Biomedical subjects
Publications and source records attributed to H Iwasa.
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BACKGROUND AND METHODS: Many missense mutations in the voltage-gated sodium channel subunit gene SCN1A were identified in patients with generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI), although GEFS+ is distinct from SMEI in terms of clinical symptoms, severity, prognosis, and responses to antiepileptic drugs. The authors analyzed the localization of missense mutations in SCN1A identified in patients with GEFS+ and SMEI to clarify the phenotype-genotype relationships. RESULTS: Mutations in SMEI occurred more frequently in the "pore" regions of SCN1A than did those in GEFS+. These SMEI mutations in the "pore" regions were more strongly associated than mutations in other regions with the presence of ataxia and tendency to early onset of disease. The possibility of participation of ion selectivity dysfunction of the channel in the pathogenesis of SMEI was suggested by a mutation in the pore region (R946C) identified in a SMEI patient. CONCLUSIONS: There was a significant phenotype-genotype relationship in generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy of infancy with SCN1A missense mutations. More severe sodium channel dysfunctions including abnormal ion selectivity that are caused by mutations in the pore regions may be involved in the pathogenesis of SMEI.
Thermoluminescence glow peaks in the temperature range 100 to 400 K are investigated for BaFX (X = Cl, Br) crystals after X irradiation at 100 K. A prominent glow peak of BaFCl around 210 K is found to be composed of a few recombination roots, that is, the peak corresponds to the recombination of hole trapped centres such as an O- centre and a dissociated Cl2- centre with the F (F-) centre and the O2--F(Cl-) pair defect. Another small glow peak around 270 K is likely to occur from thermal dissociation of the O2- -F(Cl-) pair defect. The main glow peak of BaFBr:O2- at 170 K may be attributed to a recombination of an O- centre with the F(Br-) centre.
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We provide here 29 genetic variations, including 28 novel ones, in five genes that are potentially involved in the excitement of cardiomyocytes: we found 4 in KCNA10, 2 in KCNK1, 8 in KCNK6, 11 in SLC18A1 (VMAT1), and 4 in SLC6A2 (norepinephrine transporter). We also examined their allelic frequencies in a Japanese population of long QT syndrome-affected and nonaffected individuals. These data would be useful for genetic association studies designed to investigate acquired arrhythmias.
We report here 20 single-nucleotide polymorphisms (SNPs), including 15 novel ones, in six genes that are considered to be candidates for long QT syndrome (LQTS): 2 SNPs in KCNB1, 3 in KCND3, 3 in KCNJ11, 7 in ABCC9, 3 in ADRB1, and 2 in SLC18A2. We also examined their allelic frequencies in a Japanese sample population of LQTS-affected and nonaffected individuals. These data will be useful for genetic association studies designed to investigate acquired arrhythmias.
Almost all alveolar macrophages in the mouse lung were strongly immunoreactive for epidermal-type fatty acid binding protein. At the electron microscope level, the immunoreactive material was localized diffusely in the cytoplasm but not within the nucleus. A certain number of alveolar type II epithelial cells were also immunoreactive for the protein with variable immunointensity, while a substantial number of the type II cells were immunonegative. No immunoreactive interstitial fibroblasts were encountered. Based on the present findings, possible roles of epidermal-type fatty acid binding protein in the host-defence mechanism played by alveolar macrophages are suggested.
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The expression level of type II adenylyl cyclase mRNA (ACII) was analyzed by northern blotting in amygdaloid kindled rats. Remarkable increases in ACII mRNA were observed in the bilateral cerebral cortex and hippocampus at 24 h after the last generalized seizure. The elevated expression level in the hippocampus persisted for 4 weeks on the stimulated side. There were no changes in expression level in single-stimulated and partially-kindled states. These results suggest that the involvement of ACII might have an effect on the mechanisms of seizure generalization and the maintenance of persistent epileptogenesis rather than on the acquisition process.
We examined photoparoxysmal responses (PPRs) elicited by half-field visual stimulation with deep-red flicker light to determine the neurophysiological features of photosensitive epilepsy (PSE). EEG revealed two types of PPRs. One had the focal spike in the occipital region and the other in the temporo-occipital region at the contralateral hemisphere. The equivalent current dipoles of these types were located at the occipital cortex and the inferior temporal (IT) cortex, respectively. These cortices comprise one of the main pathways in the visual system, and they play important roles in color discrimination. Thus, we propose that the visual system, especially the occipital cortex and the IT cortex, might be involved in the generator mechanism of PSE.
We describe four adolescents with the nutcracker syndrome. In three patients, the nutcracker syndrome was detected through mass urinary screening; the other patient was diagnosed after a sudden onset of dark urine. All patients underwent magnetic resonance angiography (MRA) for diagnosis of the nutcracker syndrome, which revealed dilatation of the left renal vein ranging between 7.4 and 13 mm at the hilar portion. A renal biopsy, performed in three patients, showed no remarkable abnormalities in the glomerulus or tubulointerstitial tissue. The patients complained of physical discomfort, including headache, abdominal pain, fainting, and tachycardia mimicking clinical symptoms of an orthostatic disturbance. However, no chronic systemic diseases were detected in any of the patients after repeated laboratory examinations. An orthostatic disturbance preceded diagnosis in three patients. This report indicates that the nutcracker syndrome may cause serious physical ailments that clinically mimic an orthostatic disturbance. It may be important to identify the nutcracker syndrome among children who manifest non-specific physical complaints. MRA could be a safe and reliable method for diagnosing the nutcracker syndrome.
We report here 20 single nucleotide polymorphisms (SNPs), including 10 novel ones, and their allelic frequencies detected in four genes that are known to be responsible for familial long QT syndrome in the Japanese population; 7 polymorphisms are in the KCNQ1 gene, 6 in the KCNH2 gene, 5 in the SCN5A gene, and 2 in the KCNE1 gene. These data will be of use for genetic association studies of acquired cardiac arrhythmias.
We examined the inhibitory effect of sodium D-glucaro-delta-lactam (sodium 5-amino-5-deoxy-D-glucosaccharic acid-delta-lactam: ND2001) upon liver metastases of the LMFS tumor. A permanent cell line, LMFS, was established from a spontaneously occurring murine retroperitoneal tumor of BALB/c mouse origin, and after a subcutaneous injection, the LMFS cells proliferated at the inoculation site (100% take) with liver metastases. ND2001 had little effect on the cell growth, cell cycle and phagokinesis of the LMFS cells in vitro. However, when the invasive activity was measured by the Boydem chamber method, the number of LMFS cells was reduced, with inhibition rates of 98.0%. After the LMFS cells treated with ND2001 in vitro, the numbers of hepatic metastases of subcutaneous inoculation of treated cells were reduced dose-dependently, and those of intravenous inoculation were not found by microscopical study. When the LMFS tumor-bearing mice were treated with ND2001 (0, 30, 100 mg/kg/d) from day 1, ND2001 (30 mg/kg) inhibited the liver metastases with a rate of 56.4%, and when given from day 15, ND2001 (100 mg/kg) inhibited with a rate of 47.5%. But ND2001 showed neither cytocidal nor anti-tumor activity. Combination therapy of primary tumor resection and ND2001 administration revealed that preoperative use of ND2001 was more effective in preventing liver metastases. These results suggested that ND2001 might have a potential use as an anti-metastatic agent for operative patients without metastasis.
Dipole sources of interictal epileptiform activities recorded by conventional electroencephalogram (EEG) were estimated using the dipole tracing method. Four cases of temporal lobe epilepsy with medial temporal lesions were studied. Two patients with hippocampal sclerosis, one patient with granulation in the hippocampus and one patient with cavernous angioma were involved in the study. Interictal epileptiform activities were classified into two patterns according to the topography of spikes. They were widespread spikes over the parasagittal electrodes (parasagittal spikes) and restricted spikes at the temporal electrodes (temporal spikes). Dipole sources of parasagittal spikes were localized in the medio-basal temporal lobe with vertically orientated vector moment. Dipole sources of temporal spikes were localized in the medio-basal temporal lobe with horizontally orientated vector moment. Locations of dipoles and directions of vector moments were consistent with topography and polarity of spikes. The difference in the two patterns of interictal epileptiform activities was derived from the difference in the direction of the vector moment of dipole sources. There was no difference in the location of dipole sources. Both the dipole sources and the lesions were localized in the same medio-basal temporal lobe. Dipole tracing was very useful in localizing the dipole sources of interictal epileptiform activities and in understanding the neurophysiological background.
In order to evaluate the involvement of the stimulatory G-protein (Gs)-related transduction system in the basic mechanisms of epilepsy, we examine the expression levels of Gsalpha mRNA and specific GTP-binding ability in the hippocampus of amygdaloid-kindled rats at various seizure stages. Northern blot analysis showed a significant increase in the Gsalpha mRNA expression level in the bilateral hippocampus at 24h after the last generalized seizure. The [3H]-GTP-binding assay with isoproterenol (IPN), a beta-receptor agonist, revealed a remarkable increase of Bmax values in the sham-operated control and partially kindled groups. However, the IPN-induced increase of Bmax values was abolished on both sides of the hippocampus at 24 h after and at 4 weeks after the last generalized seizure in fully kindled rats. These data suggest that alteration in the Gs function and beta-adrenergic receptor-Gs coupling might be implicated in the neurobiological basis of the induction mechanisms of the generalization of seizures and the mechanisms of the maintenance of enduring epileptogenesis. Conversely, the Gs-related transduction system might have a lesser impact on the acquisition process of epileptogenesis.
The involvement of NMDA receptor subunit, NR1, with kindling phenomenon has been reported, but the role of NR1 in epileptogenesis is still unknown. We have examined the expression levels of NR1 mRNA in the cerebral cortices of amygdaloid-kindled rats. Northern blot analysis showed a significant increase in NR1 mRNA expression level in the ipsilateral frontal and temporal cortices at 4 weeks after the last generalized seizure. At the same time, NR1 mRNA decreased in the bilateral piriform cortices. These data suggest that NR1-mediated transmission may have an impact in the neurobiological basis of enduring epileptogenesis.
To investigate the physiological role of visual gamma-band oscillation (GBO), we calculated the event-related dynamics of the EEG power-spectrum for paired visual stimuli (S1 and S2) with or without attention in 12 subjects. The visual stimuli elicited transient increases in the GBO power (around 40 Hz), which were maximal over the parietal area. The peak GBO increase appeared around 300 ms after stimulus onset, but its latency was shorter after S1 and longer after S2 under the 'with attention' than under the 'without attention' condition. This transient increase in the visual GBO is thought to reflect attention and to reset the activity of the visual system in preparation for a new stimulus.
The expressions of mRNAs encoding G protein alpha subunits were analyzed in the cerebral cortex of amygdaloid kindled rats. A remarkable increase in Gsalpha mRNA were observed on the bilateral cerebral cortex at 24 h after the last generalized seizure and persisted 3 weeks on the unstimulated side. Gi2alpha mRNA level was also increased on the stimulated side at 24 h and persisted 3 weeks. These result suggest that dysfunction of Gs and Gi2 might relate to the basic mechanisms of seizure generation and the maintenance of epileptogenesis.