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In this review study, second-generation antiepileptic drugs (AEDs) (levetiracetam, gabapentin, topiramate, lamotrigine, zonisamide, oxcarbazepine, vigabatrin, pregabalin, rufinamide, tiagabine, lacosamide, and felbamate) and injectable AEDs (levetiracetam, lacosamide, fosphenytoin, lorazepam, and valproic acid) available in North America were compared with those available in Japan. Three second-generation AEDs (gabapentin, topiramate, and lamotrigine) were recently approved in Japan. Levetiracetam is currently under review for approval by the Japanese regulatory agency. An ideal AED would have a broad-spectrum activity to control multiple types of seizures, favorable safety profile, limited potential for drug-drug interaction, many bioequivalent formulations, long half life to allow infrequent administration, and antiepileptogenic effects that may provide a fundamental cure of epileptic patients by suppressing the development of epileptogenic network and neutralizing previously established epileptogenic foci in the brain. The second-generation AEDs have been developed to possess some of these ideal properties. All the second-generation AEDs are efficacious for the treatment of patients with partial seizures. In addition, levetiracetam, topiramate, lamotrigine, and zonisamide are effective for the treatment of patients with generalized tonic-clonic seizures, absences, myoclonic seizures, Lennox-Gastaut syndrome, and West syndrome; however, lamotrigine is not effective for the treatment of patients with myoclonic seizures. Rufinamide and felbamate are useful for the treatment of patients with Lennox-Gastaut syndrome; however owing to its serious adverse effects, including aplastic anemia and hepatic failure, felbamate is used as the last resort for the treatment of patients with intractable seizures. Vigabatrin is particularly effective for the treatment of patients with West syndrome; however, the patients need to be regularly monitored for the development of peripheral visual field defect. Gabapentin, oxcarbazepine, vigabatrin, and tiagabine are ineffective for the treatment of patients with absences and/or myoclonic seizures and may aggravate these conditions. Treatment with levetiracetam or topiramate (off-label use) is the new option for patients with refractory status epilepticus, which is characterized by downregulation of the inhibitory gamma-aminobutyric acid system, because these drugs act via different mechanisms and are rapidly titratable, especially intravenous levetiracetam. The pharmacokinetic profiles of levetiracetam, gabapentin, and pregabalin are favorable: these drugs exhibit minimal protein binding, do not undergo hepatic metabolism, are not involved in any clinically relevant drug interactions, and rarely lead to the development of serious adverse effects. In general, levetiracetam is probably the closest to being the ideal AED because of its broad-spectrum favorable pharmacokinetic profile and safety profile as well as because of the availability of its parenteral formulation. Among the injectable AEDs, fosphenytoin is a water-soluble prodrug and is used to treat patients with status epilepticus. Systemic and local side effects of this drug are fewer than those of phenytoin. Lorazepam, a benzodiazepine is used as the first-line AED for the treatment of patients with status epilepticus. The effects of this drug are more prolonged than those of diazepam. Intravenous administration of valproic acid is regarded as a new treatment option for patients with status epilepticus, because sedative and negative effects on the cardiorespiratory system of this drug are lesser than those of the traditional injectable AEDs. These novel medications will aid the improvement of the quality of life of epileptic patients through improved seizure control and reduced adverse effects.

Recent cross-cultural research suggests that East Asians are more likely than their Western counterparts to be sensitive to contextual information. In this experimental research study, we presented a blinking circle situated at the center of the computer screen for 30s. Both Japanese and Western participants were alternately engaged in two different tasks: (a) A single target circle, and (b) a target circle with four surrounding circles. In either case, they were asked to focus only on the target circle while ignoring the surrounding information. The results indicated that, even though the Japanese attempted to focus on the center circle, they failed to focus only on the center circle. Their number of fixations and variances from the center to each fixation points were significantly larger than found with the Westerners. This effect was stronger when four circles surrounded the target circle compared to a single circle. These findings suggest that cultural influences on basic psychological processes may be very deep.

Objective: To review the development of epilepsy surgery for pediatric patients with intractable epilepsy at The Hospital for Sick Children in Toronto, Canada., Methods: We retrospectively collected and reviewed published papers regarding pediatric epilepsy surgery since 1930's., Results: First, McKenzie started a hemispherectomy for children. Hendrick established anatomical hemispherectomy for pediatric patients with hemiparesis and intractable seizures since 1964. Hoffman performed anterior temporal lobectomy and neocortical temporal resection for lesional tempolal lobe epilepsy with or without mesial temporal sclerosis since 1974. Thereafter, multimodal neuroimaging studies of CT scan, MRI, and XenonCT, SPECT and PET have been used to identify and remove the epileptogenic lesion and zone. In 1996, magnetoencephalography (MEG) was introduced to localize interictal spike sources and somatosensory evoked fields for children with intractable seizures. Snead and Rutka started subdural grid electrodes that were constructed by scalp video EEG, MRI and MEG findings. The clustered MEG spike source coregistered with the intraoperative neuronavigation system delineated the epileptogenic zone requiring completely excision for neocortical lesional epilepsy from 2000., Conclusion: The pediatric epilepsy surgery at the Hospital for Sick Children has been progressing from anatomical hemispherectomy to complete clusterectomy of MEG spikes sources that localized the epileptogenic zone. Cortical excision, lobectomy, hemisphelotomy, corpus callosotomy and vagal nerve stimulation have been applied to appropriate seizure types identified by advanced neurodiagnostic modalities. We furthermore develop non-invasive methods for localizing and understanding the epileptic network in pediatric epilepsy patients with developing brain.

Dopa-responsive dystonia (DRD) is a clinical syndrome characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of levodopa. There are at least three causative genes for DRD: (1) the GCH1 gene on chromosome 14q22.1-q22.2, which encodes GTP cyclohydrolase I (GTPCH), the first enzyme in the biosynthetic pathway for tetrahydrobiopterin (BH4; the essential cofactor for tyrosine hydroxylase [THI]), (2) the TH gene on 11 p15.5, coding for the enzyme TH that catalyzes the rate-limiting step in the catecholamine biosynthesis, and (3) an as yet undefined gene on 14q13 (DYT14). In reports on DRD, in which conventional genomic DNA sequencing of GCH1 was conducted in a relatively large number of pedigrees, mutations in the coding region (including the splice sites) of this gene were found in approximately 60% (range: 49-79%) of DRD families. In our series, after conducting additional GCH1 testing (Southern blotting, cDNA sequencing, etc.) and TH analysis, 86% of families with DRD or dystonia with motor delay (an intermediate phenotype between GTPCH-deficient DRD [mild] and GTPCH-deficient hyperphenylalaninemia [severe]) had identifiable GCH1 or (rarely) TH mutations. Up to the present, only one pedigree with autosomal dominant DRD linked to the DYT14 locus has been reported. Neuropathological findings (no Lewy bodies and a normal population of cells with reduced melanin in the substantia nigra) in DRD patients with GTPCH dysfunction were similar to those in a patient with DYT14 dystonia. There have been no reports of autopsied patients with TH-deficient DRD. Neurochemical data suggest that striatal dopamine reduction in GTPCH-deficient DRD is caused not only by decreased TH activity resulting from a low cofactor (BH4) level but also by actual loss of TH protein without nerve terminal loss. This TH protein reduction in the striatum, especially in the putamen, may be due to a diminished regulatory effect of BH4 on stability (rather than expression) of TH molecules or to a dysfunction of TH protein transport from the substantia nigra to the striatum. The extent of striatal TH protein loss may be critical in determining DRD symptomatology and could contribute to gender-related incomplete penetrance of GCH1 mutations in GTPCH-deficient DRD families. Notwithstanding the discovery of the three causative loci for DRD, a therapeutic trial with low doses of levodopa is still the most practical approach to the diagnosis of this treatable disorder. The trial should be considered in all children with dystonic and/or parkinsonian symptoms or with unexplained gait disorders. Analyses of total biopterin and neopterin as well as neurotransmitter metabolites in CSF appear to be useful for the diagnosis of GTPCH-deficient DRD (the major form of DRD) and of TH-deficient DRD (the mild form of TH deficiency). Findings of the precise mechanism of striatal TH protein loss in GTPCH-deficient DRD, the actual status of dopaminergic systems in TH-deficient DRD, and the novel causative gene on the DYT14 locus will better define the pathogenesis of DRD.

To investigate the effect of eye movement on suppression of binocular rivalry in the half-occluded region, which is the monocular region made by occlusion, the amount of binocular rivalry in the half-occluded region was measured in the eye movement condition and the fixating condition. In the eye movement condition, the observer moved their eyes between the occluder and the occluded object. In the fixating condition, the observers fixated the occluder (the fixating-the-occluder condition) or the occluded object (the fixating-the-occluded-object condition). Following facts were found: (a) the amount of binocular rivalry in the half-occluded region reduced more in the eye movement condition than in the two fixating conditions, (b) there was no significant difference in the amount of binocular rivalry in the half-occluded region between the two fixating conditions. These results suggested that eye movement is one of the factors to suppress binocular rivalry in the half-occluded region in natural viewing situations.

Between September 1998 to February 2000, 45 consecutive patients underwent robotic-assisted, video-enhanced coronary artery bypass grafting. All IMA's were harvested using the voice-activated robotic assistant (AESOP 3000, Computer Motion Inc, Santa Barbara, CA) and the Harmonic scalpel (Ethicon Endo-Surgery, Cincinnati, OH). Left IMA's were successfully harvested in all patients. Harvested IMA's were anastomosed to LAD's under direct vision through limited left anterior thoracotomy. The IMA harvest time was 57.8 +/- 23.2 min, intraoperative graft flow was 34.3 +/- 20.5 ml/min, postoperative hospital stay was 3.9 +/- 1.5 days. The early postoperative angiogram showed that all grafts were patent. There was no mortality, no significant morbidity. The robotic assisted, video enhanced CABG provides safe and complete LIMA dissection with minimal manipulation and assures sufficient LITA length for tension free anastomosis.

The pediatric epilepsy management team in the Hospital for Sick Children, Toronto, Canada, consists of neurologists, neurophysiologists, neurosurgeons, neuropyschologists, clinical nurse specialist/nurse practitioners, social workers, EEG technologists and psychiatrists. The patients are initially referred to us for the diagnosis of seizure disorders. Epileptic foci and eloquent cortices are identified by neurophysiological studies such as EEG, MEG and SEP. Epileptogenic lesions can be visualized by MRI, the language, motor and sensory cortices by fMRI and the regions of hypoperfusion and hypometabolism in the epileptic foci, by SPECT and PET, respectively. The results of these studies are then discussed by members of the team. For patients with lesional epilepsy, an intraoperative image guided system and intraoperative electrocorticography are used, when lesionectomy, lobectomy and additional multiple subpial transection (MST) are performed. Patients without an identifiable lesion require intracranial invasive video EEG using subdural grids or depth electrodes, which are constructed based on MEG spike sources, seizure semiology and scalp video EEG. After the identification of the epileptogenic and functional zones, maximum cortical excision and MST are performed to control seizures and to minimize functional deficits. Pediatric neurologists should assess the intractability of epilepsy, identify the epileptogenic zone, determine the excisable epileptic region, and minimize postoperative side effects, thereby leading the epilepsy management team.

Twenty five percent of children with epilepsy continue to seize despite best medical management and may be defined as medically refractory. Many children with medically refractory localization-related epilepsy, i.e. seizures which originate in a particular area of brain and secondarily spread to involve other brain regions, may benefit from a variety of surgical treatments including hemispherectomy, corpus callosotomy, focal cortical resection of the temporal lobe, focal cortical resection of extratemporal regions of brain, and multiple subpial resections. A successful outcome from epilepsy surgery is generally defined as a seizure-free state with no imposition of neurologic deficit. In order to achieve these twin goals two criteria must be fulfilled. First, precise localization of the epileptogenic zone in the brain is necessary. The epileptogenic zone may be defined as the region of epileptogenic cerebral cortex whose removal will result in a seizure-free state. Second, one must determine the anatomic localization of eloquent cortex in brain in order to spare these areas during any planned cortical excision of epileptogenic cortex. Several diagnostic measures may be used to achieve a successful surgical outcome. A clinical history to ascertain the earliest symptom in the clinical progression of the seizure (semiology) is imperative as is ictal and interictal scalp EEG, neuropsychological testing, magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computerized tomography (SPECT), interictal magnetoencephalography (MEG). In the typical child undergoing evaluation for epilepsy surgery, if the clinical, neuropsychological, EEG, and radiological data are all concordant and point to the same area of epileptogenicity in brain, cortical excision of the suspected epileptogenic zone is undertaken. However, if the data are discordant, and/or the epileptogenic zone resides wholly or in part within eloquent cortex, invasive intracranial monitoring from depth and/or subdural electrodes during a seizure is required to map out the areas of epileptogenicity in brain. The assessment of potential risks and benefits for this type of epilepsy surgery in children involve complex age-related issues, including the possible impact of uncontrolled seizures, medication, or surgery, on learning and development.

The medical records of all brain dead patients (n = 228) at the Hospital for Sick Children, Toronto from January 1990 to December 1999 were reviewed. A radionuclide cerebral blood flow study (RCBFS) as a supportive and confirmatory test was performed on 27 patients and the clinical diagnosis of brain death was confirmed on all of them. A RCBFS was performed on 10 out of 27 patients because full clinical evaluation could not be performed due to severe facial injuries or cervical injuries. A RCBFS was performed on 17 patients who underwent a full clinical evaluation, of which 15 cases were due to uncertainty in the clinical etiology of the deep coma and 2 cases were due purely to the need to persuade the family. In recent years, RCBFS was not used as extensively on patients who underwent a full clinical evaluation, reflecting social acceptance and a higher level of clinical certainty in diagnosing brain death in children. This study supports the opinion that brain death can be accurately diagnosed in pediatric patients with clinical criteria alone and confirmatory tests are not necessary in most cases.

After briefly describing the need for ethics in the development of professional regulation and analyzing the historical emergence of codes of ethics, the goal of this paper is to scrutinize the process by which the American Psychological Association developed its own Code of Ethics and proceeded to revise it periodically. Different lessons can be derived from these efforts and from the criticisms that were formulated. The need for international standards in professional and research ethics is then considered, and the results of a recent study on this subject are presented. Five major conclusions can be derived from the preceding analysis: (1) Codes of ethics can help professional recognition by stressing the importance given to the protection of the public, (2) the development of a code of ethics is usually related to the advancement of professional practice, (3) ethical standards should be in tune with the cultural values and the belief system of a given community, (4) a well-balanced code should incorporate both general aspirational principles and enforceable standards, and (5) the method used to define principles and standards should be empirically based.

Laminin-1, a major component of basement membranes, has multiple biological activities including promotion of cell adhesion, spreading, migration, growth, neurite outgrowth and tumor metastasis. Several active sites on laminin-1 have been identified previously. We modified these biologically active peptides to enhance their activities. The multimeric YIGSR (Tyr-Ile-Gly-Ser-Arg) peptides assembled on a branched lysine core were found to strongly enhance the activity of YIGSR in inhibiting tumor growth and metastasis. We also found the all-D-configuration peptide segment containing the IKVAV (Ile-Lys-Val-Ala-Val) sequence had similar biological activities to the native all-L-peptide in vitro and in vivo. These results suggest that these modified compounds are potentially useful for clinical applications. We have identified new active sequences from the laminin alpha 1 chain carboxyl-terminal globular domain (G domain). Using a systematic screening for cell binding sites with 113 overlapping synthetic peptides, we found five peptides (AG-10, AG-22, AG-32, AG-56, and AG-73) showed cell attachment activities with cell-type specificities. AG-10 and AG-32 were found to interact with integrins. AG-73 caused metastases of B16-F10 mouse melanoma cells to the liver colonization in mice. Additionally AG-73 was found to promote neurite outgrowth. Moreover, this peptide inhibited laminin mediated acinar-like development of a human submandibular gland cell line. The AG-73 domain on laminin-1 could be one of the most important biologically active sites. These active peptides may useful for study of the molecular mechanism of laminin-receptor interactions and for development of therapeutic reagents for tumor metastasis and angiogenasis.

Recent developments in the study of brain self-stimulation were reviewed with particular emphasis on the biochemical mechanism underlying the phenomenon. Several lines of evidence suggest that dopaminergic transmission in the mesolimbic system is critical for the reinforcement effect to occur. An important event is the activation of D2 dopamine receptors in the nucleus accumbens and its vicinity, but D2 receptors cannot respond to dopamine unless D1 receptors are activated first. It is necessary for these receptors to work together to initiate intracellular chemical reactions to alter the excitability of the accumbens neurons. Recent experiments suggest that the reinforcing effect of medial-forebrain-bundle stimulation depends on the activation of intracellular protein kinase in the nucleus accumbens. As in the sensitization in Aplysia and long-term potentiation in the hippocampus, protein kinases play critical role in the reinforcement of operant behaviour.

Dynamic Cardiomyoplasty is a new approach to manage patients with heart failure. The phase I study shows that the muscle stimulator and electrodes function as designed and that the operation is done without any impairment of the patient's motor function. The results of the phase II study has been made public. The hemodynamic effects on patients with dilated cardiomyoplasty have been reported to be excellent. The assisting mechanism of dynamic cardiomyoplasty is based on the conformational change of the wrapped muscle with the ability to restore its optimal length and tension. In the chronic postoperative stage, the muscle seems to form a layer outside the epicardium. This change is important for the myocardinal sparing and girdling effects which are related to the wall stress of the heart. The hypothesis that the wrapped muscle becomes another layer of the heart can explain these effects. Increasing the wall thickness of the left ventricle reduces the wall stress (myocardinal sparing effect) according to Laplace's law. Even if the wrapped muscle is not transformed or stimulated (adynamic cardiomyoplasty), the wall stress is reduced after conformation, and the dilatation of the heart may be protected (girdling effect). The systolic augmentation is shown as the increase of cardiac output, ejection fraction, and blood velocity of the ascending aorta and ejection time. The dynamic cardiomyoplasty might effect the remodelling of the impaired heart and delay its progressive dilatation. When the efficacy of dynamic cardiomyoplasty is proven by the phase III study, which has been going on in the centers of North and South Americas, it will be useful as a bridge to heart transplantation, or as one of the surgical treatment modalities for advanced heart failure.

The method of measuring cardiac output with transesophageal pulsed Doppler two-dimensional echocardiography was developed and validated by comparison with the thermodilution technique in 65 adult patients. With the use of transesophageal four-chamber view, the Doppler sample volume was placed in the center of the mitral ring and the mitral flow velocity-time integral was obtained through planimetric measurements of the mitral flow velocity curve. The diameter of the mitral valve anulus was measured at the time of peak rapid filling flow velocity, and the cross-sectional area of the mitral valve anulus was calculated, assuming a circular shape. Doppler-determined cardiac output was calculated by using the following formula: Cardiac output [1.min-1] = pi (D [cm] /2)2.MFVI [cm].heart rate [bpm].10(-3), where MFVI is mitral flow velocity-time integral, and D is the diameter of the mitral valve anulus. There was a weak correlation between thermodilution and Doppler measurements of cardiac output (r = 0.64, p less than 0.01), while a good correlation was observed between percent changes in thermodilution-derived cardiac output and those in Doppler-determined cardiac output (r = 0.92, p less than 0.01) during different loading conditions. It has been suggested that this method may be useful for assessing relative changes in cardiac output during short time periods.

Twelve infants with choroid plexus tumors were reviewed retrospectively. Enlarging head circumference, bulging fontanelle, and vomiting were the major symptoms and signs appearing 2 to 5 weeks (mean = 3.7 weeks) before diagnosis. The average age at diagnosis was 7.7 months. Total removal was performed in 11 patients with choroid plexus papilloma, and partial removal was achieved in 1 patient with a choroid plexus carcinoma. A cerebrospinal fluid (CSF) diversionary shunt was placed temporarily in 6 infants and permanently in 4. Of the two patients not requiring CSF diversionary shunt, 1 needed a subdural-peritoneal shunt postoperatively. Histologically, 11 of 12 tumors were choroid plexus papillomas, and one was a choroid plexus carcinoma. All 12 patients were followed up for 4 months to 11 years (mean = 5.6 years). Eleven of 12 patients were alive at the time of their last check-up. All 11 survivors had normal psychomotor and neurological development. The treatment and outcome of choroid plexus tumors and management of associated hydrocephalus are discussed.

Semi-closed underwater breathing apparatus has commonly been used among military and commercial divers, but never available for recreational divers because of complicated operations, difficulties of maintenance, and expensiveness. Nippon Sanso K.K. has newly deployed a semi-closed circuit underwater breathing apparatus called the "eOBA". It is especially designed for divers to enjoy shallow (max. 5 m) and short (10 min.) dives. This eOBA was evaluated from manned testing based on physiological requirements for the apparatus. Four male and four female subjects participated in the three test trials. Subjects maintained their position at the depths of 2 m and 4 m for 10 min. and e exercised on the underwater ergometer at the depth of 2.4 m. The pressure at the mouthpiece, tidal volume, breathing rate, the inspired O2 level, CO2 level were monitored on breath-by-breath basis. The inspired O2 level ranged from 45% (at exercise) to 60% (at rest) and the inspired CO2 level were kept less than 1.0% in the most cases. The P-V loop indicated relatively little external work of breathing (less than 0.1 kg.m/l) and allowable peak pressures (less than 25cmH2O). Results show that the eOBA meets the standards sufficiently under the test conditions and is a safe apparatus for recreational divers if it is properly used.

Quality of life (QOL) is defined as "representation of people's day-to-day function". It has four components: physical and occupational functions, social interaction, psychological state, and somatic sensation. QOL can be mathematical presentation of these four component factors. QOL measurement tools (questionnaires) should have core modules as well as disease-specificity, simplicity, validity and reliability. At present, several patients' self-assessment questionnaires are widely used practical at the aims to assess what happens in the cancer patients and to improve the cancer treatment. A QOL study trials should be scientific. However, QOL is popular terms that there is a tendency to abuse it, and, therefore, to set up the study to get contradictory results. The author would introduce a practical overview of the tactics to perform a QOL research trial.

Cells isolated from the avian and mammalian central and peripheral nervous system and cultured in vitro provide an opportunity to study in situ properties of neurons and glial cells under relatively simple and carefully controlled conditions. Since Harrison's success in maintaining in vitro embryonic frog spinal cord 80 years ago, neural tissue culture has developed into an important and versatile discipline of neuroscience. The techniques developed in the past fall into four broad classes: Explant cultures, which are explanted from specific neuroanatomic loci to substrates as small tissue fragments. Dissociated cell cultures, which involve the seeding of enzymatically or mechanically dispersed cells on various attachment substrates. Reaggregate cultures, which require re-association of dissociated cells into small aggregates. Purified cell populations, which are prepared by the isolation of different cell types by gradient centrifugation or other separation techniques. These cultures have been utilized in studying various aspects of brain development and function. In this review several areas of significant and stimulating development in neural cell culture have been documented. They include formulation of serum-free medium, effects of growth factors, utilization of cell type-specific markers, and isolation and culture of purified neuronal/glial cells.