Evaluation of the safety and efficacy of Glycyrrhiza uralensis root extracts produced using artificial hydroponic and artificial hydroponic-field hybrid cultivation systems.

Glycyrrhiza uralensis roots used in this study were produced using novel cultivation systems, including artificial hydroponics and artificial hydroponic-field hybrid cultivation. The equivalency between G. uralensis root extracts produced by hydroponics and/or hybrid cultivation and a commercial Glycyrrhiza crude drug were evaluated for both safety and efficacy, and there were no significant differences in terms of mutagenicity on the Ames tests. The levels of cadmium and mercury in both hydroponic roots and crude drugs were less than the limit of quantitation. Arsenic levels were lower in all hydroponic roots than in the crude drug, whereas mean lead levels in the crude drug were not significantly different from those in the hydroponically cultivated G. uralensis roots. Both hydroponic and hybrid-cultivated root extracts showed antiallergic activities against contact hypersensitivity that were similar to those of the crude drug extracts. These study results suggest that hydroponic and hybrid-cultivated roots are equivalent in safety and efficacy to those of commercial crude drugs. Further studies are necessary before the roots are applicable as replacements for the currently available commercial crude drugs produced from wild plant resources.

Discrepancy between thyroid-stimulating and thyrotropin-binding inhibitory activities of Graves' immunoglobulin Gs assessed in the mouse.

TSH receptor binding-inhibiting (TBI) and thyroid-stimulating (TSI) activities of Graves' immunoglobulin Gs (IgGs) were measured using the murine TSH receptor (mTBI) and the McKenzie LATS bioassay. In contrast to the expectation that only the IgGs positive for LATS showed mTBI activity, mTBI activity was closely correlated with TBI activity measured at the human TSH receptor regardless of LATS potency (r = 0.79; P less than 0.01), indicating a lack of species specificity of IgG in this particular aspect. In 7 to 15 IgGs positive for both mTBI and LATS, there was a significant correlation between the 2 parameters (r = -0.89; P less than 0.01). However, 4 IgGs among the 15 were positive for mTBI but negative for LATS even when tested at 3- to 7-fold concentrations of IgG.

Effect of digitalis on conduction dysfunction in Pelizaeus-Merzbacher disease.

We studied the effect of digitalis on nerve conduction dysfunction in Pelizaeus-Merzbacher disease (PMD). The patients were three Japanese boys with PMD, aged 7-10 years. Digitalis was administered orally in a daily dose of 0.06 mg/kg for 2 consecutive months, and the obtained serum concentrations ranged from 0.33 to 0.55 ng/ml. The digitalis therapy induced slight improvement of severe dysarthria and cognitive dysfunction in the two older patients. Electrophysiological examinations revealed the following results: In brainstem auditory evoked potentials (BAEPs), while waves II (or III) to V were absent before treatment, on treatment all waves of BAEPs except a wave IV were restored in all patients. While visual evoked potentials (VEPs) in response to transient flash stimulation showed markedly prolonged latencies before treatment, digitalis produced a mild, although not statistically significant, shortening of the latency of N160. There were also no significant changes in inter-peak amplitudes of VEPs. Transcranial cortical magnetic stimulation continued to fail to elicit motor evoked potentials of the first dorsal interosseous muscles in all patients. Thus, although the serum concentrations were insufficient to elicit favorable therapeutic effects, digitalis therapy provided slight relief of clinical symptoms with evidence of improvement of conduction dysfunction. It is suggested that patients with PMD may respond to symptomatic treatment modulating nerve conduction.

Transcranial magnetic stimulation in benign childhood epilepsy with centro-temporal spikes.

Motor cortical excitability was studied using transcranial magnetic stimulation (TMS) in 10 age-matched controls, and 13 children with benign childhood epilepsy with centro-temporal spikes (BECT), with a mean age of 11.2 +/- 2.0 years (five untreated, and eight treated with sodium valproate (VPA) and well controlled). Motor evoked potentials (MEPs) elicited by TMS through a circular coil were recorded from the first dorsal interosseous muscle (FDI) while relaxed. There was no significant difference in latency or duration of MEPs, or central motor conduction time among controls, untreated and treated patients. The threshold intensity for TMS in the untreated patients (63.0 +/- 14.8%, mean +/- SD) was similar to that in controls (63.0 +/- 12.5%), while the threshold intensity in the treated patients (79.4 +/- 11.8%) was significantly higher than that in the other groups. A significant increase in threshold intensity (15 +/- 4.1%) was also observed in the untreated patients retested after starting VPA treatment. No adverse effects occurred during TMS in any subjects. Thus, motor cortical hyperexcitability in BECT was not recognized in the present TMS study, while VPA was confirmed to have an effect on the threshold intensity for TMS.

Alternating hemiplegia of childhood: report of a case having a long history.

We examined a patient with alternating hemiplegia of childhood (AHC) who had over a 23-year history of AHC to investigate the origin of the neurological deterioration with increasing age. Hemiplegic attacks had occurred consistently at a frequency of a few per week since infancy, and he first experienced attacks of cerebellar ataxia at the age of 23 years. Intellectual impairment, dysarthria, dystonic posturing, and a wide-based gait had been slowly progressive, but they had been stable since he turned twenty. The electromyographic response to transcranial magnetic stimulation was normal between attacks and showed reversible alteration during an attack. MRI revealed slight dilatation of the lateral ventricles, and MR angiography showed normal cerebral blood flow. Proton MR spectroscopy between attacks showed normal peak area ratios for N-acetyl groups, choline-containing compounds, and creatine and phosphocreatine, and it also demonstrated no lactic peak. 123I-IMP SPECT between attacks demonstrated diffuse cerebral hypoperfusion despite no evidence of ischemic change in the above MR study. These results suggest that the slowly progressive neurological deficits are due to the primary underlying pathology rather than the secondary neuronal loss as a result of frequent ischemic attacks.

Acute confusional migraine and migrainous infarction in childhood.

We report two children with acute confusional migraine (ACM) and another with migrainous infarction (MI), aged 7-12 years. There was a family history of migraine in all patients. The patients, who were all right-handed, all manifested sudden onset of consciousness disturbance and other neurological deficits as the first aura in their life. The symptoms in all cases almost completely resolved spontaneously within 24 h, but transient occipital slowing on EEG with laterality corresponding to the side of migrainous origin lasted more than 24 h. In the cases of ACM in the critical phase, although MRI and MR angiography showed no abnormal findings, IMP-SPECT performed within 48 h of migraine attacks revealed a regional change in cerebral blood flow, which is one particular case demonstrated hypoperfusion in the left posterior cerebral artery (PCA) territory. Therefore, although ACM was diagnosed clinically by exclusion, SPECT was thought helpful for the diagnosis of ACM. We speculated that transient hypoperfusion affecting the dominant-sided PCA territory involving the medial temporal structures was responsible for the confusion with amnesia in ACM, in contrast to the lack of confusion or amnesia in the case of MI showing cystic encephalomalacia in the right thalamic and hippocampal regions.

Serial magnetic resonance imaging in children with postinfectious encephalitis.

We analyzed follow-up magnetic resonance images (MRI) in eight children with clinical postinfectious encephalitis (PIE), and discussed their pathogeneses. Three categories of MRI findings were apparent: (1) multifocal lesions in the white matter with/without basal ganglia involvement consistent with acute disseminated encephalomyelitis (ADEM) (three patients); (2) single or multifocal lesions localized only in the gray matter (two patients); and (3) localized lesions in the brain stem, basal ganglia or cerebellum. Some lesions in the patients in Categories 1 and 2 migrated or were resolved quickly, sometimes within 10 days. Gadolinium caused linear or spotty enhancement in the patients in Category 2. These findings suggest that Categories 1 and 2 are a self-limiting allergic angiopathy without demyelination. In contrast, the lesions in the patients in Category 3 were fixed, and not resolved within 6 months (three patients). The pathogenesis of Category 3 is not known. All except one patient had no prednisolone (PSL) therapy, however; all lesions were resolved completely or markedly reduced in size, which indicates PSL therapy is not always necessary in patients with PIE.

Fukuyama-type congenital muscular dystrophy and the Walker-Warburg syndrome.

We compared the neuropathological findings in two cases of the Walker-Warburg syndrome (WWS) with those in 6 of Fukuyama-type congenital muscular dystrophy (FCMD). Remarkable differences were noticed between the two conditions. The central nervous system (CNS) dysplasia in WWS, which involved diffuse agyria and hydrocephalus, was more severe than that in FCMD. In WWS the septum pellucidum was absent, and the corpus callosum, basal ganglia and thalami were markedly hypoplastic. The cerebellum was severely hypoplastic and the vermis was partly absent. The pyramidal tracts could not be identified. On the other hand, the general configuration of the CNS was well preserved in FCMD. The cerebral cortices exhibited diffuse or focal micropolygyria with or without a few pachygyric lesions, but the severity was variable. The cerebellum was not hypoplastic, but exhibited focal micropolygyria. The pyramidal tracts were aberrant. WWS and FCMD, however, did not show any distinct differences on microscopic analysis of the cerebral cortices. There was leptomeningeal glio-mesenchymal overgrowth, and the horizontal lamination of the nerve cells was distorted throughout by proliferating gliovascular bundles or septa. We found in this study that the CNS pathology in WWS was compatible with type II lissencephaly, and thus differed from that in FCMD. Hypoplasia of the cerebellum and a partial absence of the vermis also seemed to be predominant features of WWS, which can be used to differentiate WWS from FCMD. In this study, we concluded that FCMD and WWS are different disease entities because they differ in their clinical manifestations, including eye lesions and CNS pathology, and because no familial concomitance of FCMD and WWS has been reported.

Esophageal contractility synchronous with expiration.

On the basis of our previous finding that the cervical esophagus was closed during tracheoesophageal phonation, we postulated that the muscle of the cervical esophagus actually contracted during expiration and speculated on its possible regulation by the recurrent laryngeal nerve. Electromyography of the esophageal musculature and fluoroscopy of the esophagus were performed in laryngectomees to demonstrate whether the esophagus contracted during expiration or not. Electromyography, performed in 2 subjects, revealed a burst of discharges synchronous with expiration. Fluoroscopy during tracheoesophageal phonation was performed in 13 subjects to investigate the influence of resection of the esophageal branch of the recurrent nerve on esophageal motor activity. Among 13 subjects, 4 subjects who underwent paratracheal dissection (PTD) at the time of laryngectomy showed a lower superior limit of esophageal closure than did the 9 subjects without PTD, indicating that the cervical esophagus in PTD loses its contractility with the sacrifice of the esophageal branch of the recurrent nerve. We concluded that the cervical esophagus is closed by muscle contraction synchronous with expiration, preventing air entry into the stomach during deep expiration or phonation, and that the esophageal branch of the recurrent nerve is involved.

Prediction of transient lubricating film thickness in knee prostheses with compliant layers.

The transient lubricating film thickness in knee prostheses using compliant layers has been predicted under simulated walking conditions based upon the elastohydrodynamic lubrication theory. Qualitative agreement has been found between the present theoretical predictions and the experimental measurements using an electric resistance technique reported earlier. It has been shown that the contact geometry plays an important role in the generation of fluid film lubrication in knee prostheses using compliant layers. The maximum lubricating film thickness is predicted for the maximized contact area of a transverse conjunction where the semi-minor contact radius lies in the direction of entraining. The additional advantage of the transverse contact conjunction is that the possibility of lubricant starvation due to small stroke length can be minimized. All these factors, together with the kinematic requirements in the natural knee joint, should be taken into consideration when designing artificial knee joint replacements.

Adaptive multimode lubrication in natural synovial joints and artificial joints.

To examine the lubrication mechanisms in both natural synovial joints and artificial joints with artificial cartilages, pendulum tests of pig shoulder joints and simulator tests of sliding pairs of a stainless steel spherical component and natural articular cartilage or artificial cartilage have been conducted. Firstly, it was shown in pendulum tests of pig shoulder joints that both concentration of hyaluronic acid or viscosity and adsorbed film formation of proteins and phospholipids exerted a significant effect on frictional behaviour in swinging motion immediately after a loading of 100 N. Under a high load of 1 kN, low friction was observed under wide-ranging viscosity conditions, since a high load similar to body weight probably enhanced the squeeze film effect due to improved congruity. Next, frictional behaviour of sliding pairs in knee joint models, consisting of a stainless steel spherical surface and either specimens of pig tibial cartilage or polyvinylalcohol (PVA) hydrogel, was examined during walking in simulator tests. In these tests, the influences of lubricant viscosity and addition of protein on frictional behaviour were evaluated. For both compliant materials, the appropriate addition of gamma-globulin to sodium hyaluronate (HA) solution maintained low friction and protected rubbing surfaces under thin film conditions. These phenomena are discussed from the viewpoint of adaptive multimode lubrication.

[Three cases with acute encephalopathy related with adenovirus type 7 infection].

We studied the clinical and CT findings of 3 children with acute encephalopathy associated with adenovirus type 7 (AD-7) infection. Seizures in all the patients developed from 8 to 10 days after the onset of pyrexia. The values of serum AST, LDH and CRP elevated and those of WBC and serum protein decreased at the onset of encephalopathy. None of the patients had CSF leukocytosis. CT showed mild brain atrophy in all patients. A steroid pulse therapy was effective in one patient. The pathogenesis of encephalopathy is unknown. However, its onset and the success of the steroid pulse therapy suggested that it is a post infectious encephalitis. These findings, as well as the data of blood examination and of previous reports, implicated adverse effects of cytokines in the pathogenesis of this encephalopathy.

[Pathogenesis of acute encephalopathy with shock syndrome].

We presented 3 cases who exhibited important clinical or histopathological findings relevant to the pathogenesis of acute encephalopathy with shock syndrome (AESS). Hyperpermeability of the blood vesseles in the central nervous system was revealed by autopsy in case 1 and by enhancement CT scan in case 2, which implicated that the primary lesion of AESS was vascular damage. Although other cytokines than interleukin (IL)-6 were not evaluated, high value of IL-6 in case 3 might suggest that the some highly activated cytokines caused AESS.

[Effects of mild hypothermia and steroid pulse combination therapy on acute encephalopathy associated with influenza virus infection: report of two cases].

We treated two children with influenza-associated acute encephalopathy by a combination of mild hypothermia and steroid pulse therapy. Case 1, a 2-year-and-3-month-old boy, admitted to our hospital 7 days after the onset of central nervous symptoms. The brain MRI-CT revealed laminar cortical necrosis and severe brain edema. EEG showed very low voltage. Brain edema improved by the combination therapy. He had sequelae, but was able to eat. Case 2, a 1-year-and-10-month-old boy, admitted to our hospital 5 days after the onset of central nervous symptoms. Brain MRI showed frontal dominant cortical edema. EEG showed high voltage delta bursts. The combination therapy was effective, but he remained mental handicapped. The outcome was better compared to our previous cases of acute encephalopathy. The combination therapy is intended to counteract cytokines, and was considered to be an effective treatment against acute encephalopathy associated with an influenza virus infection.

[Clinical study in 28 patients with infection-related acute onset encephalitis].

Of the 75 patients with infection-related acute encephalopathy or encephalitis treated by us in the last 10 years, 28 had acute onset encephalitis. The results of clinical studies on these 28 patients were as follows: (1) The number of cases who exhibited CNS manifestations during (A) and after pyrexia (B) were 15 and 13, and the ages of predilection were infancy and school age, respectively. (2) MRI studies in cases of A revealed multifocal CNS lesions in 1 case, localized lesions in 7 and normal findings in 7. In B, there were 3 cases with multifocal lesions, 8 of focal lesions and 2 of normal findings. (3) The 7 cases of localized lesions in A were divided into 5 of herpes encephalitis and 2 of suspected vasculitis. Vasculitis was suspected in 3 of 8 cases of localized lesions in B. Thus, vasculitis is considered to be an important cause of encephalitis. (4) Brain lesions in the 5 cases of herpes encephalitis were occipital dominant in 4. Only one case had a temporal lesion. (5) All cases with focal MRI lesions and CSF pleocytosis, having evidence of direct viral invasion, were herpes encephalitis. Direct viral invasion was not proven in any other cases. (6) Although the term encephalitis is often used in clinical practice, the process by which the CNS lesions occur in acute viral infection is still unknown. Therefore it is not easy to establish the diagnosis. The diagnostic criteria of encephalitis should be reconsidered. New specific methods to analyze the cause of CNS lesions are necessary.

[Acute shock encephalopathy syndrome in a girl with Sotos syndrome--with special reference to differentiation from Reye syndrome].

We reported here a 5-year-old girl with Sotos syndrome who developed acute shock encephalopathy syndrome (ASES), and differentiated ASES from Reye syndrome (RS). Abrupt onset of shock and status epilepticus developed and these were followed by disseminated intervascular coagulation (DIC) and liver damage. Gradual elevation of hepatic enzymes, high serum bilirubin value, and normal serum ammonia value in acute phase were incompatible with typical RS. Liver histology showed severe, diffuse necrosis of hepatocytes consisting of granular and vacuolar degeneration, which were quite different from those of RS. Thus, the disease process of ASES was shown to be different from those of RS.

[Efficacy of methylprednisolone pulse and mild hypothermia therapies in patients with acute encephalopathy].

Five patients with acute encephalopathy underwent methylprednisolone pulse (mPSL-P), hypothermia and their combination therapies (3 cases, 1 case and 1 case, respectively), with excellent outcome. Two cases with severe brain edema survived. One had severe brain damage as a sequelae. The remaining one recovered well after the combination therapy with mPSL-p and mild hypothermia, despite complete obstruction of the fourth ventricle on the first CT scan; the sequelae, hemiplegia and intelligent disturbance, was only mild. Four patients who received mPSL-P therapy within 6 hours after the onset of CNS symptoms recovered well though one was left with epilepsy. These results indicate that mPSL-P and/or hypothermia therapy will be chosen as the treatment of acute encephalopathy.

[Focal brain lesion accompanied by exanthema subitum: report of two cases].

We report two cases with exanthem subitum in which hemioaresis developed during the acute infectious phase. Magnetic resonance imaging (MRI) demonstrated a cerebral ischemic infarct in the territory of the right lenticulostriate artery in one patient. Along the right temporal and parieto-occipital cortex of the other patient, there were high-signal-intensity lesions on T2-weighted images, which showed marked enhancement by gadolinium on T1-weighted images. These findings suggested that the brain lesions were caused by vasculopathy that accompanied human herpes virus-6 infection.

[Clinical studies on 35 patients with infection-related acute encephalopathy].

The findings on magnetic resonance imaging (MRI) or computed tomographic scan in 35 children with acute encephalopathy (AE) induced by infections were categorized into five groups: (1) normal findings (11 cases), (2) normal findings in the acute phase followed by mild brain atrophy (1 case), (3) severe brain edema which developed within 48 hours after the onset of AE (7 cases), (4) diffuse cortical necrosis which appeared around 4 days after the onset of AE (9 cases), and (5) symmetric thalamic lesions (7 cases). Their outcomes were as follows: three cases developed epilepsy in (1) and (2); six died and one had a sequel of severe brain damage (SBD) in (3); all cases survived but had SBD in (4), and four died, one had SBD, and 2 recovered in (5). Serum AST were elevated in 7.7 and 6 cases in (3), (4) and (5), respectively. In all of them, there were more than one case having liver histologies consistent with Reye syndrome.

[Hyperintense brain lesions on T1-weighted MRI after parenteral nutrition].

We experienced five children having T1-shortening lesions in basal ganglia or thalami on magnetic resonance imaging (MRI), which were supposed to be caused by manganese (Mn) overdoses. Instead of the presence of above mentioned lesions, no neurological manifestations corresponding to them had developed in all patients. This observation suggests that a MRI is useful for detecting the side effects caused by overdoses of Mn in patients having parenteral nutrition.