Cytokine-related and sodium channel polymorphism as candidate predisposing factors for childhood encephalopathy FIRES/AERRPS.

Febrile infection-related epilepsy syndrome (FIRES), or acute encephalitis with refractory, repetitive partial seizures (AERRPS), is an epileptic encephalopathy beginning with fever-mediated seizures. The etiology remains unclear. To elucidate the genetic background of FIRES/AERRPS (hereafter FIRES), we recruited 19 Japanese patients, genotyped polymorphisms of the IL1B, IL6, IL10, TNFA, IL1RN, SCN1A and SCN2A genes, and compared their frequency between the patients and controls. For IL1RN, the frequency of a variable number of tandem repeat (VNTR) allele, RN2, was significantly higher in the patients than in controls (p=0.0067), and A allele at rs4251981 in 5' upstream of IL1RN with borderline significance (p=0.015). Haplotype containing RN2 was associated with an increased risk of FIRES (OR 3.88, 95%CI 1.40-10.8, p=0.0057). For SCN1A, no polymorphisms showed a significant association, whereas a missense mutation, R1575C, was found in two patients. For SCN2A, the minor allele frequency of G allele at rs1864885 was higher in patients with borderline significance (p=0.011). We demonstrated the association of IL1RN haplotype containing RN2 with FIRES, and showed a possible association of IL1RN rs4251981 G>A and SCN2A rs1864885 A>G, in Japanese patients. These preliminary findings suggest the involvement of multiple genetic factors in FIRES, which needs to be confirmed by future studies in a larger number of FIRES cases.

Antidepressant-like effect of sildenafil through oxytocin-dependent cyclic AMP response element-binding protein phosphorylation.

Oxytocin (OT) levels in plasma increase during sexual response and are significantly lower in patients with depression. A drug for the treatment of sexual dysfunction, sildenafil, enhances the electrically evoked release of OT from the posterior pituitary. In this study, we showed that sildenafil had an antidepressant-like effect through activation of an OT signaling pathway. Application of sildenafil reduced depression-related behavior in male mice. The antidepressant-like effect was blocked by an OT receptor (OTR) antagonist and was absent in OTR knockout (KO) mice. Sildenafil increased the phosphorylation of cAMP response element-binding protein (CREB) in the hippocampus. The OTR antagonist inhibited sildenafil-induced CREB phosphorylation and sildenafil had no effect on CREB phosphorylation in OTR KO mice. These results suggest sildenafil to have an antidepressant-like effect through the activation of OT signaling and to be a promising drug for the treatment of depression.

[Complications of video-assisted thoracoscopic surgery].

We introduced video-assisted thoracoscopic surgery (VATS) for chest disorders in our institution in March, 1992. At first, many of the subjects' disorders were non-malignant diseases such as spontaneous pneumothorax, but later we started to perform this procedure for lung cancer and mediastinum neoplasm, with improved result over thoracoscopic surgical procedures. Now most of the chest disorders at our institution are treated with VATS. However, many kinds of complications due to manual techniques and instrument troubles surfaced during this period. Therefore, in this article we would like to describe the complications that we have experienced in our institution using VATS and discuss how we have attempted to deal with these complications.

The relationship between paroxysmal kinesigenic choreoathetosis and epilepsy.

PURPOSE: To clarify the relationship between paroxysmal kinesigenic choreoathetosis (PKC) and epilepsy, we investigated the clinical and electroencephalographic (EEG) findings of patients with familial PKC and epilepsy, as well as sporadic cases with both PKC and epilepsy. PATIENTS AND METHODS: Patients consisted of 12 familial cases from seven families and three sporadic cases. The period of follow-up ranged from 17 months to 33 years, 7 months (average: 16 years, 8 months). During the follow-up, a total of 163 EEGs (11 EEGs per subject) were studied, including interictal and ictal EEGs. RESULTS: Transient epileptic discharges were found in ten of the 15 patients (66.7 %) during the clinical course. As for focus, centro-midtemporal and frontal spikes were most often observed. The ictal EEG of an afebrile convulsion in one patient showed a partial seizure with secondary generalization which originated from the frontal area. CONCLUSIONS: It appears that patients who suffer from both PKC and epilepsy have a functional abnormality of the cerebral cortex, particularly in the perirolandic and frontal regions.

Clinical spectrum of epileptic spasms associated with cortical malformation.

The spectrum of clinico-electrical characteristics of epileptic spasms associated with cortical malformation was studied in detail. The subjects were 15 patients suffering from spasms and cortical malformation demonstrated by MRI. The types of cortical malformation causing spasms were various, including hemimegalencephaly, diffuse pachygyria, focal cortical dysplasia, and polymicrogyria. Ohtahara syndrome was diagnosed in 3 patients, and West syndrome in 8. Symptomatic localization-related epilepsy preceded West syndrome in 4 patients, and a transition from Ohtahara syndrome to West syndrome was observed in one. West syndrome was followed by symptomatic generalized epilepsy including Lennox-Gastaut syndrome in 4 patients. Nine patients showed a condition which was labeled "epilepsy with partial seizures and spasms" (EPS) and characterized by the coexistence of partial seizures and spasms, and multifocal epileptic discharges on EEG. Spasms occurred only as EPS in 5 patients. EPS appeared following Ohtahara syndrome or West syndrome in 4 patients, and showed a transition to symptomatic localization-related epilepsy in 4. However, EPS did not evolve into generalized epilepsy, and persisted until the time of last follow-up in 5 patients. Therefore, the clinico-electrical pictures of patients with spasms and cortical malformation were diverse and not always limited within those of typical generalized epilepsy.

A population-based neuroepidemiological survey of West syndrome in Okayama Prefecture, Japan.

It is important for the fields of child neurology and child public health to clarify the prevalence and incidence rates of West syndrome because this syndrome is a major cause of developmental disorders.However, there have been few reports in Japan on the prevalence rate of West syndrome in the general population. We carried out a population-based survey in Okayama Prefecture, in western Japan in 1994. The population under 2 years of age in Okayama Prefecture in 1994 was 37,085. Six cases of West syndrome were identified. The prevalence rate was 0.16 per 1000.

Anodontia with hypohidrotic ectodermal dysplasia in a young female: a case report.

A five-year-old Japanese girl was referred to our clinic for non-eruption of the teeth. Panoramic radiographs revealed absence of all teeth of both primary and permanent dentitions. She showed hypotricosis, hypohidrosis, and anodontia. In this article, the reported cases of anodontia were reviewed and the fabricating procedure of full dentures for a young child was described.

[Clinical applications and the effect of mexiletine on refractory epilepsies].

Twenty-four patients with refractory epilepsy were treated with mexiletine as an additional antiepileptic drug. As the initial responses, seizures were decreased by 50% or more in 7 (46.7%) of 15 patients with symptomatic partial epilepsy (SPE), in none of 7 with symptomatic generalized epilepsy (SGE), and in 1 of 2 with undetermined epilepsy. Seizures increased in 3 patients (20.0%) with SPE, and in 3 (42.9%) with SGE. Concerning seizure types, mexiletine had significant effects on 1 of 2 patients with simple partial seizures, on 7 of 13 with complex partial seizures, on 1 of 5 with secondarily generalized seizures, and on 1 of 8 with tonic seizures. No patients with a myoclonic seizure or atypical absence improved. Exacerbation of the seizures was observed in 2 of 13 patients with complex partial seizures, in 1 of 5 with secondarily generalized seizures, in 3 of 8 with tonic seizures, and in 2 of 3 with myoclonic seizures. Partial seizures were controlled well, whereas generalized seizures sometimes worsened. EEG improved in 3 patients with SPE; decrease of focal spikes in 2 patients and disappearance of secondary generalization in 1. Follow-up for more than 3 months showed seizures to be lessened in 2 patients. Mexiletine is useful for the treatment of refractory epilepsies, especially SPE.

Analysis of ictal EEGs of epilepsy associated with tuberous sclerosis.

PURPOSE: To investigate the significance of cortical pathology of tonic spasms in patients with tuberous sclerosis. METHODS: The subjects were 38 patients with epilepsy associated with tuberous sclerosis. We analyzed ictal EEGs of tonic spasms and partial seizures by means of video-EEG monitoring for a total of 763 tonic spasms in 20 patients and 107 partial seizures in 15 patients. We also investigated the relation between partial seizures and magnetic resonance imaging (MRI) findings of these patients. RESULTS: Ictal EEG patterns of tonic spasms were divided into generalized and focal patterns. Thirteen patients had only generalized patterns, whereas seven had both patterns. In five patients who had focal ictal patterns of tonic spasms and partial seizures, the location of focal patterns corresponded with the location of onset of partial seizures. Focal discharges were seen immediately before, after, and in the middle of tonic spasms in series in 13 patients. The location of focal discharges also corresponded with the location of the onset of partial seizures in 10 of the 13 patients. Regarding partial seizures, four patients had multiple active epileptogenic foci during the same period, and two others had shifting epileptogenic foci with increasing age. CONCLUSIONS: These findings indicate that cortical pathology plays an important role in the occurrence not only of partial seizures but also of tonic spasms in patients with tuberous sclerosis.

Long-term follow-up of childhood epilepsy associated with tuberous sclerosis.

PURPOSE: To study the clinical and electroencephalographic (EEG) characteristics of patients whose epilepsy is associated with tuberous sclerosis, with special reference to their clinical course. METHODS: We investigated the electroclinical and radiologic features of 38 patients with epilepsy associated with tuberous sclerosis. RESULTS: Eleven patients showed only generalized epilepsy, and 10 showed only localization-related epilepsy throughout their clinical course. Among the other 17 cases, the nature of the epilepsy changed between generalized and localization-related epilepsies during the clinical course. A shift from generalized to localization-related epilepsies was more common than the reverse. Seventeen had West syndrome (WS), three had Lennox-Gastaut syndrome (LGS), and eight had epilepsies that evolved from WS to LGS. Tonic spasms, mostly in series, were seen in all 28 patients with generalized epilepsy. Eleven of the 28 patients had partial seizures and tonic spasms in the same period. Six of them showed "simultaneous seizures," consisting of tonic spasms in series and a partial seizure. Partial seizures were the main seizure type in 27 patients with localization-related epilepsy, but three of them also showed tonic spasms that included "simultaneous seizures." Ictal EEGs revealed multiple active foci in the same period that could shift during the clinical course. Neither the location nor number of tubers was related to the clinical course. As for seizure outcome, 12 (32%) of 38 patients were free from seizures at follow-up. CONCLUSIONS: In epilepsies associated with tuberous sclerosis, there may be an interrelation between generalized and localization-related epilepsies, as well as one between generalized and partial seizures.

Electroclinical study of localization-related epilepsies in early infancy.

To clarify the characteristics of localization-related epilepsies in early infancy, we performed an electroclinical study of 28 epileptic patients whose first seizures occurred before 6 months of age. The patients were retrospectively divided into two groups: the seizure-controlled group (8 patients) and the refractory group (20 patients). The seizure-controlled group included the patients whose seizures were suppressed within 1 year after onset; the refractory group included all other patients. The characteristics of the refractory group were as follows: (1) most patients had serious underlying pathologies; (2) the seizure type in most cases was simple partial seizure or complex partial seizure without secondary generalization; (3) the interictal EEG showed focal abnormalities and severe dysrhythmia on the basic pattern associated with multifocal spikes in most cases; and (4) in some patients, West syndrome developed after localization-related epilepsies and generalized seizures appeared later in some cases.

Sensitive chemiluminescence enzyme immunoassay for vascular endothelial growth factor/vascular permeability factor in human serum.

A sandwich chemiluminescence enzyme immunoassay for measuring the level of VEGF/VPF in serum was constructed. The detectability of the assay is very low (1.0 pg/ml) and the measurable range of the assay was very wide (1-1000 pg/ml). The assay showed that the average level of VEGF/VPF in human sera from healthy blood donors was approximately 19 pg/ml.

[A case of localized fibrous tumor of the pleura with bloody pleural effusion].

A 25-year-old female came to our hospital with the chief complaint of right dorsal pain. On her initial chest X-ray, the tumor (5 x 3 cm) was recognized in the right lower lung field. The tumor grew rapidly during the three month period between the initial X-ray taken on her first visit and her getting admitted in the hospital. A preoperative diagnosis was done by percutaneous aspiration biopsy. Initial diagnosis of spindle cell tumor was made. Partial resection of right lower lobe with chest wall resection was carried out. There were about 500 ml of bloody pleural effusion. Macroscopically, the tumor was encapsulated, measuring 8.0 x 6.0 x 5.0 cm. The cross section was of a yellowish brown solid tumor. The histological diagnosis was of a low grade malignant fibrous mesothelioma. Only 14 cases of localized mesothelioma with pleural effusion including our case have been reported in Japan. She is still alive nine months after surgery. This patient should be carefully followed for the recurrence of the disease.

The shortest isoform of human vascular endothelial growth factor/vascular permeability factor (VEGF/VPF121) produced by Saccharomyces cerevisiae promotes both angiogenesis and vascular permeability.

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is a multifunctional cytokine that is expressed as four isoforms having 206, 189, 165, and 121 amino acids in humans. We constructed a system that produces the shortest isoform of human VEGF/VPF in Saccharomyces cerevisiae (yVEGF/VPF121). Active yVEGF/VPF121 was secreted from the yeast cells as a glycosylated dimeric protein. Various biological activities of the purified yVEGF/VPF121 were examined. It bound to cell surface receptor(s) and stimulated the growth of human umbilical vein endothelial cells in culture at a dose similar to that of native VEGF/VPF. Purified yVEGF/VPF121 also induced angiogenesis in mice, and promoted the extravasation of plasma proteins from the blood vessels. These observations demonstrated that the shortest isoform of VEGF/VPF with an amino acid sequence of 121 residues contains enough information necessary to trigger both angiogenesis and the induction of vascular permeability upon binding to its cognate receptor(s).

Vascular endothelial growth factor/vascular permeability factor is detectable in the sera of tumor-bearing mice and cancer patients.

We developed an enzyme-linked immunosorbent assay (ELISA) for vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). The assay revealed that VEGF/VPF levels in the sera of mice were significantly increased from undetectable level by s.c. transplantation with a solid tumor. We also measured VEGF/VPF levels in serum specimens obtained from cancer patients with several types of cancers. VEGF/VPF levels in the sera from cancer patients were significantly higher than those in the sera from the individuals with no sign of cancer.

Hyperthermic potentiation of bleomycin cytotoxicity in the presence of Bacillus thuringiensis subsp. israelenis delta-endotoxin.

We previously reported that a 25-kDa Bacillus thuringiensis subsp. israelensis (BTI) delta-endotoxin potentiated the antitumor activity of bleomycin (BLM) in both in vitro and in vivo systems. We report here a characteristic hyperthermic synergy toward the cytocidal activity of BLM in the presence of BTI endotoxin in cultured L1210 cells. Cytocidal gain, i.e., the ratio of the IC50 of BLM in the absence versus the presence of BTI delta-endotoxin, reached ca. 20 at 40 degrees C, suggesting that a more effective heat-BLM combination treatment may be achieved in the presence of BTI delta-endotoxin.

Potentiation of antitumor activity of bleomycin towards solid tumors in mice by Bacillus thuringiensis subsp. israelensis toxin.

We previously reported that a 25-kDa Bacillus thuringiensis subsp. israelensis (BTI) toxin is cytotoxic to cultured tumor cells and can also potentiate the cytotoxic effect of some antitumor agents in vitro. In this study, we examined the in vivo effect of BTI toxin on the potentiation of antitumor activity of bleomycin (BLM) against solid tumor-bearing mice. Three tumor cell lines, Ehrlich carcinoma, B16 melanoma and Meth A fibrosarcoma, were employed. It was shown that dose of BTI toxin, ineffective alone, potentiated the antitumor activity of BLM when used in combination.

[A histological observation of the primary teeth with enamel hypoplasia resulting from perinatal disturbance].

Two primary teeth with enamel hypoplasia from two cerebralpalsied children were subjected to histological examination. One primary tooth was B and the other was C. The location of enamel hypoplasia in these teeth was considered to coincide with the neonatal line reaching the enamel surface. The purpose of this study was to examine the location of the enamel hypoplasia in these teeth in relation to the neonatal line, and to detail the histological structure of the teeth. They were examined morphologically as well as histologically, by using a stereoscopic microscope, SEM, a light microscope and a microradiogram. The results obtained were as follows: 1. The size of the tooth crown of these teeth was smaller than the normal standard, but the form of tooth crown was normal. 2. Based on streomicroscopic observation, enamel hypoplasia was found on the labial and lingual surfaces in B, and on labial surface only in C. In B, the enamel hypoplasia on labial surface was extended widely to incisal 2/3 of the crown, while that on the lingual surface was minimum. In C, there were two spots of enamel hypoplasia located on the mesial and distal incisal edges respectively. 3. Based on SEM observation, the hypoplastic enamel was formed right after their birth. 5. Based on microradiographic observation, the neonatal lines were radiolucent, and the adjacent areas of the neonatal line did not show any poor calcification. 6. From these histological observations, it was found that the perinatal disturbance directly affected the tooth enamel formation and these enamel hypoplasias were positively caused by the cerebral palsy of these children.