1:100. The cocultured cells were then maintained in serum-free medium with B27 supplement, ascorbic acid (50 µg/ml), NGF (10 ng/ml), and recombinant soluble neuregulin-1 type III (25 ng/ml). Myelin formation was illustrated by light and electron microscopy performed at day 28 of coculture. The stable PC12-IFRS1 coculture system is free of technical and ethical problems arising from the primary culture and can be a valuable tool to study peripheral nerve degeneration and regeneration.

Spontaneously immortalized Schwann cells from adult Fischer rat as a valuable tool for exploring neuron-Schwann cell interactions.

We established spontaneously immortalized Schwann cell lines from long-term cultures of adult Fischer 344 rat dorsal root ganglia (DRG) and peripheral nerves. One of these cell lines, designated immortalized Fischer rat Schwann cells 1 (IFRS1), showed spindle-shaped morphology; immunoreactivity for S100, p75 neurotrophin receptor (p75(NTR) ), glial fibrillary acidic protein (GFAP), laminin, and vimentin; and mRNA expression of neurotrophic factors (NGF, GDNF, and CNTF), neurotrophin receptors (p75(NTR) , truncated TrkB, and TrkC), cell adhesion molecules (L1, NCAM, and N-cadherin), myelin proteins [P0, PMP22, and myelin-associated glycoprotein (MAG)], transcription factors (Krox20, Sox10, and Oct6), neuregulin-1 receptors (ErbB2 and ErbB3), and an orphan G protein-coupled receptor (Gpr126). Conditioned medium (CM) obtained from IFRS1 cells exhibited potent biological activity for the promotion of neuronal survival and neurite outgrowth of cultured adult rat DRG neurons. Furthermore, light and electron microscopic analyses revealed that IFRS1 cells were capable of myelinating neurites while in coculture with adult rat DRG neurons. These findings indicate that IFRS1 cells possess some biological properties of mature Schwann cells and that the coculture system with adult DRG neurons and IFRS1 cells can be a useful tool for the study of peripheral nerve degeneration and regeneration.

Prognostic Impact of Early Induction of Intra-Aortic Balloon Pump Counterpulsation in High-Risk Patients With Acute Heart Failure.

BACKGROUND: Intra-aortic balloon pumping (IABP) counterpulsation provides potent supports on hemodynamic status of patients with cardiogenic shock. However, only limited numbers of patients with acute heart failure (AHF) under collapsed hemodynamic status received such benefit of IABP. We aimed to evaluate the impact of the timing of IABP induction on clinical prognosis in AHF patients at very high risk. METHODS: Of 404 consecutive AHF patients, 57 patients both with left ventricular ejection fraction (LVEF) <35% and systolic blood pressure on admission <100 mmHg were ultimately enrolled in this observational study. They were divided into 3 groups depending on IABP use; Early-IABP group (induction at ≤3 days after admission, n = 17), Late-IABP group (>3 days, n = 15) and No-IABP group (n = 25). The primary endpoint was a composite of in-hospital cardiovascular (CV) death and ventricular assisted device implantation. RESULTS: This high-risk population was typically mid-age (60 years-old), 61% male, and 75% with chronic kidney disease, and its average LVEF was 24.7%. Clinical profiles on admission were comparable among 3 subgroups, except prehospital prescription rate of loop diuretics. During hospital stay, intravenous inotropes were significantly more frequently administered in the Late-IABP group than other 2 groups. The primary endpoint was developed in 17.6% of patients in the Early-IABP group, which was significantly lower than that in the Late-IABP group (53.3%, p = 0.034) and was comparable to the No-IABP group (40.0%, p = 0.12). CONCLUSIONS: Early induction of IABP is one of the therapeutic options for improvement of in-hospital prognosis in AHF patients at very high risk.

Degeneration of astrocytic processes and their mitochondria in cerebral cortical regions peripheral to the cortical infarction: heterogeneity of their disintegration is closely associated with disseminated selective neuronal necrosis and maturation of injury.

BACKGROUND AND PURPOSE: Astrocytes support neuronal functions by regulating the extracellular ion-homeostasis and levels of neurotransmitters, and by providing fuel such as lactate to the neurons via their astrocytic processes (APs). Whether injured APs are associated with neuronal survival/death is still an unanswered question. We investigated APs in the neuropil, especially those around astrocytes and normal-appearing, degenerating, and dead neurons in cerebral cortical regions peripheral to the cortical infarction (RPI). METHODS: Stroke-positive gerbils were euthanized at various times after the ischemic insult. Ultrathin sections were obtained from the RPI sectioned coronally at the infundibular level. We counted the number of normal-appearing, degenerated, and dead neurons and astrocytes in paraffin sections, the number of cut-ends and mitochondria in APs in the neuropil on electron-microscopic photographs, and determined the percent-volume of APs by Weibel point-counting method. We compared the number of cut-ends and mitochondria and percent-volume of APs around astrocytes at 5 hours and 48 hours, and around normal-appearing, degenerated, and dead neurons at 12 hours. RESULTS: Although the number of astrocytes did not change (average of 12.3+/-0.20%) during 0 to 48 hours, that of the dead neurons increased from 9.71+/-1.34 to 44.39+/-1.40% during 5 to 48 hours postischemia. The number of normal-appearing APs and mitochondria in APs decreased respectively from 13.49+/-0.65 to 1.61+/-0.14/28.20 microm(2) and from 1.86+/-0.18 to 0.61+/-0.07/28.20 microm(2) in the neuropil during 0 to 48 hours. The number of normal-appearing APs around astrocytes decreased from 12.3+/-0.19 to 1.7+/-0.05/38.33 microm(2) with an increase in percent-volume of degenerated APs from 1.17+/-0.04 to 11.45+/-0.23%, from 5 to 48 hours postischemia. The number of normal-appearing APs decreased from 4.36+/-0.52 to 1.56+/-0.17/38.33 microm(2) with an increase in percent-volume of degenerated APs, from 2.41+/-0.52 to 12.55+/-1.0%, from around the normal-appearing to dead neurons, at 12 hours. CONCLUSIONS: In the RPI, heterogeneous degeneration of APs was closely associated with disseminated selective neuronal necrosis and the maturation phenomenon seen in ischemic neuronal injury.

Magnesium concentration in the cerebrospinal fluid of mice and its response to changes in serum magnesium concentration.

Magnesium (Mg) is essential for cell functions such as the transport of calcium and potassium ions, and modulates signal transduction, energy metabolism, and cell proliferation. Although mice have been used as models of various neurological diseases of humans, and for investigating the therapeutic effects of Mg, neither the normal concentration of Mg in cerebrospinal fluid (CSF), nor its response to alteration of the serum level of Mg has yet been reported. The present study investigated the normal Mg concentration in the CSF of C57BL/6J (B6) and ICR mice and its response to elevation of the serum Mg level in B6 mice. In B6 mice, the normal Mg concentration in the CSF was 0.89 ± 0.11 mM, being lower than that in serum, which was 1.38 ± 0.12 mM, whereas in ICR mice the corresponding values were 1.00 ± 0.12 mM and 1.10 ± 0.09 mM, respectively. No significant alteration was found in the CSF of B6 mice injected intraperitoneally with Mg, even though the serum Mg concentration was significantly increased.

Relationship between ribosomal RNA gene transcription activity and motoneuron death: observations of avulsion and axotomy of the facial nerve in rats.

Motoneuron number and expression of cytoplasmic RNA and ribosomal RNA (rRNA) gene transcription activity in the facial nucleus were examined quantitatively and chronologically for up to 4 weeks in rats after facial nerve axotomy and avulsion in order to elucidate interrelationships in axonal changes. The right facial nerves of adult Fischer rats were avulsed at a portion of the outlet or axotomized at a portion of the foramen stylomastoideus. The number of large motoneurons in the facial nucleus was reduced by 40% 2 weeks after avulsion and by 70% 4 weeks after avulsion but displayed a 19% loss even 4 weeks after axotomy. The amount of cytoplasmic RNA decreased significantly and progressively from 1 day after avulsion. rRNA gene transcription activity in the large motoneurons of the facial nucleus decreased significantly beginning 30 min after both axotomy and avulsion, but the severity of the decrease was far more marked in the avulsion group, showing a 59% loss from the control value 4 weeks after avulsion. These findings indicate that rRNA gene transcription activity, expression of cytoplasmic RNA, and the number of motoneurons that survive are interrelated and that the decrease in rRNA gene transcription activity is a very early event in the phenomena observed in the axonal reactions of motoneurons.

Fate of disseminated dead neurons in the cortical ischemic penumbra: ultrastructure indicating a novel scavenger mechanism of microglia and astrocytes.

BACKGROUND AND PURPOSE: Because the mechanism for scavenging acidophilic electron-dense dead neurons disseminated among the neuritic networks of surviving neurons in the ischemic penumbra of the cerebral cortex is still obscure, we investigated the fate of them up to 24 weeks after the ischemic insult. METHODS: Stroke-positive animals were selected according to their stroke index score during the first 10-minute left carotid occlusion done twice with a 5-hour interval. The animals were killed at various times after the second ischemic insult. Ultrathin sections including the second through fourth cortical layers were obtained from the neocortex coronally sectioned at the infundibular level in which the penumbra appeared and was observed by electron microscopy. We determined the percentages of resting, activated, and phagocytic microglia and astrocytes in the specimens obtained at various times postischemia. RESULTS: The electron-dense neurons had been fragmented into granular pieces by invading astrocytic processes from the periphery of the dead neurons and only the central portion remained. These granular pieces were dispersed along the extracellular spaces in the neuropil. By 8 to 24 weeks, the central core portion became a tiny vesicular particle (3.5 to 5.5 mum in diameter) with a central dot. Microglia and astrocytes phagocytized these dispersed granular pieces. CONCLUSIONS: We found a novel scavenger mechanism in the ischemic penumbra, one by which dead neurons were fragmented by invading small astrocytic processes and only a thinned-out core portion remained, which finally became a tiny vesicular particle. The dispersed fragmented pieces were phagocytized by the microglia and astrocytes late, at 8 to 24 weeks postischemia.

Formation and spreading of TDP-43 aggregates in cultured neuronal and glial cells demonstrated by time-lapse imaging.

TAR DNA-binding protein 43 (TDP-43) is a main constituent of cytoplasmic aggregates in neuronal and glial cells in cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We have previously demonstrated that adenovirus-transduced artificial TDP-43 cytoplasmic aggregates formation is enhanced by proteasome inhibition in vitro and in vivo. However, the relationship between cytoplasmic aggregate formation and cell death remains unclear. In the present study, rat neural stem cell lines stably transfected with EGFP- or Sirius-expression vectors under the control of tubulin beta III, glial fibrillary acidic protein, or 2',3'-cyclic nucleotide 3'-phosphodiesterase promoter were differentiated into neurons, astrocytes, and oligodendrocytes, respectively, in the presence of retinoic acid. The differentiated cells were then transduced with adenoviruses expressing DsRed-tagged human wild type and C-terminal fragment TDP-43 under the condition of proteasome inhibition. Time-lapse imaging analyses revealed growing cytoplasmic aggregates in the transduced neuronal and glial cells, followed by collapse of the cell. The aggregates remained insoluble in culture media, consisted of sarkosyl-insoluble granular materials, and contained phosphorylated TDP-43. Moreover, the released aggregates were incorporated into neighboring neuronal cells, suggesting cell-to-cell spreading. The present study provides a novel tool for analyzing the detailed molecular mechanisms of TDP-43 proteinopathy in vitro.

L-leucine and SPNS1 coordinately ameliorate dysfunction of autophagy in mouse and human Niemann-Pick type C disease.

Lysosomal storage disorders are characterized by progressive accumulation of undigested macromolecules within the cell due to lysosomal dysfunction. 573C10 is a Schwann cell line derived from a mouse model of Niemann-Pick type C disease-1, NPC (-/-). Under serum-starved conditions, NPC (-/-) cells manifested impaired autophagy accompanied by an increase in the amount of p62 and lysosome enlargement. Addition of L-leucine to serum-starved NPC (-/-) cells ameliorated the enlargement of lysosomes and the p62 accumulation. Similar autophagy defects were observed in NPC (-/-) cells even without serum starvation upon the knockdown of Spinster-like 1 (SPNS1), a putative transporter protein thought to function in lysosomal recycling. Conversely, SPNS1 overexpression impeded the enlargement of lysosomes, p62 accumulation and mislocalization of the phosphorylated form of the mechanistic Target of rapamycin in NPC (-/-) cells. In addition, we found a reduction in endogenous SPNS1 expression in fibroblasts derived from NPC-1 patients compared with normal fibroblasts. We propose that SPNS1-dependent L-leucine export across the lysosomal membrane is a key step for triggering autophagy, and that this mechanism is impaired in NPC-1.

Temporal profiles of axon terminals, synapses and spines in the ischemic penumbra of the cerebral cortex: ultrastructure of neuronal remodeling.

BACKGROUND AND PURPOSE: Because the recovery process of axon terminals, synapses, and spine-dendrites in the ischemic penumbra of the cerebral cortex is obscure, we studied the temporal profile of these structures up to 12 weeks after the ischemic insult, using a gerbil model. METHODS: Stroke-positive animals were selected according to their stroke index score during the first 10-minute left carotid occlusion done twice with 5-hour interval. The animals were euthanized at various times after the second ischemic insult. Ultra-thin sections including the 2nd to 4th cortical layers were obtained from the neocortex coronally sectioned at the infundibular level, in which the penumbra appeared. We counted the number of synapses, spines and multiple synapse boutons, measured neurite thickness, and determined the percent volume of the axon terminals and spines by Weibel point counting method. RESULTS: The number of synapses, synaptic vesicles and spines and the total percent volume of the axon terminals and spines decreased until the 4th day. From 1 to 12 weeks after the ischemic insult, these values increased to or exceeded the control ones, and neuritic thickening and increase in number of multiple synapse boutons occurred. CONCLUSIONS: In the ischemic penumbra, the above structures degenerated, with a reduction in their number and size, until 4 days and then recovered from 1 to 12 weeks after the ischemic insult.

Oxidized galectin-1 advances the functional recovery after peripheral nerve injury.

Oxidized galectin-1 has been shown to promote axonal regeneration from transected-nerve sites in an in vitro dorsal root ganglion (DRG) explant model as well as in in vivo peripheral nerve axotomy models. The present study provides evidence that oxidized galectin-1 advances the restoration of nerve function after peripheral nerve injury. The sciatic nerve of adult rats was transected and the distal nerve was frozen after being sutured into a proximal site with four epineurial stitches. An osmotic pump delivered oxidized galectin-1 peripherally to the surgical site. Functional recovery was assessed by measurement of the degree of toe spread of the hind paw for 3 months after the sciatic nerve lesion. The recovery curves of toe spread in the test group showed a statistically significant improvement of functional recovery after day 21 by the application of oxidized recombinant human galectin-1 (rhGAL-1/Ox) compared to the control group. This functional recovery was supported by histological analysis performed by light microscopic examination. The regenerating myelinated fibers at the site 21 mm distal to the nerve-transected site were quantitatively examined at 100 days after the operation. The frequency distribution of myelinated fiber diameters showed that exogenous rhGAL-1/Ox increased the number and diameter of regenerating myelinated fibers; the number of medium-sized (6-11 microm in diameter) fibers increased significantly (P<0.05). These results indicate that oxidized galectin-1 promotes the restoration of nerve function after peripheral nerve injury. Thus, rhGAL-1/Ox may be a factor for functional restoration of injured peripheral nerves.

Temporary [corrected] cerebral ischemia results in swollen astrocytic end-feet that compress microvessels and lead to delayed [corrected] focal cortical infarction.

We examined the mechanisms underlying the abrupt onset of the focal infarction in disseminated selective neuronal necrosis (DSNN) after temporary ischemia. Stroke-positive animals were selected according to their stroke-index score during the first 10 minutes after left carotid occlusion performed twice at a 5-hour interval. The animals were euthanized at various times after the second ischemia. Light- and electron-microscopical studies were performed chronologically on the coronal-cut surface of the cerebral cortex at the chiasmatic level, where focal infarction evolved in the maturing DSNN. We counted the number of neurons, astrocytes, and astrocytic processes (APs); measured the areas of end-feet and astrocytes; and counted the numbers of obstructed microvessels and carbon-black-suspension-perfused microvessels (CBSPm). Between 0.5 and 5 hours after ischemia, DSNN matured, with the numbers of degenerated and dead neurons increasing, and those of APs cut-ends decreasing; whereas the area of the end-feet and the numbers of obstructed microvessels increased and those of CBSPm decreased. At 12 and 24 hours after ischemia, the infarction evolved, with the area of end-feet and astrocytic number decreased; whereas the numbers of obstructed microvessels decreased and the CBSPm number increased. The focal infarction evolved by temporary microvascular obstruction because of compression by swollen end-feet.

Immortalized adult rodent Schwann cells as in vitro models to study diabetic neuropathy.

We have established spontaneously immortalized Schwann cell lines from normal adult mice and rats and murine disease models. One of the normal mouse cell lines, IMS32, possesses some biological properties of mature Schwann cells and high proliferative activities. The IMS32 cells under hyperglycemic and/or hyperlipidemic conditions have been utilized to investigate the pathogenesis of diabetic neuropathy, especially the polyol pathway hyperactivity, glycation, increased oxidative stress, and reduced synthesis of neurotrophic factors. In addition to the mouse cell lines, our current study focuses on the characterization of a normal rat cell line, IFRS1, under normal and high glucose conditions. These Schwann cell lines can be valuable tools for exploring the detailed mechanisms leading to diabetic neuropathy and novel therapeutic approaches against that condition.

Magnesium deficiency over generations in rats with special references to the pathogenesis of the Parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam.

Parkinsonism-dementia complex (PDC) and amyotrophic lateral sclerosis (ALS) are fatal neurological diseases. The incidence on Guam was very high between 1950 and 1965 but decreased dramatically after 1965. It is thought that drinking water containing low levels of calcium (Ca) and magnesium (Mg), and high levels of aluminum and of a plant excitatory neurotoxin are involved in the pathogenesis of these diseases. The present experiment was performed in rats that were exposed to low Ca and/or Mg intake over two generations, thus simulating the conditions of human life on Guam, where several generations live continuously in the same environment. Significant loss of dopaminergic neurons was identified exclusively in the substantia nigra in 1-year-old rats that had been exposed continuously to low Mg intake (one-fifth of the normal level) over generations. The present study suggests that low Mg intake over generations may be involved in the pathogenesis of substantia nigra degeneration in humans.

Klotho insufficiency causes decrease of ribosomal RNA gene transcription activity, cytoplasmic RNA and rough ER in the spinal anterior horn cells.

The klotho gene was identified in 1997 as the gene whose severe insufficiency (kl/kl) causes a syndrome resembling human aging, such as osteoporosis, arteriosclerosis, gonadal atrophy, emphysema, and short life span in a mouse strain. Regarding the gait disturbance reported in kl/kl mice, the present study examined the spinal cord of kl/kl mice, and revealed decreases in the number of large anterior horn cells (AHCs), the amount of cytoplasmic RNA, the number of ribosomes and rough endoplasmic reticulum (rER), and the activity of ribosomal (r) RNA gene transcription without significant loss of the total number of neurons in the ventral gray matter. Increased immunostaining of phosphorylated neurofilament in the AHCs and of glial fibrillary acidic protein in reactive astrocytes in the anterior horn of kl/kl mice were also observed. On the other hand, the posterior horn was quite well preserved. The results suggest that the kl/kl insufficiency causes atrophy and dysfunction of the spinal AHCs through decreased activity of rRNA gene transcription, which may reduce the amount of cytoplasmic RNA and the number of ribosomes and rER. These findings resemble those found in the spinal cord of patients with classic amyotrophic lateral sclerosis (ALS). The results show that klotho gene insufficiency causes dysfunction of the protein synthesizing system in the AHCs, and might indicate the klotho gene is involved in the pathological mechanism of classic ALS. The kl/kl is a new animal model of AHC degeneration, and may provide clues to understanding the etiology of classic ALS.

Widespread vertebral and epidural venous plexus metastasis of prostatic carcinoma presenting wedge-shaped radial lesions in the spinal cord.

The present case is the first autopsy case of prostatic carcinoma presenting widespread spinal epidural venous plexus tumor cell emboli with wedge-shaped spinal cord lesions. There has been no previous report of prostatic carcinoma showing tumor cell emboli in the spinal and cranial base epidural venous plexus, in spite of the fact that the incidence of vertebral metastasis in prostatic carcinoma is high, and that presence of continuity from pelvic organs to venous plexus around vertebrae, up to foramen magnum, has been reported. The present case shows that the possibility of spinal cord injury, not by direct compression, but by venous circulatory disturbance as a result of tumor cell emboli to veins, should be taken into consideration on medical treatment of prostatic carcinoma.