Sleep is associated with offline improvement of motor sequence skill in children.

In adults, sleep is necessary for the offline improvement of certain skills, such as sequential finger tapping, but whether children show a similar effect is still debatable. Here, we tested whether sleep is associated with offline performance improvement in children. Nine- and 11-year-old children trained on an explicit sequential finger tapping task. On the night following training, their parents observed and recorded the duration of each child's sleep. The following day, all children performed a surprise retest session on the previously trained sequence. In both 9- and 11-year-old children, skill performance was significantly improved during the first retest session relative to the end of training on the previous day, confirming the offline improvement in performance. There was a significant correlation between the degree of improvement and sleep duration the night after training, suggesting that in children, as in adults, sleep is associated with offline skill enhancement.

A study of the standard brain in Japanese children: morphological comparison with the MNI template.

Functional magnetic resonance imaging (MRI) studies involve normalization so that the brains of different subjects can be described using the same coordinate system. However, standard brain templates, including the Montreal Neurological Institute (MNI) template that is most frequently used at present, were created based on the brains of Western adults. Because morphological characteristics of the brain differ by race and ethnicity and between adults and children, errors are likely to occur when data from the brains of non-Western individuals are processed using these templates. Therefore, this study was conducted to collect basic data for the creation of a Japanese pediatric standard brain. Participants in this study were 45 healthy children (contributing 65 brain images) between the ages of 6 and 9 years, who had nothing notable in their perinatal and other histories and neurological findings, had normal physical findings and cognitive function, exhibited no behavioral abnormalities, and provided analyzable MR images. 3D-T1-weighted images were obtained using a 1.5-T MRI device, and images from each child were adjusted to the reference image by affine transformation using SPM8. The lengths were measured and compared with those of the MNI template. The Western adult standard brain and the Japanese pediatric standard brain obtained in this study differed greatly in size, particularly along the anteroposterior diameter and in height, suggesting that the correction rates are high, and that errors are likely to occur in the normalization of pediatric brain images. We propose that the use of the Japanese pediatric standard brain created in this study will improve the accuracy of identification of brain regions in functional brain imaging studies involving children.

Distinction between the literal and intended meanings of sentences: a functional magnetic resonance imaging study of metaphor and sarcasm.

To comprehend figurative utterances such as metaphor or sarcasm, a listener must both judge the literal meaning of the statement and infer the speaker's intended meaning (mentalizing; Amodio and Frith, 2006). To delineate the neural substrates of pragmatic comprehension, we conducted functional magnetic resonance imaging (fMRI) with 20 normal adult volunteers. Participants read short stories followed by a target sentence. Depending on the context provided by the preceding stories, the target sentences were classified as follows: (1) metaphor versus literally coherent; (2) metaphor versus literally incoherent; (3) sarcasm versus literally coherent; and (4) sarcasm versus literally incoherent. For each task pair, we directly compared the activations evoked by the same target sentences in the different contexts. The contrast images were incorporated into a 2 (metaphor and sarcasm)×2 (literal coherency and incoherency) design. Metaphor-specific activation was found in the head of the caudate, which might be involved in associating statements with potential meanings, and restricting sentence meanings within a set of possible candidates for what the speaker intended. Sarcasm-specific activation was found in the left amygdala, which is an important component of the neural substrates of social behavior. Conjunction analysis revealed that both metaphor and sarcasm activated the anterior rostral medial frontal cortex (arMFC), which is a key node of mentalizing. A distinct literal coherency effect was found in the orbital MFC, which is thought to be involved in monitoring. These mesial frontal areas are jointly involved in monitoring literal coherency and mentalizing within social contexts in order to comprehend the pragmatic meanings of utterances.

Acute accidental overdosage of haloperidol in children.

We report the details of an accidental overdosage of haloperidol in 24 children in one hospital in Kyushu, Japan. Evidence of acute toxicity included disturbances in consciousness (24/24), tremors in the extremities (16/24), an oculogyric or similar crisis (14/24), dysarthria (9/17), drooling (8/24), akathisia (6/20), hyperreflexia (6/24) and opisthotonos (3/24). Laboratory examinations revealed late-onset transient thrombocytosis (5/24), elevated AST and GPT (1/24) and abnormal ECG with prolonged QT interval in 2 of 8 children. We detected haloperidol in 11 of 18 children whose blood was specifically examined within four days after the final haloperidol administration. The maximum serum haloperidol level was 28.9 ng/ml. The mean half-life of haloperidol in the serum of five children (age range 2-10 years) was 18.6 +/- 12.2 h (mean +/- SD) (range 9.1-39.4 h).

[Neurotoxicity of allyl chloride in rats. Dose-effect relationship following long-term exposure].

To elucidate the dose-effect relationship of neurotoxicity of allyl chloride (AC) in Donryu rats, 5 animals each were exposed to 10, 50 and 100 ppm AC for 8 h/d and 5 d/wk for a period of 34 wk. Nerve conduction velocities of the tail nerve in rats were determined before and after 4, 8, 12, 16, 22, 28 and 34 wk of exposure, and the width of landing foot-spread after 8, 12, 16, 28 and 34 wk. Animals subjected to 100 ppm AC showed significant (p less than 0.01) reduction of motor and sensory nerve conduction velocities and nerve action potentials (NAP) after 28 wk when clinical signs of neuropathy were observed, i.e., weakness of hindlimbs and significantly (p less than 0.01) extended landing foot-spreads. Motor distal latency was retarded in rats exposed to 100 ppm AC at the last period of exposure. In rats exposed to 50 and 100 ppm AC, no remarkable electrophysiological findings or abnormal clinical signs were observed except for depressed amplitude of NAP in 50 ppm-exposed rats when compared with those exposed to 10 ppm.

[Chemotherapy with Cisplatin-Phosphatidyl-choline-Lipiodol (CPL) suspension in unresectable hepatocellular carcinoma].

Twenty-seven patients with unresectable hepatocellular carcinoma (HCC) were treated with Cisplatin-Phosphatidyl-choline-Lipiodol (CPL) suspension. PR was obtained in two of ten cases (20%) by one shot therapy. AFP decreased in 9 of 10 patients by one shot therapy with a 62.1% rate of decrease. In all of 13 patients by TAE, AFP decreased and the rate of decrease was 64.8%. The concentration of CDDP in the peripheral venous blood was lower and continued longer than that of CDDP on the market. Nausea, vomiting and fever were noted in most cases as adverse effects, but they were slight. These results suggest that CPL agents were very chemotherapeutic for unresectable HCC.

Identification and quantification of 5-hydroxypipecolic acid and hydroxyproline in mammalian brain and blood by selected ion monitoring.

A method for the analysis of 5-hydroxypipecolic acid and 4-hydroxyproline in mammalian brain and blood is reported. The identification and quantification of the two hydroxyimino acids were accomplished with gas chromatography/mass spectrometry including a selected ion-monitoring technique following HPLC prepurification. The lower limit of detection for the method is 2 to 10 pmol. The amounts of 5-hydroxypipecolic acid and 4-hydroxyproline in blood were 20 to 30 pmol/ml and 3 to 6 nmol/ml, respectively. Their concentrations in the rabbit whole brain were determined to be 5 and 120 pmol/g, respectively.

Pipecolic acid enhancement of GABA response in single neurons of rat brain.

Using unit recording and microelectrophoresis, influence of pipecolic acid (PA), a major metabolite of lysine in the brain, on GABA and glycine responses was studied in the cerebral cortical and hippocampal pyramidal neurons of rats. With small currents, PA had no effect on the single neuron activities but enhanced GABA response without affecting glycine response. The finding provides a new evidence that PA may have a connection with central GABA system.

Imino acid and related alicyclic amine levels in biological fluids.

Imino acid and related alicyclic amine concentrations in blood and urine of mammals including humans were concurrently determined by a selected ion monitoring technique. Nanomole levels of proline and pipecolic acid, and pyrrolidine and piperidine as well, were found in human urine. Proline levels but not pipecolic acid levels were higher in blood of humans than in urine. Pyrrolidine and piperidine levels in blood of humans were picomole levels and much lower than those in urine. Similar tendencies were also recognized when these 4 compounds were analyzed using animal blood and urine, although the levels were generally higher in animals than in humans. Significantly high concentrations of the imino acids and the amines were found also in animal semen.

Effects of vitamin B12 and B6 on 2,5-hexanedione-induced neuropathy.

The therapeutic effect of Vitamin B12 or Vitamin B6 on 2,5-hexanedione induced-neuropathy in animals was examined by using our electrodiagnostic technique in order to investigate the mechanism of the development of the neuropathy. Pyridoxal phosphate and two forms of Vitamin B12 were administered to rats intoxicated by the neurotoxin for a period of 18 weeks, and the sensory and motor fiber conduction velocity and the motor distal latency of the tail nerve were periodically determined. None of the groups treated with the therapeutic drugs exhibited a definite improvement in the nerve fiber conduction velocity and motor distal latency of the rat tail nerve, as compared with those of the 2,5-hexanedione-treated controls.

[Pharmacokinetics of cisplatin and the effect of sodium thiosulfate].

The pharmacokinetics of cisplatin (cis-dichlorodiammineplatinum (II), CDDP) have been studied in 11 patients. Plasma and urine CDDP concentrations were determined by flameless atomic absorption spectrophotometry. The treatment schedule was administered either by a 3-hour and 4-hour i.v. infusion or a 1.5-hour i.a. infusion. In the 3-hour i.v. infusion, the peak level of plasma total CDDP was 4.09 micrograms/ml after the end of infusion and non-protein-bound CDDP was 0.78 microgram/ml. Plasma total CDDP level declined with two peaks, the half-life of the alpha phase being 3.3 hours and that of the beta phase being 5.29 days. The half-life of non-protein-bound CDDP was 1.6 hours. CDDP might have remained for a long time, because CDDP values were obtained 3 weeks after infusion and urinary recovery of CDDP showed low values. Its urinary recovery was 40.3% of the dose infusion in the first 24 hours and 48.0% in 96 hours. The protein-binding of CDDP was inhibited by sodium thiosulfate(STS) and renal urinary excretion was enhanced. Our data suggest that STS can be applied as a neutralizer of CDDP.

Questionable role of glucose-insulin in cardioplegic solution.

To evaluate the myocardial protective effect of glucose-insulin (GI) in a cold cardioplegic solution, we compared the effect of a solution not containing GI (solution I) with that of an identical solution containing GI (solution II) under cardiopulmonary bypass in mongrel dogs. After 120 minutes of ischemic arrest, defibrillation was necessary to restore cardiac activity in 12.5% of the solution I group and 42.8% of the solution II group, respectively. No distinct intergroup differences were noted in recovery of left ventricular function, oxygen and lactate extraction of the myocardium during the post-arrest period, the myocardial ultrastructure, and myocardial ATP levels. Although creatine phosphate was less well preserved, glucose-6-phosphate and lactate were more accumulated in the solution II group than in the solution I group. Thus, significant advantages of substrate enhancement by addition of GI to cold cardioplegic solution were not found in spite of multidose cardioplegia and presence of noncoronary collateral blood flow.

On the sites of antitussive action of dl-glaucine phosphate.

The sites of antitussive action of dl-1,2,9,10-tetramethoxy-6a,alpha-aporphine phosphate (dl-glaucine phosphate, DL-832) were studied. It was assumed from the following results that DL-832 acts on the cough center per se. a) When DL-832 was given by the routes leading to the brain stem such as the vertebral artery and the cerebello-medullary cistern, far smaller doses were sufficient to obtain the same effect as that by i.v. administration. b) DL-832 showed neither effect on the afferent pathway for cough reflex nor influence on pulmonary stretch receptors. c) It exhibited practically no influence on the efferent pathways for cough reflex, that is, that for innervating respiratory muscle movement as well as that for controlling bronchial muscle tone. d) Decerebration exerted no influence on the antitussive effect. e) DL-832 definitely depressed the potentials of both the recurrent and internal intercostal nerves evoked by the superior laryngeal nerve stimulation. f) In deafferentated and decerebrate cats, DL-832 rather increased the spontaneous discharges of the phrenic nerve, whereas codeine decreased them.

Pharmacological studies on dl-glaucine phosphate as an antitussive.

Antitussive effect, toxicity and other related pharmacological properties of dl-1,2,9,10-tetramethoxy-6a,alpha-aporphine phosphate (dl-glaucine phosphate, DL-832) were studied in comparison with those of codeine. Acute toxicity of DL-832 in mice was 2/5 to 7/10 of that of codeine for any routes of i.v., i.p., s.c. and p.o. The antitussive effect as tested by "coughing dog and cat" methods and Domenjoz's method in cats was 1/5 to 4/5 that of codeine, according to the routes administered. Safety margin in antitussive effect was similar to or less than that of codeine. Differing from codeine, levallorphan exerted no influence on the antitussive effect of DL-832. In vitro, DL-832 exerted moderate relaxant actions on normal tone and on contractions induced by histamine and acetylcholine of tracheal muscle. In vivo, it showed a moderate relaxant effect on histamine-induced bronchial constriction. The decrease in the volume of respiratory tract fluid caused by DL-832 was smaller than that by codeine. DL-832 slightly reduced the transportation rate of intratracheal foreign body, although to much lesser extent as compared to codeine. On respiration, blood pressure and heart rate, DL-832 showed depressant effects and moreover it caused changes in ECG. However, all of these effects were similar to and a little weaker than those observed with codeine. DL-832 prolonged hexobarbital sleeping time significantly. Neither analgesic nor anticonvulsant effect was observed. When given in larger doses, DL-832 inhibited intestinal transportation in vivo, although this effect was much weaker than that of codeine. DL-832 showed slight local anesthetic effect.

Analysis of endogenous pyrrolidine levels by mass fragmentography.

Pyrrolidine, one of biogenic volatile amines, possesses nicotine-like synaptotropic actions on the nervous systems. In the present study, pyrrolidine levels in the tissues were examined by using mass fragmentographic technique. High concentrations of pyrrolidine were found in the seminal vesicle and lung of rabbits. Only trace amounts of pyrrolidine existed in the brain of mice and rats, although higher concentrations were detected in the brain of rabbits. In the rat brain, however, high levels of pyrrolidine were found in the pineal gland, pituitary gland and corpus striatum.

Potentiation of phenobarbital-induced anticonvulsant activity by pipecolic acid.

Pipecolic acid (PA) is an intermediate of lysine metabolism in the mammalian brain. Recent findings suggest a functional connection of PA as neuromodulator in GABAergic transmission. Since many drugs are postulated to produce their effects by interaction with the central GABA system, the influence of PA on the anticonvulsant activity of phenobarbital was examined. Pretreatment of mice with 50 mg . kg-1 of PA potentiated the suppressing effects of the barbiturate on electrically and chemically induced convulsions. However, there was no potentiation of the behavioral effects and hypothermia induced by phenobarbital. PA itself had no or only little effect on the convulsions, motor function and rectal temperature when given in i.p. doses up to 500 mg . kg-1. Intraventricular administration of 500 microgram of PA also did not suppress either type of convulsion, although it produced ptosis, hypotonia, sedation and hypothermia. The results are discussed in relation to GABA system.

Pipecolic acid: a new type of alpha-amino acid possessing bicuculline-sensitive action in the mammalian brain.

Using unit recording and electrophoretic techniques, pharmacological properties of pipecolic acid (PA) were studied in the brain neurons of rats. PA response was blocked by bicuculline more effectively than GABA response but not blocked by strychnine. Stereochemical findings obtained using the HGS-model demonstrated that PA structure is almost the same as a part of bicuculline structure. The present results suggest that PA might be a new type of substance possessing bicuculline-sensitive action. The site of the action of PA was also discussed.

Changes in brain piperidine levels under anesthesia: mass fragmentographic analysis.

Piperidine is a biogenic alicyclic amine possessing potent pharmacological activity. Interest has recently been focussed on its possible role as an endogenous hypnogenic substance. Using a mass fragmentographic technique with deuterium-labelled piperidine as an internal standard, the time relations of the change in brain levels of piperidine and the anesthetic activity of urethane were determined in mice. The brain piperidine level increased prior to the loss of the righting reflex and the elevated level declined prior to the reappearance of the reflex. The change in brain piperidine level correlated with neither that in spontaneous motility nor that in body temperature. The findings favor the idea that piperidine might at least partly regulate the level of consciousness.

A new method for evaluating mucolytic expectorant activity and its application. II. Application to two proteolytic enzymes, serratiopeptidase and seaprose.

Using our new method described in a preceding paper, in vivo effects of two proteolytic enzymes such as serratiopeptidase (SER) and seaprose (SAP) on sputa collected from bronchitis rabbits were examined. SER (20 mg/kg) and SAP (30 mg/kg) significantly reduced the viscosity of sputum (P less than 0.05) at the 1-3-h periods and the 4-6-h periods, respectively, after intraduodenal administration. 50 mg/kg of SER also significantly decreased not only viscosity (P less than 0.001) but also amount of freeze-dried substance (P less than 0.05) of sputum at the 1-3-h periods, but SAP did not affect the amount of dried substance. Both enzymes significantly increased the volume of sputum, probably as the result of liquefaction. Thus, mucolytic expectorant activity of both enzymes can be demonstrated first by the reduction in viscosity and next of the increase in volume of sputa. However, the decrease in amount of freeze-dried substance is not always in accord with the reduction viscosity.