[Effects of midazolam on acute phase of stroke in two patients with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes].
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Child↗
Biomedical subjects
M Osawa
Publications and source records attributed to M Osawa.
[Proposal to obtain a licensed application for midazolam (Dormicam) as a drug effective for status epilepticus].
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Adolescent↗
Treatment and long-term prognosis of myoclonic-astatic epilepsy of early childhood.
PURPOSE: We retrospectively studied patients with myoclonic-astatic epilepsy of early childhood (MAE) to investigate the most effective treatment and long-term seizure and intellectual prognosis. SUBJECTS: Eighty-one patients with MAE were recruited from among 3600 patients with childhood epilepsy according to the ILAE criteria of MAE. METHODS: We retrospectively investigated the clinical characteristics and ultimate prognosis of the patients with MAE from the medical records. The effects of various antiepileptic drugs, ketogenic diet and ACTH treatments on myoclonic-astatic seizures (MS/AS), apparently a hallmark of this unique epileptic syndrome, were also studied. RESULTS: MS/AS in 89 % of the patients disappeared within 1 to 3 years despite initial resistance, but generalized tonic-clonic or clonic seizures [G(T)CS] tended to continue. The most effective treatment for the MS/AS was ketogenic diet, followed by ACTH and ESM. At the last follow-up, 55 patients or 68 % of all the patients had remission of epilepsy, 11 patients or 14 % experienced a recurrence of GTCS after a long remission period but easily regained control, and the remaining 15 patients or 18 % continued to have seizures and intellectual outcomes were poor. In one half of these patients with poor outcomes, repeated minor epileptic status and nocturnal generalized tonic seizures persisted. A family history of epilepsy and a combination of minor epileptic status are risk factors for poor outcomes. CONCLUSION: MAE is considered to form a clinical spectrum ranging in its main seizure type from myoclonic to atonic, and in seizure and intellectual outcomes from benign to malignant. The overall prognosis, despite initial resistance to treatment, appears to be much better than originally thought when ILAE definitions excluding SME are followed.
Adolescent↗
[A case of Klüver-Bucy syndrome after acute encephalopathy treated with selective serotonin reuptake inhibitor (fluvoxamine)].
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Acute Disease↗
A transmembrane trap method for efficient cloning of genes encoding proteins possessing transmembrane domain.
To facilitate searching for genes encoding cell membrane proteins, we developed a method for isolating cDNAs that contain sequences for hydrophobic transmembrane runs. This cloning strategy, termed the "transmembrane (TM) trap method," utilizes a vector that directs the cell surface expression of mouse CD4 fusion protein when an insert encoding hydrophobic transmembrane sequences is cloned in-frame with correct orientation. We applied this novel method to isolation of cytokine receptor cDNAs. Our strategy enabled efficient isolation of relatively rare species encoding receptors such as IL-2Rgamma, IL-3Rbeta, IL-4Ralpha, IL-5Ralpha, and IL-6Ralpha. This method also could be used to isolate cDNAs for intracellular molecules with a transmembrane region, e.g., bcl-2. These results indicate that the TM trap method provides an efficient cloning strategy for identification of various families of genes encoding proteins with one or more transmembrane regions.
Animals↗
Molecular cloning and characterization of mouse Tspan-3, a novel member of the tetraspanin superfamily, expressed on resting dendritic cells.
Dendritic cells (DCs) are the most potent antigen-presenting cells and play an essential role for triggering T-cell-mediated immune responses. In search for novel cell surface molecules expressed on DCs involved in T cell priming by representational differential analysis, we identified a mouse homologue of Tspan-3 (mTspan-3), a novel member of the tetraspanin superfamily. The mTspan-3 consists of four hydrophobic, putative transmembrane regions, forming a small and a large extracellular loop, with short intracellular amino and carboxil tails. Although the mTspan-3 is expressed on a variety of immune cell types including resting DCs, its expression on DCs is downregulated during activation induced by cross-linking CD40 with anti-CD40 monoclonal antibody. These results suggest that mTspan-3 may be involved in the function of DCs in association with T cell stimulation.
Amino Acid Sequence↗
Target-induced conformational adaptation of calmodulin revealed by the crystal structure of a complex with nematode Ca(2+)/calmodulin-dependent kinase kinase peptide.
Calmodulin (CaM) is a ubiquitous calcium (Ca(2+)) sensor which binds and regulates protein serine/threonine kinases along with many other proteins in a Ca(2+)-dependent manner. For this multi-functionality, conformational plasticity is essential; however, the nature and magnitude of CaM's plasticity still remains largely undetermined. Here, we present the 1.8 A resolution crystal structure of Ca(2+)/CaM, complexed with the 27-residue synthetic peptide corresponding to the CaM-binding domain of the nematode Caenorhabditis elegans Ca(2+)/CaM-dependent kinase kinase (CaMKK). The peptide bound in this crystal structure is a homologue of the previously NMR-derived complex with rat CaMKK, but benefits from improved structural resolution. Careful comparison of the present structure to previous crystal structures of CaM complexed with unrelated peptides derived from myosin light chain kinase and CaM kinase II, allow a quantitative analysis of the differences in the relative orientation of the N and C-terminal domains of CaM, defined as a screw axis rotation angle ranging from 156 degrees to 196 degrees. The principal differences in CaM interaction with various peptides are associated with the N-terminal domain of CaM. Unlike the C-terminal domain, which remains unchanged internally, the N-terminal domain of CaM displays significant differences in the EF-hand helix orientation between this and other CaM structures. Three hydrogen bonds between CaM and the peptide (E87-R336, E87-T339 and K75-T339) along with two salt bridges (E11-R349 and E114-K334) are the most probable determinants for the binding direction of the CaMKK peptide to CaM.
Amino Acid Sequence↗
Calcium-regulated DNA binding and oligomerization of the neuronal calcium-sensing protein, calsenilin/DREAM/KChIP3.
Calsenilin/DREAM/KChIP3, a member of the recoverin branch of the EF-hand superfamily, interacts with presenilins, serves as a calcium-regulated transcriptional repressor, and interacts with A-type potassium channels. Here we report physicochemical characterization of calcium binding, oligomerization, and DNA binding of human calsenilin/DREAM/KChIP3. Equilibrium Ca(2+) binding measurements indicate that the protein binds 3 Ca(2+) with a dissociation constant of 14 microM and a Hill coefficient of 0.7. Dynamic light scattering and size exclusion chromatography show that the Ca(2+)-bound protein exists as a dimer at protein concentrations lower than 150 microM and forms a tetramer at concentrations above 200 microM. The Ca(2+)-free protein is a tetramer in the concentration range 20-450 microM. Isothermal titration calorimetry and dynamic light scattering indicate that the Ca(2+)-free protein tetramer binds endothermically (DeltaH = +25 kcal/mol) to four molecules of DNA derived from the downstream regulatory element (DRE) of either the prodynorphin or c-fos genes. One DRE molecule binds tightly to the protein with a dissociation constant (K(d)) of 75 nM, and the other three bind more weakly (K(d) = 640 nM). No significant DNA binding was observed for the Ca(2+)-bound protein. The N-terminal protein fragment (residues 1-70) binds nonspecifically to DRE in a Ca(2+)-independent manner, whereas a C-terminal fragment containing the four EF-hands (residues 65-256) binds DRE (K(d) = 200 nM) in a Ca(2+)-regulated and sequence-specific fashion. The C-terminal fragment is a tetramer in the Ca(2+)-free state and dissociates into dimers at saturating Ca(2+) levels.
Amino Acid Sequence↗
Identification of two rodent genes encoding homologues to seminal vesicle autoantigen: a gene family including the gene for prolactin-inducible protein.
We cloned two new paralogous genes that encode proteins homologous to seminal vesicle autoantigen (SVA) in rodents. The open reading frame of one mouse gene encodes a polypeptide consisting of 151 amino acid residues which has 43% identity to SVA. RT-PCR analysis showed selective expression in the colon, and thus the protein was tentatively named "SVA-like protein in the colon (SLP-C)". The other mouse gene has an open reading frame encoding 144 amino acid residues with 46 and 65% identity to SVA and SLP-C, respectively. Expression of this gene was detected in the mammary, submaxillary, parotid, and lacrimal glands, and this protein was named "SLP in the mammary gland (SLP-M)". Orthologs of both genes were also found in rats. The three homologous genes coding for SVA, SLP-C, and SLP-M may have been generated by gene duplication with divergence of tissue expression in the course of evolution. They comprise a unique structurally-related gene family. Moreover, these genes share significant sequence homology with that of another secretory glycoprotein, prolactin-inducible protein.
Amino Acid Sequence↗
Multiplex amplified product-length polymorphism analysis for rapid detection of human mitochondrial DNA variations.
A number of mutations in coding and noncoding regions of mitochondrial DNA (mtDNA) have previously been studied. In the present study, we simultaneously typed six mutation sites in the coding region by use of amplified product-length polymorphism (APLP) analysis. The mtDNA variations of 2471 individuals from 20 populations of Japanese, Korean, Chinese, and German were examined and classified into 18 haplotypes. Two of these haplotypes, B1 (estimated ancestral haplotype) and C1, were distributed among all populations tested. However, the haplotypes A1, A2, B2, B3, and C2 were mostly restricted to the Mongoloid populations, whereas haplotypes B5 and C5 appeared almost exclusively in the German population. Phylogenetic analysis by the neighbor-joining method revealed that the Japanese populations were more closely related to each other than to the other East Asian populations surveyed. The multiplex APLP method is suitable for large-scale screening studies of mtDNA variability because it is both rapid and economical.
DNA, Mitochondrial↗
Results of direct surgery for aneurysmal subarachnoid haemorrhage: outcome of 2055 patients who underwent direct aneurysm surgery and profile of ruptured intracranial aneurysms.
BACKGROUND AND PURPOSE: The purpose of this study is to evaluate the therapeutic value of our surgical treatment of subarachnoid haemorrhage in a large series with standardized surgical principles. METHODS: Results of 2055 direct operations on ruptured intracranial aneurysms, treated in our institutions, where surgical indications, instruments and techniques were standardized, between 1988 and 1998, were retrospectively evaluated and outcome of the patients was discussed; cases treated by intravascular procedures were excluded. RESULTS: According to the evaluation at discharge, 1083 (52.7%) patients were excellent, 324 (15.8%) good and 223 (10.9%) fair. There were 160 (7.8%) patients of poor outcome and the remaining 265 (12.9%) died. There were no differences in the outcome between pre-operative Hunt & Kosnik grade I and II, Fisher Scale 1 and 2, anterior circulation aneurysms and posterior circulation aneurysms except those at and around the basilar bifurcation, men and women, and those clipped and not clipped. CONCLUSIONS: The factors related to poor outcomes were, age of 60 years or over, pre-operative Hunt & Kosnik grade II or more, Fisher Scale 3 or more, aneurysm size over 15 mm in diameter, and location at and around the basilar artery bifurcation. The results presented in this study show the status of our direct surgical management of subarachnoid haemorrhage in a large series with standardized surgical principles and procedures.
Adolescent↗
Clinicopathological study on eyes from cases of Fukuyama type congenital muscular dystrophy.
Fukuyama type congenital muscular dystrophy (FCMD) is an autosomal recessive disorder characterized by progressive muscular dystrophy and dysgenesis of the central nervous system and eyes. To clarify the pathomechanism of the ocular involvement in FCMD, we performed postmortem pathological analyses of eyes from three postnatal FCMD cases, two fetal FCMD cases, and three control cases by macroscopic, histopathological, immunohistochemical and in situ hybridization approaches. The macroscopic and histopathological examinations revealed a variety of ocular abnormalities such as folding, fusion or dysplasia of the retinas in the FCMD cases both with and without ophthalmological alterations. Immunoreactivities for collagen IV and laminin, produced by Müller cells, as the basement membrane components, were less intense in the inner limiting membrane of the FCMD retinas than in that of the control retinas. A number of the perivascular glial cells containing S-100 protein and glial fibrillary acidic protein were increased in the postnatal FCMD cases. Immunoreactivities for vimentin, glutamate transporter-1, glutamine synthase and ornithine aminotransferase, expressed in the Müller cells, were undetectable in the fetal FCMD retinas, and reduced in the postnatal FCMD retinas compared with the control retinas. Fukutin mRNA signals were distributed diffusely in the retinoblast layer of the control retinas, focally in the retinoblast layer of the fetal FCMD retinas, and only in the dysplastic areas with rosette formation of the postnatal FCMD retinas, composed of retinoblasts and other retinal cells including the Müller cells. The present findings suggest that the Müller cells are implicated in the retinal pathology of FCMD.
Adolescent↗
Acquired epileptiform opercular syndrome: a case report and results of single photon emission computed tomography and computer-assisted electroencephalographic analysis.
We report here a girl aged 5 years 3 months with cryptogenic localization-related epilepsy who showed a prolonged episode characterized by dysarthria, dysphagia, drooling and paresis of the right arm associated with almost continuous diffuse sharp-slow wave complexes during sleep. These symptoms were not directly related to seizures or to each sharp-slow wave complex revealed by examination during the video electroencephalographic (EEG) recording. The interictal single photon emission compute tomography showed a localized high perfusion area in the left posterior frontal region. The introduction of clonazepam completely controlled the clinical symptoms as well as the EEG abnormality within 2 weeks. After 4 months of remission, a similar episode recurred which was associated with aggravation of EEG. The clinical and EEG characteristics of this patient were identical to those of acquired epileptiform opercular syndrome (AEOS), a newly proposed epileptic syndrome, in which a transient operculum syndrome develops in association with continuous spike-and-wave activity during slow sleep (CSWS). Computer-assisted EEG analysis demonstrated that the epileptic EEG focus was located in the left sylvian fissure, and produced secondary bilateral synchronous sharp-slow complexes. The present study further supports the hypothesis that the electrical interference by CSWS creates bilateral opercular dysfunction through the mechanism of secondary bilateral synchrony, thus producing AEOS.
Child, Preschool↗
Long-term effect of flunarizine on patients with alternating hemiplegia of childhood in Japan.
To determine the effect of flunarizine therapy on patients with alternating hemiplegia of childhood (AHC), we sent a questionnaire by mail to council members of the Japanese Society of Child Neurology. We collected 28 AHC patients, and studied their clinical courses and the effects of drug therapy. All of the patients had received flunarizine. In 18 of the 28 patients, flunarizine reduced the severity, duration, or frequency of the hemiplegic attacks. No other drug was more effective than flunarizine. Some flunarizine non-effective patients were severely deteriorated, for example, they had dementia or were ventilator-assisted. Flunarizine had not only a short-term effect, i.e. it reduced the hemiplegic attacks, but also a long-term effect on the motor and intellectual development in some patients with AHC. Flunarizine is still an essential drug for treating AHC.
Adolescent↗
Severe myoclonic epilepsy in infants--a review based on the Tokyo Women's Medical University series of 84 cases.
Severe myoclonic epilepsy in infants (SME) is one of the most malignant epileptic syndromes recognized in the latest classification of epileptic syndromes. The clinical details and electroencephalographic (EEG) characteristics have been elucidated by Dravet et al. The diagnosis of SME depends largely on the combination of clinical and EEG manifestations at different ages, of which the presence of myoclonic seizures appears to be the most important. However, because of the inclusion of different types of myoclonic attack and the lack of strict criteria for diagnosing SME, there has been some confusion as to whether patients without myoclonic seizures or myoclonus should be classified as SME, despite other identical clinical symptoms (SME borderlands (SMEB) group). Among the various clinical manifestations characterizing SME, special attention has been paid to seizures easily precipitated by fever and hot baths in Japan. We have demonstrated that the onset of myoclonic attack in these patients is very sensitive to the elevation of body temperature itself rather than its etiology. Using simultaneous EEG and rectal temperature monitoring during hot water immersion, we showed that epileptic discharges increased in frequency, and eventually developed into seizures at temperatures over 38 degrees C. We believe that the unique fever sensitivity observed in SME is similar to, but more intense than that of febrile convulsions. We have also identified a group of cases who have had innumerous myoclonic and atypical absence seizures daily which were sensitive to the constant bright light illumination. In these cases, spike discharges increased or decreased depending on the intensity of constant light illumination. Although these cases form the most resistant SME group, they lost the constant light sensitivity with increasing age, leaving only relatively common types of fever-sensitive grand mal seizures (FSGM) at the age of around 5 years. In the long run, only convulsive seizures continue, while myoclonic or absence seizures and photosensitivity disappear with advancing age, thus it is conceivable that SMEB constitutes a basic epileptic condition underlying SME. There is a clinical continuum that extends from the mildest end of SMEB to the severest end of SME with constant light sensitivity, with intermediates of frequent or infrequent myoclonic and absence seizures in-between. This spectrum concept appropriately explains the clinical variabilities between SME and SMEB during early childhood.
Electroencephalography↗
Myoclonic-astatic epilepsy of early childhood--clinical and EEG analysis of myoclonic-astatic seizures, and discussions on the nosology of the syndrome.
PURPOSE: The aim of this study is to elucidate the clinical and neurophysiological characteristics of the myoclonic, myoclonic-astatic, or astatic seizures in patients with myoclonic-astatic epilepsy (MAE) of early childhood, and to discuss on the nosology of this unique epileptic syndrome. SUBJECTS: The subjects included 30 patients, who fulfilled the following modified International League Against Epilepsy (ILAE) criteria for MAE, and whose main seizures were captured by video-electroencephalographs (EEG) or polygraphs. The modified ILAE criteria includes: (1) normal development before onset of epilepsy and absence of organic cerebral abnormalities; (2) onset of myoclonic, myoclonic-astatic or astatic seizures between 7 months and 6 years of age; (3) presence of generalized spike- or polyspike-wave EEG discharges at 2-3 Hz, without focal spike discharges; and (4) exclusion of severe and benign myoclonic epilepsy (SME, BME) in infants and cryptogenic Lennox-Gastaut syndrome based on the ILAE definitions. RESULTS: The seizures were investigated precisely by video-EEG (n=5), polygraph (n=2), and video-polygraph (n=23), which identified myoclonic seizures in 16 cases (myoclonic group), atonic seizures, with or without preceding minor myoclonus, in 11 cases (atonic group), and myoclonic-atonic seizures in three cases. All patients had a history of drop attacks, apart from ten patients with myoclonic seizures. Myoclonic seizures, involving mainly the axial muscles were classified into those with mild intensity not sufficient to cause the patients to fall (n=10) and those that are stronger and sufficient to cause astatic falling due to flexion of the waist or extension of the trunk (n=6). Patients in the atonic group fell straight downward, landed on their buttocks, and recovered immediately. Analysis of the ictal EEGs showed that all attacks corresponded to the generalized spike or polyspikes-and-wave complexes. In the atonic form, the spike-and-wave morphology was characterized by a positive-negative-deep-positive wave followed by a large negative slow wave. In two patients, the intensity of the atonia appeared to correspond to the depth of the positive component of the spike-and-wave complexes. We did not detect any significant differences in the clinical and EEG features and prognosis, between the atonic and myoclonic groups. CONCLUSIONS: Although the determination of exact seizure type is a prerequisite for diagnosing an epileptic syndrome, the strict differentiation of seizure type into either a myoclonic or atonic form, does not appear to have a significant impact on the outcome or in delineating this unique epileptic syndrome. At present, we consider it better to follow the current International Classification of Epileptic Syndromes and Epilepsies until a more appropriate system than the clinico-electrical approach for classifying patients with MAE is available.
Child, Preschool↗
Study on early-onset benign occipital seizure susceptibility syndrome.
We prospectively studied the early-onset benign occipital seizure susceptibility syndrome to confirm the benign prognosis. The patients were 37 children followed for more than 2 years after meeting the following criteria on the first examination: (1) normal development before the onset of epilepsy, (2) onset between 1 and 8 years of age, (3) normal brain MRI and cranial CT findings, (4) partial seizures manifested both initial ictal vomiting and tonic eye-deviations, and (5) normal background activity with or without epileptic EEG foci regardless of location. The incidence and clinical characteristics of seizures, response to treatment, and EEG findings were analyzed. The total number of seizures ranged from one (n = 6) to 27 times, with a median of five times. Recurrent prolonged attacks resistant to antiepileptic drugs were recognized in 15 children, who had earlier onset of epilepsy and more frequent complications than the remaining 22 children. Interictal EEG revealed occipital foci in 26 children, 17 of whom later revealed a shift in predominant foci. At the final examinations, 28 patients had been seizure-free for at least 2 years. The clinical picture of this syndrome ranges from those with a few seizures to those with recurrent prolonged seizures initially resistant to antiepileptic drugs despite ultimate remission by 12 years of age.
Age Factors↗
A case of MERRF associated with chronic pancreatitis.
We report the first case to our knowledge of chronic pancreatitis associated with mitochondrial encephalopathy with the A8344G mitochondrial DNA (mtDNA) mutation. This 10-year-old-girl had suffered from recurrent abdominal pain with elevated serum amylase and lipase since the age of 6, and easy fatigability, tremor and astatic seizures since the age of 8. A biopsy of quadriceps muscle revealed ragged-red-fibers and cytochrome c oxidase deficiency. Analysis of mtDNA in peripheral blood identified an A8344G mutation in the mitochondrial tRNA(Lys) gene. Taken together with physical signs of myoclonic seizures and cerebellar dysfunction, we diagnosed her as myoclonic epilepsy with ragged-red fibers associated with chronic pancreatitis. Although no association between mitochondrial disease and pancreatitis has yet been established, this case suggests it is necessary to consider the participation of mitochondrial abnormality in the pathogenesis of recurrent pancreatitis.
Brain↗