Characterization of unexpected postural changes during robot-assisted gait training in paraplegic patients.

STUDY DESIGN: This is a retrospective study. OBJECTIVES: The objectives of this study were to categorize unexpected postural changes (UPCs) during gait training in paraplegic patients with wearable gait-assist robots, to reveal the incidence of the UPC and its time-dependent changes during initial gait training period and to investigate neurological level-specific differences. SETTING: This study was conducted in Fujita Health University, Aichi, Japan. METHODS: We investigated five patients (46.2±14.6 years; lesion level: T6:3, T12:2). All patients had previously achieved gait with wearable robot and walker at supervision level. The UPCs were counted for 2 years and classified according to their type. The time-course data were calculated from the incidence of UPCs for 10 days from initial gait training with the walker. The neurological level-specific differences were investigated between T6 and T12 injuries. RESULTS: Eighty-five UPCs were observed and classified into three categories: anterior breakdown, posterior breakdown (PBD) and mal-timing. The average rate over the entire period was 0.96±0.62 (incidents/h/subject). PBD, which was defined as hyperflexion of both hip joints, occurred with the highest frequency (0.64±0.64 incidents/h/subject). During initial gait training, there was a gradual decrease in the occurrence of UPC. For neurological level-specific differences, UPCs were observed more frequently in T6 injuries (1.36±0.35 incidents/h/subject) compared with T12 injuries (0.36±0.31 incidents/h/subject). CONCLUSION: PBDs might be the result of near collisions between the trunk of the user and the walker, which make it difficult for the users to move their trunk over an anterior stance limb. Training that is focused upon well-timed forward movements of the walker might be required to avoid the occurrence of this common UPC.

Permanent acceptance of mouse cardiac allografts with CD40 siRNA to induce regulatory myeloid cells by use of a novel polysaccharide siRNA delivery system.

The CD40/CD154 co-stimulatory pathway is crucial in alloimmune response. We developed a novel small interfering RNA (siRNA) delivery system with a poly-dA extension at the 5'-end of the siRNA sense strand that was stably incorporated into 1,3-ß-glucan (schizophyllan, SPG). This was captured and incorporated into dendritic cells (DCs) through its receptor, Dectin-1, specifically silencing CD40 genes (siCD40) to exert immunoregulatory activity. siCD40/SPG-treated CBA mice permanently accepted B10 fully mismatched cardiac allografts. Consistent with graft survival, the infiltration of CD4(+), CD8(+) T cells into the graft was lower, and that the numbers of CD40(low)CD11c(+) DCs cells and CD4(+)Foxp3(+)cells were increased in both the graft and in the recipient spleen. In addition, naive CBA recipients given an adoptive transfer of splenocytes from the primary recipients with siCD40/SPG accepted a heart graft from donor-type B10, but not third-party Balb/c mice. In conclusion, the treatment with siCD40/SPG targeting DCs could generate antigen-specific Tregs, resulting in the permanent acceptance of mouse cardiac allografts. These findings have important implications for clarifying the mechanism underlying the induction of tolerance in DCs, and also highlight the potential of immunomodulation and the feasibility of siRNA-based clinical therapy in the transplantation field.

Evidence against a role of gap junctions in vestibular compensation.

Vestibular compensation following unilateral labyrinthectomy is associated with modifications of the membrane and firing properties of central vestibular neurons. To determine whether gap junctions could be involved in this process, immunofluorescent detection of neuronal connexin 36 and astrocytic connexin 43 was performed in the medial vestibular nucleus (MVN) of rats. In non-lesioned animals, strong staining was observed with anti-connexin 43 antibodies, while moderate staining was obtained with the anti-connexin 36 antibody. However, the expression of either type of connexin was not modified following unilateral labyrinthectomy. These morphological observations were complemented by pharmacological tests performed during extracellular recordings of MVN neurons in guinea pig brainstem slices. In non-lesioned animals, the gap junction blocker carbenoxolone reversibly decreased or suppressed the spontaneous discharge of about 60% of MVN neurons. This reduction was often associated with a long-duration disruption of the regularity of spike discharge. Both effects were mimicked by several other gap junction blockers, but not by glycyrrhizic acid, an analog of carbenoxolone that does not block gap junctions but reproduces its non-specific effects, nor by the selective inhibitor of astrocytic connexin-based networks endothelin-1. Similar effects of carbenoxolone were obtained on the spontaneous activity of ipsilesional MVN neurons recorded in brainstem slices taken from labyrinthectomized animals. Altogether, these results suggest that neuronal gap junctions are involved in shaping the spontaneous activity of MVN neurons. However, unilateral labyrinthectomy does not affect the expression of gap junctions in vestibular nuclei nor their implication in the regulation of neuronal activity.

Natural course of the remission of vertigo in patients with benign paroxysmal positional vertigo.

The authors assessed the natural course of benign paroxysmal positional vertigo (BPPV) in 108 patients who were not treated with canalith repositioning procedure. The average number of days from onset to remission of positional vertigo in patients with posterior canal BPPV (P-BPPV) (39 days) was longer than in those with horizontal canal BPPV (H-BPPV) (16 days). The ratio of patients with H-BPPV to those with BPPV was 33%.

Vestibular function and vasopressin.

OBJECTIVE: To investigate the relation between the vestibular system and vasopressin (AVP). MATERIAL AND METHODS: We examined the effects of electrical and caloric vestibular stimulation on plasma AVP levels in anesthetized rats. Plasma AVP levels of patients with intractable Ménière's disease who were subjected to endolymphatic drainage and steroid instillation surgery (EDSS) or intratympanic gentamicin (GM) injection were measured before and after these interventions. RESULTS: Electrical vestibular stimulation increased plasma AVP levels in a current intensity-dependent manner. Plasma AVP levels were also increased by caloric stimulation with cold water. Plasma AVP levels decreased rapidly after EDSS, and were maintained at a low level even 6-12 months following EDSS or intratympanic GM injection. CONCLUSIONS: Vestibular activation or inhibition-induced imbalance of intervestibular activities increased plasma AVP levels in rats. Therefore, vestibular disorder would seem to increase plasma AVP and thus worsen endolymphatic hydrops. EDSS rapidly decreased plasma AVP and would seem to reduce hydrops. Inhibition of vertigo spells by EDSS or intratympanic GM injection would reduce a possible stress response, resulting in a decrease in plasma AVP levels a long time after the treatments. This resultant decrease in AVP would beneficially inhibit the formation and/or maintenance of hydrops and thus prevent vertigo spells.

Vestibular modulation of plasma vasopressin levels in rats.

Recent studies, which have shown an increase of plasma vasopressin (VP) in experimental motion sickness and the efficacy of VP antagonists for motion sickness, suggest an important role of VP in the development of vestibulo-autonomic responses. We have recently found evidence of the co-existence of vasopressinergic neurons with the stress-sensitive chemokinergic neuronal system in the hypothalamo-pituitary pathway in rats, which uses cytokine-induced neutrophil chemoattractant (CINC) as an effector molecule. In this study, to elucidate possible roles of VP and CINC in the vestibulo-autonomic responses, we simultaneously measured plasma VP and CINC concentrations after electrical or caloric vestibular stimulation in urethane-anesthetized rats. Electrical vestibular stimulation with more than 200 microA increased the plasma levels of VP in a current intensity-dependent manner, and stimulation with 500 microA increased the plasma VP levels to 350% of the normal control group, which received no stimulation. Caloric vestibular stimulation with cold water increased the plasma VP levels to 262% of the control group, which received caloric stimulation with water at 37 degrees C, and stimulation with warm water tended to increase the plasma VP levels. Plasma CINC levels were neither affected by electrical nor caloric vestibular stimulation. These findings indicate that vestibular stimulation increased plasma levels of VP but not CINC, and this vestibular-induced activation of VP neurons may be involved in a mechanism of vestibulo-autonomic responses.

Role of cholinergic mossy fibers in vestibular nuclei in the development of vestibular compensation.

Several lines of evidence have suggested that acetylcholine is a possible neurotransmitter/neuromodulator involved in vestibular compensation. However, details of cholinergic effective sites during vestibular compensation remain unclear. In this study, we selectively damaged the rat vestibulo-floccular cholinergic mossy fibers using ethylcholine mustard aziridinium ion. In these animals, unilateral labyrinthectomy caused more severe vestibulo-ocular deficits, especially in the initial stage. These findings suggest that the vestibulo-floccular cholinergic mossy fibers serve to restore the balance between intervestibular nuclear activities in order to induce vestibular compensation in the initial stage.

[A girl with chief compliance of "easy to forget"--cognitive neuropsychological evaluations and cerebral blood flow].

Cognitive-neuropsychological evaluations were performed on a 12-year-old girl with memory disorder to study the higher brain function of this patient. The cerebral blood flow (r-CBF) was also studied. The results showed that the auditory-verbal memory of this patient were impaired. The regional cerebral blood flow was reduced in the left hippocampus which reportedly cause memory disorder. The disturbance of visual cognition and disability of construction in this patient seem to be related to reduced cerebral blood flow in the left parietal region.

Neural mechanisms of motion sickness.

Three kinds of neurotransmitters: histamine, acetylcholine and noradrenaline, play important roles in the neural processes of motion sickness, because antihistamines, scopolamine and amphetamine are effective in preventing motion sickness. Histamine H1-receptors are involved in the development of the symptoms and signs of motion sickness, including emesis. On provocative motion stimuli, a neural mismatch signal activates the histaminergic neuron system in the hypothalamus, and the histaminergic descending impulse stimulates H1-receptors in the emetic center of the brainstem. The histaminergic input to the emetic center through H1-receptors is independent of dopamine D2-receptors in the chemoreceptor trigger zone in the area postrema and serotonin 5HT3-receptors in the visceral afferent, which are also involved in the emetic reflex. Antihistamines block emetic H1-receptors to prevent motion sickness. Scopolamine prevents motion sickness by modifying the neural store to reduce the neural mismatch signal and by facilitating the adaptation/habituation processes. The noradrenergic neuron system in the locus coeruleus is suppressed by the neural mismatch signal. Amphetamine antagonizes mismatch-induced suppression of noradrenergic neural transmission, resulting in preventing motion sickness.

Effect of AF64A, a cholinergic neurotoxin, on footshock stimulation-induced locus coeruleus excitation in rats.

We studied the effect of ethylcholine mustard aziridinium ion (AF64A), a cholinergic neurotoxin, on the footshock stimulation (FS)-induced excitation of the locus coeruleus (LC) neurons in rats. The FS-evoked LC excitation was significantly reduced in AF64A-treated rats, in comparison with normal rats. In particular, the early component of LC excitation was less pronounced. The number of choline acetyltransferase immunoreactive neurons in the septal complex was significantly lower than those in normal rats, except for in the ventral subgroup. These findings suggest that the cholinergic neuron system is involved in the early component of LC excitation in rats.

Role of cholinergic mossy fibers in medial vestibular and prepositus hypoglossal nuclei in vestibular compensation.

Several lines of evidence have suggested that acetylcholine is a possible neurotransmitter/neuromodulator involved in vestibular compensation. Further, the central vestibular system, oculo- and spino-motor neurons and peripheral vestibular efferents contain abundant cholinergic neurons. However, details of cholinergic effective sites during vestibular compensation remain to be clarified. In the present study, we selectively damaged rat vestibulo-floccular and vestibulo-uvulonodular cholinergic mossy fibers using ethylcholine mustard aziridinium ions. In these treated animals, unilateral labyrinthectomy caused more severe vestibulo-ocular deficits especially during the initial stage. From these findings we suggest that vestibulo-floccular and vestibulo-uvulonodular cholinergic mossy fibers contribute to the restoration of a balance between intervestibular nuclear activities for the induction of vestibular compensation during the initial stage.

[Clinical features of benign paroxysmal positional vertigo].

Our understanding of the pathomechanism of benign paroxysmal positional vertigo (BPPV) has improved dramatically. A type of BPPV featuring mixed torsional and vertical nystagmus induced by the Dix-Hallpike maneuver involves the posterior semicircular canal (P-BPPV). The other type of BPPV featuring horizontal nystagmus induced by spine-to-lateral head positioning involves the horizontal canal BPPV (H-BPPV). In complaints of vertigo or dizziness, 619 patients visited our department last year. Of these, 142 (23%) was had positional nystagmus consistent with a diagnosis of BPPV, 118 (19%) had no nystagmus but were suspected of BPPV due to vertigo episodes. BPPV was the most frequent diagnosis. H-BPPV was not rare, but accounted for 30% of BPPV. Of H-BPPV, 73% featured direction changing geotropic nystagmus, and 27% direction changing apogeotropic nystagmus. H-BPPV resolved faster than P-BPPV. Most cases caused by head trauma were P-BPPV. Transition between P- and H-BPPV was found in 6 cases. Women outnumbered men by about 3 to 2 in both P- and H-BPPV. Peak incidence was found in the those in their 60s and 70s, suggesting that the etiologies of both types of BPPV are essentially the same.

[Statistical observation of vertigo and dizziness patients].

Subjects visiting the Department of Otolaryngology at Suita Municipal Hospital reporting vertigo or dizziness numbered 664 women and 343 men from April 1999 to December 2000. As a city hospital, we play an important role in the diagnosis and treatment of acute vertigo or dizziness. The frequency of diagnosis of these cases was divided almost equally into 5 groups: (1) benign paroxysmal positional vertigo (BPPV) 23%; (2) suspected BPPV, 18%; (3) peripheral vestibular disorders other than BPPV, 22%; (4) disorders other than peripheral origin, 18%; and (5) undiagnosed, 19%. Based on our results, BPPV, other peripheral vestibular disorders, and disorders of other origins should be differentiated from the first screening. BPPV was most frequent and diagnosed by typical positioning nystagmus. Many other peripheral vestibular disorders were accompanied by nystagmus. It is also important to differentiate serious illnesses such as cerebrovascular disease (7%), space-occupying lesions in the posterior fossa (1.2%), and cardio-circulatory disease (3.6%).

[Effects of steroid therapy on long-term canal prognosis and activity in the daily life of vestibular neuronitis patients].

We studied 28 patients with vestibular neuronitis treated at our hospital between 1997 and 1999. To determine the effects of steroid therapy on long-term canal prognosis and daily activity, we examined caloric tests and gave questionnaires to 12 steroid-treated and 16 nonsteroid-treated patients 2 years after onset. We found that canal improvement was 50% in the nonsteroid-treated group and 75% in the steroid-treated one. In cases with severe canal paresis (CP > or = 60%), canal improvement was 33% in the nonsteroid-treated group and 67% in the steroid-treated one. Steroid therapy at the acute stage of this disease significantly reduced the duration of spontaneous nystagmus and handicap in daily life due to dizziness induced by head and body movement, decreasing mood disturbance.

Purification and characterization of two lectins from a toxic moray, Gymnothrax javanicus.

Two lectins, Gymnothrax javanicus lectin-I (GJL-I) and Gymnothrax javanicus lectin-II (GJL-II) were isolated from the stomach and intestine, and the liver, respectively, of a toxic moray eel, Gymnothrax javanicus. GJL-I is a polymer of two heterogeneous subunits of 67 and 51 kDa. In a hemagglutination inhibition assay, it had sugar-binding specificity toward lactose and lactulose among the mono- or oligo-saccharides and bovine submaxillary mucin (BSM) among the glycoproteins tested. The lectin stimulated nerve growth factor (NGF) synthesis by astroglial cells. GJL-II was a polymer of subunit of 41 kDa. This lectin had N-acetyllactosamine binding specificity.

Long-term changes in middle latency response and evidence of retrograde degeneration in the medial geniculate body after auditory cortical ablation in cats.

Short- and long-term changes in the middle latency response (MLR) after bilateral ablation of the auditory cortices were studied in awake cats. The amplitude of the negative peak with a latency of about 15 ms (NA) decreased to 60% of the original value 1 week after ablation (short-term change). In the long term, i.e. 11-30 months, NA either decreased further (decreased group) or remained unchanged (non-decreased group). A histological study with light microscopy revealed degeneration of neurons in the ventral nucleus of the medial geniculate body (MGv) in the decreased group, whereas the neurons in this region were preserved in the non-decreased group. This study suggests that long-term changes in NA reflect retrograde degeneration in the MGv after auditory cortical ablation.

Temporal stream of cortical representation for auditory spatial localization in human hemispheres.

We measured human evoked magnetic fields to binaural sounds with an interaural time delay as a cue for auditory localization. By analyzing the topography of auditory-evoked magnetic fields in the middle-latency, we demonstrated that particular cortical regions represent the direction of sound localization by their activity level. Upon presenting a binaural sound, the first representations were found in the middle frontal region as well as the superior temporal region of the right hemisphere approximately 19 ms after the stimulation, but their patterns differed. Other cortical regions including the prefrontal and parietal spatial areas were affected within roughly 60 ms. The results showed that the right hemisphere is dominant even in the preattentive stage of auditory spatial processing of sounds from different directions.

[Medical, educational, and social supports required by parents of persons with LD and related conditions].

The authors surveyed handicaps in daily life of persons with learning disability (LD) or its related conditions. Among 470 parents of persons with LD, 266 (56.6%) responded. The required assistance differed according to the age and handicaps. Whereas 18.0% of the respondents were utilizing current social services, 75.3% agreed on the establishment of special welfare for LD. Social supports, comprehending medicine, education, occupation, and law are needed.

Effects of vestibular cerebellum lesion on motion sickness in rats.

The importance of the vestibular apparatus in the development of motion sickness is widely accepted, although the role of the vestibular cerebellum remains controversial. We examined the effects of vestibular cerebellum lesion on the development of motion sickness in rats. Rats do not vomit, but the behaviour known as "pica", the eating of non-nutritive substances, such as kaolin, can be used as an index of motion sickness. A 2 h load of hypergravity induced pica in rats, indicating that they suffered from motion sickness. Pica was induced by hypergravity load even after surgical lesion to the bilateral cerebellar flocculus or to the cerebellar vermis. We concluded that the vestibular cerebellum was not essential in the development of motion sickness in rats.

Cholinergic influence on vestibular stimulation-induced locus coeruleus inhibition in rats.

In our previous study, caloric stimulation (CS) of the vestibular apparatus inhibited noradrenergic neuronal activity in the locus coeruleus (LC) in urethane-anaesthetized rats. Therefore, the inhibition of LC noradrenergic neurons is involved in vestibulo-autonomic responses. Since motion sickness can be cured by scopolamine, cholinergic neuron system may also be involved in vestibulo-autonomic responses. The present study examined the effects of intracerebroventricular injection of ethylcholine mustard aziridinium ion (AF64A), a presynaptic cholinergic neurotoxin, on CS-induced LC inhibition. In AF64A-treated rats, the CS-induced LC inhibition was less pronounced than in normal rats. In a subsequent series of experiments, the intravenous injection of scopolamine blocked the CS-induced LC inhibition. These findings suggest that central cholinergic neurons are associated with noradrenergic neuronal inhibition during the vestibulo-autonomic reflex.