We report a 6-month-old female infant with status convulsivus which appeared during intravenous drip infusion of aminophylline. She had an extremely high serum theophylline concentration (79 micrograms/ml), which was effectively reduced by plasmapheresis and dialysis. Three days later, she developed status convulsivus again, though her serum theophylline was undetectable at that time. A CT on 14th day of illness revealed mild widening of frontal sulci and Sylvian fissure. The patient apparently recovered her healthy condition, but psychomotor developmental delay, especially in speech and social behavior, was noted at the age of 2 years 6 months (DQ = 55). A delay of myelination was observed on brain MRI at 4 year 1 months, suggesting an irreversible brain injury caused by theophylline intoxication.

Brain↗

PubMed1999

Migration of epileptic foci in children.

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Adolescent↗

PubMed1999

Symmetric covalent linkage of N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) results in novel derivatives with increased inhibitory activities against calcium/calmodulin complex.

A useful calmodulin (CaM) antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), was invented by Hidaka et al. in 1978 (J. Pharmacol. Exp. Ther. 207, 8-15). Here, we have designed new CaM antagonists on the basis of the three-dimensional structure of Ca2+/CaM complexed with W-7. Eleven new compounds all share a similar architecture, in which two W-7 molecules are linked between their aminohexyl termini by a linker with different functionalities. A wide range of inhibitory activities against Ca2+/CaM-dependent protein kinase I (CaM kinase I) has been observed with these self-crosslinked W-7 analogs, (W-7)2. In vitro competitive CaM kinase I assays using CaM kinase I and nuclear magnetic resonance studies indicated that one (W-7)2 molecule binds to one CaM molecule as expected, with the two chloronaphthalene rings of (W-7)2 being anchored separately to the N- and C-terminal hydrophobic pockets of Ca2+/CaM. The most potent compound, N,N'-bis[6-(5-chloro-1-naphthalenesulfonyl)-amino-1-hexyl]-p-xylen e-diamine ((W-7)2 - 10), inhibits CaM kinase I activity at an IC50 value of 0.23 microM; about 75 times more effectively than W-7. The length and basicity of the linker sequence in (W-7)2 significantly contribute to inhibitory activity. The present study opens an avenue for developing powerful CaM antagonists that could be used at low doses in vivo.

Animals↗

PubMed1998

Increased complex formation of Gc globulin with actin in plasma from human cadavers.

Gc globulin binds actin at an equimolar ratio with a high affinity. It has been revealed that complexes of Gc with actin are present in the plasma of human cadavers. In the present study, an immunoassay which we developed using a specific anti-Gc monoclonal antibody was applied to evaluate the complexed Gc in cadaver plasma. The percentage of Gc in the complexed form was found to be 38.3 +/- 19.8% (n = 45), and a significantly higher percentage was observed in the plasma of cadavers from burn death. However, the plot of the complex percentage against the time since death showed a relatively low correlation, with a coefficient (r) of 0.51. This was supposed to be due to different environmental conditions after death. Since the complex formation represents the release of cytoplasmic actin into plasma from collapsed cells, the phenomenon should be noted in forensic postmortem chemistry.

Actins↗

PubMed1998

An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy.

Fukuyama-type congenital muscular dystrophy (FCMD), one of the most common autosomal recessive disorders in Japan (incidence is 0.7-1.2 per 10,000 births), is characterized by congenital muscular dystrophy associated with brain malformation (micropolygria) due to a defect in the migration of neurons. We previously mapped the FCMD gene to a region of less than 100 kilobases which included the marker locus D9S2107 on chromosome 9q31. We have also described a haplotype that is shared by more than 80% of FCMD chromosomes, indicating that most chromosomes bearing the FCMD mutation could be derived from a single ancestor. Here we report that there is a retrotransposal insertion of tandemly repeated sequences within this candidate-gene interval in all FCMD chromosomes carrying the founder haplotype (87%). The inserted sequence is about 3 kilobases long and is located in the 3' untranslated region of a gene encoding a new 461-amino-acid protein. This gene is expressed in various tissues in normal individuals, but not in FCMD patients who carry the insertion. Two independent point mutations confirm that mutation of this gene is responsible for FCMD. The predicted protein, which we term fukutin, contains an amino-terminal signal sequence, which together with results from transfection experiments suggests that fukutin is a secreted protein. To our knowledge, FCMD is the first human disease to be caused by an ancient retrotransposal integration.

Amino Acid Sequence↗

PubMed1998

Prenatal diagnosis of Fukuyama type congenital muscular dystrophy in eight Japanese families by haplotype analysis using new markers closest to the gene.

We conducted prenatal diagnosis by haplotype analysis, using newly developed microsatellite markers, in eight Fukuyama type congenital muscular dystrophy (FCMD) families. In addition to six new families, two previously reported families were reexamined by haplotype analysis including detection of an ancestral founder haplotype (138-183-301) for 3 microsatellite markers closest to the FCMD gene, designated D9S2105-D9S2107-D9S172, the distances of which from the FCMD gene are presumed to be approximately 140, approximately 20, and approximately 280 kb, respectively. Five fetuses from five families were diagnosed as nonaffected, and were subsequently confirmed to be healthy. Three fetuses of the other three families were diagnosed as having a high probability of being affected by FCMD. In the prenatal diagnosis conducted for these eight families, the ancestral founder allele was observed in 13 of 16 (81%) FCMD-bearing chromosomes. Detection of the ancestral haplotype facilitated achieving accurate prenatal diagnosis of FCMD. The brains of all three fetuses prenatally diagnosed as FCMD-affected showed the initial stage of cortical dysplasia, strong evidence of FCMD.

Brain↗

PubMed1998

Solution structure of calmodulin-W-7 complex: the basis of diversity in molecular recognition.

The solution structure of calcium-bound calmodulin (CaM) complexed with an antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), has been determined by multidimensional NMR spectroscopy. The structure consists of one molecule of W-7 binding to each of the two domains of CaM. In each domain, the W-7 chloronaphthalene ring interacts with four methionine methyl groups and other aliphatic or aromatic side-chains in a deep hydrophobic pocket, the site responsible for CaM binding to CaM-dependent enzymes such as myosin light chain kinases (MLCKs) and CaM kinase II. This competitive binding at the same site between W-7 and CaM-dependent enzymes suggests the mechanism by which W-7 inhibits CaM to activate the enzymes. The orientation of the W-7 naphthalene ring in the N-terminal pocket is rotated approximately 40 degrees with respect to that in the C-terminal pocket. The W-7 ring orientation differs significantly from the Trp800 indole ring of smooth muscle MLCK bound to the C-terminal pocket and the phenothiazine ring of trifluoperazine bound to the N or C-terminal pocket. These comparative structural analyses demonstrate that the two hydrophobic pockets of CaM can accommodate a variety of bulky aromatic rings, which provides a plausible structural basis for the diversity in CaM-mediated molecular recognition.

Animals↗

PubMed1998

Acute effects of various GABA receptor agonists and glutamate antagonists on focal hippocampal seizures in freely moving rats elicited by low-frequency stimulation.

In this study, we examined the acute anticonvulsant spectrum of (1) dizocilpine (0.03-3 mg/kg), CGS 19755 (1-10 mg/kg), and 7-chlorokynurenic acid (1-100 nmol) (NMDA receptor/ionophore complex antagonists); (2) muscimol (0.1-10 nmol; direct GABA(A) agonist); (3) YM90K (3-10 mg/kg; AMPA receptor antagonist); and (4) diazepam (2 and 5 mg/kg) and carbamazepine (5 and 20 mg/kg), two standard anticonvulsants, using the partially-kindled hippocampal model for epileptic seizures in freely moving rats. The anticonvulsant effect of these compounds were assessed by determining (1) the afterdischarge (AD), which is indicative of the severity of the seizure and related to seizure maintenance, and (2) the pulse number threshold (PNT), which is indicative of the seizure threshold or initiation. In addition, ataxia, a measure of CNS dysfunction, was assessed for each compound. Overall, our results indicated that the anticonvulsant compounds examined could be classified into three categories based on effects on the AD and PNT: (1) elevation of PNT (carbamazepine, dizocilpine, CGS 19755 and 7-chlorokynurenic acid); (2) reduction of AD (diazepam and muscimol); and (3) mixed action, i.e., increased PNT and decreased AD (YM90K). Behavioral data indicated that all compounds, except carbamazepine, produced a dose- or concentration-dependent ataxia. Overall, our results suggest that NMDA receptors play a role in seizure initiation, whereas the GABA(A) receptors appear to be involved in seizure maintenance and AMPA receptors may be involved in both phenomena.

Animals↗

PubMed1998

Compound A concentration is decreased by cooling anaesthetic circuit during low-flow sevoflurane anaesthesia.

PURPOSE: In the presence of carbon dioxide absorbents, sevoflurane is degraded to CF2 = C(CF3)OCH2F, an olefin compound A. There remains some concern of the hepatic and renal toxicity that compound A poses when using low-flow anaesthetic techniques. We investigated a device to decrease the concentration of compound A products by decreasing the temperature of exhaled air and soda lime in semi-closed low-flow anaesthesia technique in surgical patients. METHODS: Ten patients, ASA 1 or 2, were studied. Five received anaesthesia using a cooling circuit, that consisting of an anaesthetic circuit and an intercooler device interposed in the expiratory tube. The intercooler was dipped in an iced water tank. Anaesthesia was given through this circuit from induction to emergence. Another five patients received anaesthesia without cooling. Anaesthesia was maintained with sevoflurane and O2 50%/N2O during four to six hours of operation. A fixed concentration of sevoflurane 2% at a total flow of 1 L.min-1 was administered. Gas samples were taken every hour and compound A was quantitated by gas chromatography. The temperatures of canister, circuit and body were measured every hour. RESULTS: The device effectively lowered the temperatures [24 +/- 3.4 to 5 +/- 1.3 degrees C] and the concentrations of compound A [27.1 +/- 3.8 ppm to 16.3 +/- 2.08 ppm, P < 0.05] in the circuit. The body temperatures were not lowered. CONCLUSION: Compound A concentrations were reduced by cooling the anaesthetic circuit in clinical settings.

Absorption↗

PubMed1998

Clinical analysis of internal carotid artery aneurysms with reference to classification and clipping techniques.

An intraoperative classification of intradural internal carotid artery (ICA) aneurysms not related to the arterial division but based on their operative presentation and clipping techniques is introduced. On the basis of the surgeon's view of the operative field via the pterional approach in 156 operated intradural ICA aneurysms in 143 patients, these aneurysms were classified according to their location in relation to the long axis of the ICA as either proximal, middle or distal in type and also according to their relation to the cross section of the ICA as either lateral, medial, ventral or dorsal in type. Numerically the largest in frequency is the middle type of aneurysm by axial location and the lateral type of aneurysms by cross sectional location. Eighty five percent of the lateral type aneurysms were at the arterial division. The majority of the large to giant aneurysms were of the ventral type and no dorsal type aneurysms were seen. About one third of the ICA aneurysms in this series were located free of the arterial division. All dorsal type aneurysms and most of the medial type aneurysms were not related to the arterial division. Clipping techniques were classified into perpendicular and parallel clipping, as to the direction of the clip-blades in relation to the carotid axis. The parallel clipping was further classified into forward clipping, in which a clip was applied from the distal side of the ICA, and reversed clipping, in which a clip was applied from the proximal side of the ICA. Most of the aneurysms located at the arterial division required the perpendicular clipping and those free of the arterial division required the parallel clipping. Furthermore, the forward clipping was useful for proximal type aneurysms and the reversed clipping for distal type aneurysms. For the middle type aneurysms clipping was performed bidirectionally. This classification includes all types of the ICA aneurysms located at any points along its long axis and on its cross section, and is useful for planning safe and exact clipping of the ICA aneurysms.

Adult↗

PubMed1998

Study on surgical treatment of intractable childhood epilepsy.

We studied the clinical details of 14 children with intractable epilepsies, all of whom underwent epilepsy surgery before age 18 years. All 14 suffered catastrophic seizures, which were resistant to the full range of available medical treatments. The ages at operation ranged from 4 years 7 months to 17 years 2 months, with a mean of 9 years 11 months. In nine patients, the age at onset of epilepsy was less than 2 years. The seizure disorders were classified as temporal lobe epilepsy in two patients, extratemporal lobe epilepsy in 10, and symptomatic generalized epilepsy in two. Eight patients had a hemicorporeal deficit (hemiparesis or hemiplegia) preoperatively. All 14 patients showed localized magnetic resonance imaging (MRI), single photon emission computer tomography (SPECT) and/or positron emission tomography (PET) abnormalities, providing crucial information regarding the epileptic focus. As to the surgical outcomes, four patients became seizure-free and the other 10 showed significant improvement during a mean follow-up period of 2 years 5 months. As to etiology, cortical dysplasia was identified in seven patients. Epilepsy surgery should be considered for intractable childhood epilepsy based on individual clinical characteristics, including seizure status, cognitive development, and evidence indicating location of the seizure focus, rather than age.

Adolescent↗

PubMed1998

Long-term outcomes of pediatric moyamoya disease monitored to adulthood.

The long-term outcomes of 25 patients with childhood moyamoya disease (18 with the transient ischemic attack [TIA] type and seven with the non-TIA type), who were monitored to adulthood (older than 20 years of age), were evaluated in terms of residual clinical symptoms, intellectual development, and activities of daily living. Surgical treatment was performed in ten patients, encephaloduroarteriosynangiosis in nine, and superficial temporal artery to middle cerebral artery anastomosis plus encephalomyosynangiosis in one. Only seven with the TIA type (three surgically and four medically treated) demonstrated good activities of daily living without TIA or headache and normal IQ. Two patients with the TIA type and three with the non-TIA type demonstrated poor outcomes. Three of these patients with poor outcomes had renal artery stenosis. Surgery was effective in nine. Since the long-term outcomes of patients with childhood moyamoya disease are generally poor, surgical treatment is believed to be an effective procedure for preventing the progression of clinical symptoms.

Activities of Daily Living↗

PubMed1998

Dramatic effect of ethosuximide on epileptic negative myoclonus: implications for the neurophysiological mechanism.

Epileptic negative myoclonus (ENM) is a recently defined epileptic seizure type seen in various epileptic syndromes. Although the long-term prognosis appears to be favorable, the treatment of localization-related epilepsy (LRE) with ENM in childhood is sometimes difficult due to the apparently pharmaco-resistant nature of ENM. We evaluated the effects of antiepileptic drugs (AEDs) in 10 patients with ENM. Carbamazepine was administered to eight patients, none of whom improved. Responses to clonazepam and valproic acid were unpredictable, whereas ethosuximide (ESM) achieved complete control of ENM in all six cases treated with this drug as adjunctive therapy. The pharmacological responses of ENM to CBZ and ESM were quite similar to those of absence seizures. According to the SPECT and ictal EEG findings in addition to the pharmacological responses from this study, we favor to postulate that ENM is produced by a direct inhibitory action on the motor cortex resulting in the interruption of voluntary muscle contraction as generated by sharp-slow wave complexes, compatible with the mechanism considered to underlie absence seizures. ENM are refractory to treatment and persisting if the wrong AEDs, such as PHT or CBZ, are selected at the diagnosis of LRE. We recommended a trial of ESM when ENM develops during the clinical course of LRE regardless of etiology.

Adolescent↗

PubMed1998

Epitope analysis of monoclonal antibodies to human Gc globulin (vitamin D-binding protein).

Gc globulin, also called vitamin D-binding protein, is a human 56 kDa plasma protein. Antigenic epitopes of the protein recognized by 12 different monoclonal antibodies (MoAbs), including the previously prepared MoAb E12 of which binding to Gc is inhibited by actin, were analyzed in relation to the functional domains of the protein. To map the epitopes recognized by the respective antibody, the reactivities of the MoAbs were tested by immunoblotting against the recombinant Gc fragments expressed in E. coli cells, and then a competitive ELISA was performed. The results showed that the antibodies were classified into at least six groups. Furthermore, in addition to E12, actin inhibited the reactivity of MoAb 21, of which the epitope was located within residues Asp320 to Glu379, in an ELISA in the presence of the ligand. This result must indicate that this antibody-binding site is near the site that interacts with actin. In contrast, no inhibitory effect by 25-hydroxyvitamin D to any antibodies was observed. Furthermore, all antibodies, including E12 and 21, reacted with membrane-bound Gc of lymphocytes by an immunofluorescence study, suggesting that Gc is unlikely to bind to the plasma membrane in its interaction with actin.

Actins↗