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Previous studies have suggested submarine landslides as sources of the tsunami that damaged coastal areas of Palu Bay after the 2018 Sulawesi earthquake. Indeed, tsunami run-up heights as high as 10 m determined by field surveys cannot be explained by the earthquake source alone although the earthquake is definitely the primary cause of the tsunami. The quantitatively re-examined results using the earthquake fault models reported so far showed that none of them could fully explain the observed tsunami data: tsunami waveforms inferred from video footage and the field survey run-up tsunami height distribution. Here, we present probable tsunami source models including submarine landslides that are consistent with the observed tsunami data. We simulated tsunamis generated by submarine landslides using a simplified depth-averaged two-dimensional model. The estimated submarine landslide model consisted of two sources in the northern and southern parts of the bay, and it explained the observed tsunami data well. Their volumes were 0.02 and 0.07 km3. The radius of the major axis and the maximum thickness of the initial paraboloid masses and the maximum horizontal velocity of the masses were 0.8 km, 40 m and 21 m/s in the northern bay, and 2.0 km, 15 m and 19 m/s in the southern bay, respectively. The landslide source in the northern bay needed to start to move about 70 s after the earthquake to match the calculated and observed arrival times.

AIM: Most patients with dementia frequently encounter various problems in their daily lives. Those troubles embarrass both the patients and their families, and cause problems for society. However, there have been few scientific reports on the difficulties in the daily life of patients with dementia. Therefore, we tried to clarify the frequency and characteristics of troubles experienced by patients with dementia. METHODS: Seven medical centers treating dementia patients in Okayama Prefecture, Japan, participated in this survey. A total of 737 patients were placed in one of the three groups: a dementia group (n = 478), a mild cognitive impairment group (n = 199) and a control group (n = 60). The frequency of 13 difficulties was scored for each patient. RESULTS: Among normal participants, no person caused these problems once a year or more frequently. "Massive, recurrent buying" and "acts that risk causing a fire" were reported once a year or more for >10% of mild cognitive impairment patients. "Troubles with wealth management" and "troubles with money management" were the most frequent problems of dementia patients. CONCLUSIONS: Several problems are already sometimes encountered in patients with mild cognitive impairment. It would be useful to know which social difficulties are often seen in dementia patients in order to protect the safety of the patients. It is always difficult to balance respecting the autonomy of dementia patients and ensuring their safely.

AIM: Most patients with dementia frequently encounter various problems in their daily lives. Those troubles embarrass both the patients and their families, and cause problems for society. However, there have been few scientific reports on the difficulties in the daily life of patients with dementia. Therefore, we tried to clarify the frequency and characteristics of troubles experienced by patients with dementia. METHODS: Seven medical centers treating dementia patients in Okayama Prefecture, Japan, participated in this survey. A total of 737 patients were placed in one of the three groups: a dementia group (n = 478), a mild cognitive impairment group (n = 199) and a control group (n = 60). The frequency of 13 difficulties was scored for each patient. RESULTS: Among normal participants, no person caused these problems once a year or more frequently. "Massive, recurrent buying" and "acts that risk causing a fire" were reported once a year or more for >10% of mild cognitive impairment patients. "Troubles with wealth management" and "troubles with money management" were the most frequent problems of dementia patients. CONCLUSIONS: Several problems are already sometimes encountered in patients with mild cognitive impairment. It would be useful to know which social difficulties are often seen in dementia patients in order to protect the safety of the patients. It is always difficult to balance respecting the autonomy of dementia patients and ensuring their safely.

Background It is widely supposed that there has been no evidence of increased survival in patients with advanced dementia receiving enteral tube feeding. However, more than a few studies have reported no harmful outcome from tube feeding in dementia patients compared to in patients without dementia. Methods This was a retrospective study. Nine psychiatric hospitals in Okayama Prefecture participated in this survey. All inpatients fulfilling the entry criteria were evaluated. All subjects suffered from difficulty with oral intake. Attending physicians thought that the patients could not live without long-term artificial nutrition. The physicians decided whether to make use of long-term artificial nutrition between January 2012 and December 2014. Results We evaluated 185 patients. Their mean age was 76.6 ± 11.4 years. Of all subjects, patients with probable Alzheimer's disease (n = 78) formed the biggest group, schizophrenia patients (n = 44) the second, and those with vascular dementia (n = 30) the third. The median survival times were 711 days for patients with tube feeding and 61 days for patients without tube feeding. In a comparison different types of tube feeding, median survival times were 611 days for patients with a nasogastric tube and more than 1000 days for those with a percutaneous endoscopic gastrostomy tube. Conclusion Patients with tube feeding survived longer than those without tube feeding, even among dementia patients. This study suggests that enteral nutrition for patients with dementia prolongs survival. Additionally, percutaneous endoscopic gastrostomy tube feeding may be safer than nasogastric tube feeding among patients in psychiatric hospitals.

Around the Ogasawara Islands, only a few seismic stations in the area can be used to determine the hypocenters of regional earthquakes; thus, hypocenter location precision tends to be low. To more precisely determine hypocenter locations, we deployed a temporary seismic observation network of pop-up ocean bottom seismometers around the Ogasawara Islands from July to October 2015. We identified a double seismic zone in the 70–200 km depth range associated with the subducting Pacific slab. The slab-normal distance between the two planes of the double seismic zone is about 30–35 km, similar to such distances observed along the Japan and Mariana trenches. Furthermore, we found unusual seismicity in the mantle wedge at 20–50 km depth beneath the Ogasawara trough that might be related to structure formed at the onset of the oceanic slab subduction. The hypocenters determined from the ocean bottom seismometer observation were horizontally separated by a few tens of kilometers from hypocenters published by the Seismological Bulletin of Japan. USGS locations (Preliminary Determination of Epicenters) seem to be offset westward about 30 km compared with the locations determined in this study.

On 17 July 1998, a tsunami caused serious damage on the northern coast of Papua New Guinea about 20 min after the mainshock of an Mw 7.0 earthquake. The tsunami has been attributed to a submarine landslide that occurred about 13 min after the mainshock because its arrival at the coast was too late and its height too great to be the direct result of the fault slip of the earthquake. Bathymetric data recorded after the tsunami revealed an amphitheater-like structure that was consistent with a recent submarine landslide. Most current tsunami warning systems are based on analysis of the early arrivals of seismic waves generated by an earthquake. In this study we investigated whether evidence of the landslide could be identified in the coda waves recorded after the mainshock. Based on previous studies of the tsunami source, we constructed synthetic seismograms to represent the submarine landslide and compared them to the observed coda waves of the preceding earthquake, with particular attention to the period around 13 min after the mainshock. We found phases possibly corresponding to the landslide event. However, they were easily covered with coda waves from the mainshock. We concluded that the 1998 landslide was too small to be evident in the coda waves following the magnitude 7 earthquake.

Aim Artificial nutrition, including tube feeding, continues to be given to dementia patients in numerous geriatric facilities in Japan. However, the clinical characteristics of patients receiving artificial nutrition have not been fully investigated. Therefore, we tried to evaluate the clinical features of those patients in this study. Methods Various clinical characteristics of all inpatients at 18 of 20 psychiatric hospitals in Okayama Prefecture, Japan, with a percutaneous endoscopic gastrostomy tube, nasogastric tube, or total parenteral nutrition were evaluated. Results Two hundred twenty-one patients (5.4% of all inpatients) had been receiving artificial nutrition for more than 1 month, and 187 (130 women, 57 men; 84.6% of 221 patients) were fully investigated. The mean age was 78.3 years old, and the mean duration of artificial nutrition was 29.8 months. Eighty-four patients (44.7% of 187 patients) were receiving artificial nutrition for more than 2 years. Patients with Alzheimer's disease (n = 78) formed the biggest group, schizophrenia (n = 37) the second, and vascular dementia (n = 26) the third. Conclusion About one-fifth of the subjects receiving artificial nutrition were in a vegetative state. More than a few patients with mental disorders, including schizophrenia, also received long-term artificial nutrition. We should pay more attention to chronic dysphasia syndrome in mental disorders.

To enhance the tsunami warning operation system in the Philippines caused by earthquakes in and around the country, staff members of the Japan Meteorological Agency (JMA) joined the SATREPS program in 2012 to help building a tsunami simulation database in the Philippine Institute of Volcanology and Seismology (PHIVOLCS), which storesmultiple results of tsunami simulations such as estimated tsunami arrival times and heights at coasts for multiple hypothetical earthquakes of various hypocenter locations and magnitudes. The procedure to construct a database consists of several steps starting from setting assumed fault parameters and others, proceeding to tsunami simulations and data creation to be stored in the database, and as the last step, creating a searching system which picks results from the database according to the location and magnitude of an earthquake. As of July 2014, the PHIVOLCS has stored the results of tsunami simulations conducted for more than 30,000 assumed faults for local tsunamis. The searching system is also prepared which enables to get a quick grasp of expected tsunami features quantitatively. With this database and the searching system, the PHIVOLCS is in near future to issue initial tsunami warnings based on the information of estimated tsunami arrival times and heights immediately after the hypocenter location and magnitude of an earthquake are determined. When the necessary coordination with related organizations as well as the public education for the system and warning messages are ready, the PHIVOLCS will start the enhanced local tsunami warning operation.

Background/Aims: Most patients with dementia suffer from dysphagia in the terminal stage of the disease. In Japan, most elderly patients with dysphagia receive either tube feeding or total parenteral nutrition. Methods: In this study, we investigated the factors determining longer survival with artificial nutrition. Various clinical characteristics of 168 inpatients receiving artificial nutrition without oral intake in psychiatric hospitals in Okayama Prefecture, Japan, were evaluated. Results: Multiple logistic regression analysis showed that the duration of artificial nutrition was associated with a percutaneous endoscopic gastrostomy (PEG) tube, diagnosis of mental disorder, low MMSE score, and absence of decubitus. Conclusion: Patients with mental disorders survived longer than those with dementia diseases on artificial nutrition. A PEG tube and good nutrition seem to be important for long-term survival.

It is widely supposed that there has been no evidence of increased survival in patients with advanced dementia receiving enteral tube feeding. However, more than a few studies have reported no harmful outcome from tube feeding in dementia patients compared to in patients without dementia.This was a retrospective study. Nine psychiatric hospitals in Okayama Prefecture participated in this survey. All inpatients fulfilling the entry criteria were evaluated. All subjects suffered from difficulty with oral intake. Attending physicians thought that the patients could not live without long-term artificial nutrition. The physicians decided whether to make use of long-term artificial nutrition between January 2012 and December 2014.We evaluated 185 patients. Their mean age was 76.6 ± 11.4 years. Of all subjects, patients with probable Alzheimer's disease (n = 78) formed the biggest group, schizophrenia patients (n = 44) the second, and those with vascular dementia (n = 30) the third. The median survival times were 711 days for patients with tube feeding and 61 days for patients without tube feeding. In a comparison different types of tube feeding, median survival times were 611 days for patients with a nasogastric tube and more than 1000 days for those with a percutaneous endoscopic gastrostomy tube.Patients with tube feeding survived longer than those without tube feeding, even among dementia patients. This study suggests that enteral nutrition for patients with dementia prolongs survival. Additionally, percutaneous endoscopic gastrostomy tube feeding may be safer than nasogastric tube feeding among patients in psychiatric hospitals.

Methamphetamine psychosis is considered as one of the pharmacological models of schizophrenia, and a hyperdopaminergic one. However, many lines of experimental evidence indicate that glutamatergic signaling is also involved in development of methamphetamine psychosis. Several genes related to glutamate function, e.g. the DTNBP1 , G72 , and GRM3 genes, were shown to be associated with schizophrenia susceptibility. Recently, we found significant association of the DTNBP1 gene with methamphetamine psychosis. This finding prompted us to examine the G72 gene encoding the d-amino acid oxidase activator (DAOA), which metabolizes d-serine, an NMDA co-agonist, in methamphetamine psychosis. Six SNPs of the G72 gene, which previously showed significant association with schizophrenia, were analyzed in 209 patients with methamphetamine psychosis and 291 age- and sex-matched normal controls. One SNP of M22 (rs778293) showed a significant association with methamphetamine psychosis (genotype: p = 0.00016, allele: p = 0.0015). Two haplotypes G-A of M12 (rs3916965)-M15 (rs2391191) ( p = 0.00024) and T-T of M23 (rs947267)-M24 (rs1421292) ( p = 0.00085) also showed associations with methamphetamine psychosis. The present findings suggest that the G72 gene may contribute to a predisposition to not only schizophrenia but also to methamphetamine psychosis.

Two functionally different MAP kinase phosphatases (MKPs) were investigated to clarify their roles in behavioral sensitization to methamphetamine (METH). MKP-1 mRNA levels increased substantially by about 60–300% in a range of brain regions, including several cortices, the striatum and thalamus 0.5–1 h after acute METH administration. After chronic METH administration its increase was less pronounced, but a more than 50% increase was still seen in the frontal cortex. MKP-1 protein levels also increased 3 h after acute or chronic METH administration. MKP-3 mRNA levels increased by about 30–50% in several cortices, the striatum and hippocampus 1 h after acute METH administration, but only in the hippocampus CA1 after chronic METH administration. Pre-treatment with the D1 dopamine receptor antagonist, SCH23390, attenuated the METH-induced increase of MKP-1 and MKP-3 mRNA in every brain region, while pre-treatment with the NMDA receptor antagonist, MK-801, attenuated it in some regions. These findings suggest that in METH-induced sensitization, MKP-1 and MKP-3 play important roles in the neural plastic modification in widespread brain regions in the earlier induction process, but in the later maintenance process, they do so only in restricted brain regions such as MKP-1 in the frontal cortices and MKP-3 in the hippocampus.

Artificial nutrition, including tube feeding, continues to be given to dementia patients in numerous geriatric facilities in Japan. However, the clinical characteristics of patients receiving artificial nutrition have not been fully investigated. Therefore, we tried to evaluate the clinical features of those patients in this study.Various clinical characteristics of all inpatients at 18 of 20 psychiatric hospitals in Okayama Prefecture, Japan, with a percutaneous endoscopic gastrostomy tube, nasogastric tube, or total parenteral nutrition were evaluated.Two hundred twenty-one patients (5.4% of all inpatients) had been receiving artificial nutrition for more than 1 month, and 187 (130 women, 57 men; 84.6% of 221 patients) were fully investigated. The mean age was 78.3 years old, and the mean duration of artificial nutrition was 29.8 months. Eighty-four patients (44.7% of 187 patients) were receiving artificial nutrition for more than 2 years. Patients with Alzheimer's disease (n = 78) formed the biggest group, schizophrenia (n = 37) the second, and vascular dementia (n = 26) the third.About one-fifth of the subjects receiving artificial nutrition were in a vegetative state. More than a few patients with mental disorders, including schizophrenia, also received long-term artificial nutrition. We should pay more attention to chronic dysphasia syndrome in mental disorders.

Several lines of evidence suggest that genetic factors might contribute to drug abuse vulnerability. Recent genomic scans for association demonstrated that the brain-derived neurotrophic factor (BDNF) gene was associated with drug abuse vulnerability. In this study, we analyzed association of two BDNF gene single nucleotide polymorphisms (SNPs), 132CT (C270T named formerly) in the noncoding region of exon V and 196GA (val66met) in the coding region of exon XIIIA, with methamphetamine (MAP) abuse in Japan. No significant differences were found in the frequency of the genotype or allele in these two SNPs between MAP abusers and controls (132CT in exon V: genotype, P = 0.586, allele, P = 0.594; 196GA (val66met) in exon XIIIA: genotype, P = 0.889, allele, P = 0.713). Furthermore, there was no difference between clinical parameters (e.g., prognosis psychosis, spontaneous relapse, or poly-substance abuse) and the two SNPs of BDNF gene. These results suggest that the two SNPs (132CT in exon V and 196GA (val66met) in exon XIIIA) of the BDNF gene may not be associated with Japanese MAP abusers. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299:1/suppmat/index.html.

Neprilysin (NEP), also known as neutral endopeptidase, enkephalinase, CD 10, and common acute lymphoblastic leukemia antigen, is a 97-kD protein. NEP can degrade amyloid β peptides, and its mRNA and protein levels are known to be reduced in the brains of patients with Alzheimer’s disease (AD), making the NEP gene a substantial candidate for an AD risk factor. We examined the genetic association of three NEP polymorphisms, a GT-repeat polymorphism and two single nucleotide polymorphisms (SNPs, –1075A>G and –1284G>C) in its promoter region, with AD in a Japanese case-control sample (240 patients and 163 controls). The GT-repeat polymorphism, but not the SNPs, was significantly associated with late-onset AD (p = 0.0007). Our findings suggest that the GT-repeat polymorphism in the promoter region of the NEP gene or some other unknown polymorphisms, which are in a linkage disequilibrium, confer a susceptibility to late-onset AD.

Neurodevelopmental abnormalities have been reported in studies on the pathogenesis of schizophrenia. The Wnt-signaling pathway has been implicated in a variety of processes in neurodevelopment, and the frizzled proteins have been identified as receptors for Wnt ligands. Of the frizzled proteins, frizzled-3 (FZD3) is required for formation of the neural crest and for development of major fiber tracts in the CNS. The human FZD3 gene is located on chromosome 8p21, a positive linkage locus for schizophrenia. We analyzed polymorphisms of the FZD3 gene in patients with schizophrenia and control subjects in the Japanese population. We found a significant association between schizophrenia and the FZD3 gene in single nucleotide polymorphisms and haplotype analyses. Our data suggest that dysregulation of the Wnt-signaling pathway may be involved in the susceptibility to schizophrenia.

To determine if there are common genes that contribute to the susceptibility for schizophrenia, first-stage genome-wide scan was carried out by genotyping 417 short-tandem repeat (STR) markers in 338 individuals from 130 families with 148 affected sib-pairs identified at 16 sites nationwide in Japan. Data was from the Japanese Schizophrenia Sib-pair Linkage Group (JSSLG), which is a multi-site collaborative study group established to create a national resource for genetic studies of schizophrenia in Japan. All subjects were Japanese, and the probands and their siblings had schizophrenia. Multipoint non-parametric linkage analysis and exclusion mapping were performed with GENEHUNTER software. Simulation studies suggested that in the absence of linkage we could expect one multipoint maximum LOD score (MLS) of 1.9 per genome scan. An MLS of 3.7 would be expected only once in every 20 genome scans and thus corresponds to a genome-wide significance of 0.05. No loci in the initial screen fulfilled the criteria for significant or suggestive evidence for linkage. Ten chromosomes (1, 2, 3, 4, 5, 8, 9, 14, 17, and 20) had at least one region with a nominal P value

Brain-derived neurotrophic factor (BDNF) belongs to a family of neurotrophic factors and has been demonstrated to promote the survival, differentiation, and maintenance of a broad variety of central nervous system neurons. Several reports have suggested that the BDNF gene is a plausible functional candidate gene underlying the predisposition for developing bipolar disorder (BPD). In the present study, we investigated the possible role of the BDNF gene in the etiology of BPD using a matched case-control association design in a Japanese population. There was no evidence for an allelic or genotypic association of two polymorphisms (−1360C>T and 196G>A) of the BDNF gene with BPD. Furthermore, no significant association was observed between these polymorphisms and either of two diagnostic subtypes (bipolars I and II disorder). The results suggest that the BDNF gene is unlikely to confer susceptibility to BPD.

Susceptibility to drug dependence and drug-induced psychoses is influenced not only by the pharmacological effects of the drug but also by the genetic factors of the individual. To clarify the latter, we investigated the association between methamphetamine (METH) dependence/psychosis and the hDAT1 gene (SLC6A3) encoding the dopamine transporter, which is the primary site of METH activity in the brain. Four exonic polymorphisms of the hDAT1 gene, 242C/T (exon 2), 1342A/G (exon 9), 2319G/A (3'UTR), and VNTR (3'UTR) were examined. Although there was no significant difference in genotypic and allelic distribution of the four polymorphisms between all METH dependence/psychosis patients (N=124) and controls (N=160), the patients with METH psychosis lasting for 1 month or more after discontinuance of METH consumption showed a significant excess of nine- or fewer repeat alleles of the VNTR in 3'UTR of the hDAT1 gene (P=0.0054, OR=4.24, 95% CI=2.46-7.31). The present study demonstrated that the presence of nine- or fewer repeat alleles of hDAT1 is a strong risk factor for a worse prognosis of METH psychosis.

Recent advances in genomic and genetic knowledge and technology have opened the way to deciphering the extremely complex molecular mechanisms underlying schizophrenia. Despite accumulated pharmacological and clinical evidence for the dopamine hypothesis of schizophrenia, genetic studies have shown that monoamine-related genes, including dopamine D3 and 5-HT(2A) receptors, are associated with only a modest risk of susceptibility to schizophrenia. However, recent studies have revealed many attractive candidate genes, such as: cytosolic phospholipase A2, potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3, sigma receptor type 1, cannabinoid receptor 1, dihydropyridimdinase-related protein 2, proline dehydrogenase 2, Disc-1, dysbindin and neuregulin 1. These molecules are involved in a wide range of brain functions and may become targets for novel therapy of schizophrenia in the immediate future.

Disrupted-In-Schizophrenia-1 ( DISC1 ) is a promising susceptibility gene for major mental illness, but the mechanism of the clinical association is unknown. We searched for DISC1 transcripts in adult and fetal human brain and tested whether their expression is altered in patients with schizophrenia and is associated with genetic variation in DISC1 . Many alternatively spliced transcripts were identified, including groups lacking exon 3 (Δ3), exons 7 and 8 (Δ7Δ8), an exon 3 insertion variant (extra short variant-1, Esv1), and intergenic splicing between TSNAX and DISC1 . Isoforms Δ7Δ8, Esv1, and Δ3, which encode truncated DISC1 proteins, were expressed more abundantly during fetal development than during postnatal ages, and their expression was higher in the hippocampus of patients with schizophrenia. Schizophrenia risk-associated polymorphisms [non-synonymous SNPs rs821616 (Cys704Ser) and rs6675281 (Leu607Phe), and rs821597] were associated with the expression of Δ3 and Δ7Δ8. Moreover, the same allele at rs6675281, which predicted higher expression of these transcripts in the hippocampus, was associated with higher expression of DISC1 Δ7Δ8 in lymphoblasts in an independent sample. Our results implicate a molecular mechanism of genetic risk associated with DISC1 involving specific alterations in gene processing.

Recent progress in genotyping technology and the development of public databases has enabled large-scale genome-wide association tests with diseases. We performed a two-stage genome-wide association study (GWAS) of bipolar disorder (BD) in Japanese cohorts. First we used Affymetrix 100K GeneChip arrays in the analysis of 107 cases with bipolar I disorder and 107 controls, and selected markers that were nominally significant (P < 0.01) in at least one of the three models (1,577 markers in total). In the follow-up stage, we analyzed these markers using an Illumina platform (1,526 markers; 51 markers were not designable for the platform) and an independent sample set, which consisted of 395 cases (bipolar I + II) and 409 controls. We also assessed the population stratification of current samples using principal components analysis. After the two-stage analysis, 89 markers remained nominally significant (allelic P < 0.05) with the same allele being consistently over-represented in both the first and the follow-up stages. However, none of these were significant after correction for multiple-testing by false discovery rates. Sample stratification was virtually negligible. Collectively, this is the first GWAS of BD in the Japanese population. But given the small sample size and the limited genomic coverage, these results should be taken as preliminary.

Plasmacytoma is the disease with tumor-like growth of plasma cell or of their cognate, and often generates in the bone tissues of the entire body as multiple myeloma. Also, unusually, it develops in soft tissue as extramedullary plasmacytoma.We present a case of extramedullary plasmacytoma which originated in the upper lip, which might be the first case to be reported in Japan.A 33-year-old woman had been aware of the tumor developing on the inner side of upper lip for two months, and then visited us with a complaint of its discomfort. Upon pathological examination, this tumor was completely excised and was suspected of being plasmacytoma.General examinations followed, which denied the possibility of multiple myeloma. Furthermore, we investigated an excised sample by immunohistological examination, and identified it as extrameduallary plasmacytoma with IgA and κ-chain. In order to prevent its recurrence and metastasis, chemotherapy with Cyclophosphamide, Vincristine, Doxorubicin, and Predonisolone was done, and after a year and two months she is still in excellent condition.

Nuclear factor kappaB (NF-kappaB) is one of the critical transcription factors in inflammatory responses and replication of viruses such as human immunodeficiency virus (HIV). In fact, it has been demonstrated that various NF-kappaB inhibitors could block HIV replication. To explore more potent NF-kappaB inhibitors, we focused on carbocyclic adenine nucleosides that had been reported to have anti-inflammatory effects. We synthesized 15 carbocyclic adenine nucleoside compounds and examined their effects on the NF-kappaB-dependent gene expression using HEK293 cell line. Among these compounds, noraristeromycin (NAM) exhibited the most potent inhibitory effect on the NF-kappaB activity under the non-cytotoxic concentrations. NAM-inhibited IkappaBalpha phosphorylation and degradation upon stimulation of cells with tumour necrosis factor-alpha (TNF-alpha). In addition, NAM prevented p65 phoshorylation. These findings suggested that both IkappaB kinase-alpha (IKK-alpha) and -beta were targeted by NAM. Interestingly, in vitro kinase assay revealed that NAM inhibited the kinase activity of IKK-alpha more potently than that of IKK-beta. When we treated the cell lines, OM10.1 and Molt4/IIIB, in which HIV-1 is latently and chronically infected, we found a strong suppressive effect of NAM on HIV-1 viral replication upon stimulation with TNF-alpha.

Pituitary apoplexy, a syndrome caused by haemorrhage into the pituitary gland, typically manifests as sudden severe headache, visual symptoms and hypopituitarism, including adrenal insufficiency. We report a case of a 65-year-old man with adrenal insufficiency due to pituitary apoplexy presenting with anorexia following temporal headache and diagnosed through evaluation for hyponatraemia. MRI focusing on the pituitary gland helped to confirm the diagnosis. Our experience serves as a useful reminder of this atypical presentation of pituitary apoplexy, also known as ‘subclinical pituitary apoplexy,’ and underscores the importance of careful evaluation for hyponatraemia using serial urine osmolality, which is useful to distinguish hypovolaemic hyponatraemia from euvolaemic hyponatraemia. Clinicians should consider pituitary apoplexy as a differential diagnosis in cases of anorexia, loss of energy or hyponatraemia, following headache even when the patient is lacking classical symptoms such as severe headache or visual symptoms.

Dihydropyrimidinase-related protein 2 (DRP-2 or DPYSL-2)mediates the intracellular response to collapsin, a repulsive extracellular guidance cue or axonal outgrowth. DRP-2 is also referred to as collapsin response mediator protein 2 (CRMP-2). We have previously demonstrated that the DRP-2 gene is associated with susceptibility to schizophrenia, but not to bipolar disorders. In addition, a genetic association was observed with paranoid-type schizophrenia, but not with hebephrenic-type schizophrenia. It has been well documented that repeated abuse of methamphetamine (METH) for a long period frequently produces psychotic symptoms, such as auditory hallucinations and delusions that are hardly distinguishable from those of paranoid-type schizophrenia. Therefore, we hypothesized that a certain genetic variant of the DRP-2 gene may affect individual vulnerability to the development of METH-induced psychosis. We examined the genetic association by a case-control method. The polymorphism *2236T>C in the 3' untranslated region of the DRP-2 gene, which has been shown to be a negative genetic risk factor for paranoid-type schizophrenia, was analyzed in 198 patients with METH psychosis and 221 corresponding healthy controls in a Japanese population. No significant association of the DRP-2 gene with METH psychosis was found. Neither did we find an association with the clinical phenotype of METH psychosis, such as the age of first consumption of METH, latency to development of psychosis after METH abuse, prognosis of psychosis after detoxification from METH use, complication of spontaneous relapse of psychosis without reconsumption of the drug, or multisubstance abuse status. These findings indicate that a genetic variant of the DRP-2 gene may not affect the risk of METH psychosis or any clinical phenotype of the disorder.

The dihydropyrimidinase-related protein (DRP) family, also called the collapsin response mediator protein, is implicated in the developmental process of the nervous system. Dysfunction of DRPs may result in neurodevelopmental abnormalities, which have been assumed to be a possible factor in the pathogenesis of schizophrenia. It has been reported that in humans, the expression of one member of the DRP family, DRP-2, is decreased in the brains of individuals with schizophrenia. In addition, the DRP-2 gene is located on chromosome 8p21, a region that has been implicated in schizophrenia in genetic linkage studies. We investigated a genetic association between five polymorphisms of the DRP-2 gene and schizophrenia in the Japanese population. The *2236TC polymorphism in the 3' untranslated region (3'UTR) exhibited significant differences with respect to the distribution of the genotype and allele in patients compared with controls. The frequency of the *2236C allele was significantly higher in controls than in patients with schizophrenia (P = 0.0097) and patients with paranoid-type schizophrenia (P = 0.0083). These results suggest that the *2236C allele in the 3'UTR of the DRP-2 gene, or an unknown mutation in linkage disequilibrium with this allele, may reduce the susceptibility to schizophrenia, especially the paranoid subtype.

Susceptibility to Alzheimer's disease (AD) is thought to be regulated by multiple genetic factors. Recently, three independent studies have reported that loci on chromosome 10q are linked with AD, and the insulin degrading enzyme (IDE; MIM 146680) gene located on chromosome 10q23-q25; IDE is located close to the maker D10S583, which exhibits a maximum LOD score for late-onset AD. We examined seven polymorphisms in the IDE gene, the marker D10S583 in the 5' flanking region, and SNPs in introns 1, 3, 11, 20, 21, and 22 (rs#1999764, 1855915, 1970244, 538469, 551266, and 489517, respectively). Four SNPs in introns 3, 11, 20, and 22 did not exhibit any polymorphisms in the Japanese population that was studied. D10S583 and two SNPs in introns 1 and 21 did not exhibit a significant association with early- or late-onset AD. In addition, no associations were observed for subgroups of AD grouped according to APOE status. The present study indicates that the IDE gene polymorphisms do not confer susceptibility to early- or late-onset AD at least in a Japanese population.

Several susceptibility loci for both of schizophrenia and bipolar disorder (BPD) have been found to overlap on several chromosomes including 8p21. Expression of dihydropyrimidinase-related protein 2 (DRP-2), which gene is located on 8p21, was found to be reduced in the brains of individuals with schizophrenia and BPD. Recently, we demonstrated a significant association between the DRP-2 gene and schizophrenia. Based on the rationale, we investigated the genetic association of the DRP-2 gene with BPD using a case-control study in the Japanese population. However, no significant associations were found between five polymorphisms of the DRP-2 gene (-975C>G, 352G>A, 426C>T, 1506T>C, and *2236T>C), and BPD, nor were associations detected between either of the polymorphisms and any subtype of BPD, bipolars I and II. The present study did not provide any evidence for a contribution of the DRP-2 gene to susceptibility to BPD.

Neprilysin (NEP), also known as neutral endopeptidase, enkephalinase, CD 10, and common acute lymphoblastic leukemia antigen, is a 97-kD protein. NEP can degrade amyloid beta peptides, and its mRNA and protein levels are known to be reduced in the brains of patients with Alzheimer's disease (AD), making the NEP gene a substantial candidate for an AD risk factor. We examined the genetic association of three NEP polymorphisms, a GT-repeat polymorphism and two single nucleotide polymorphisms (SNPs, -1075AG and -1284GC) in its promoter region, with AD in a Japanese case-control sample (240 patients and 163 controls). The GT-repeat polymorphism, but not the SNPs, was significantly associated with late-onset AD (p = 0.0007). Our findings suggest that the GT-repeat polymorphism in the promoter region of the NEP gene or some other unknown polymorphisms, which are in a linkage disequilibrium, confer a susceptibility to late-onset AD.

Backgroud The dihydropyrimidinase-related protein (DRP) family, also called the collapsin response mediator protein, is implicated in the developmental process of the nervous system. Dysfunction of DRPs may result in neurodevelopmental abnormalities, which may be a factor in the pathogenesis of schizophrenia. The expression of one member of DRP-2 in humans has been reported to be decreased in the brains of people with schizophrenia. In addition, the DRP-2 gene (Dihydropyrimidinaselike 2; DPYSL2) is located on chromosome 8p21, a region that has been implicated in schizophrenia in genetic linkage studies. Methods We investigated a genetic association between five polymorphisms of the DRP-2 gene and schizophrenia in the Japanese population. Results The *2236 T >C polymorphism in the 3′ untranslated region (3′UTR) exhibited significant differences with respect to the distribution of the genotype and allele in patients compared with control subjects. The frequency of the *2236C allele was significantly higher in control subjects than patients with schizophrenia ( p = .0097) and paranoid-type schizophrenia ( p = .0083). Conclusions Our results suggest that the *2236C allele in the 3′UTR of the DRP-2 gene, or an unknown mutation in linkage disequilibrium with this allele, may reduce the susceptibility to schizophrenia, especially the paranoid subtype.

Fibronectin is one of the cell adhesion proteins. Adhesion molecules play an important role in neural and synaptic genesis, and their dysfunction may result in neurodevelopmental abnormalities, which have been assumed to be a factor in the pathogenesis of schizophrenia. To examine the possible involvement of fibronectin in the etiology of schizophrenia, we analyzed six polymorphisms, located in introns 2, 21, 24, and 26, and exons 20 and 28, in the human fibronectin gene (FN1) of schizophrenic patients in the Japanese population (n = 104) and age-and gender-matched controls (n = 104). No significant positive association was observed between either of the polymorphisms and schizophrenia, nor was an association found between either of the polymorphisms and any subtypes of schizophrenia. These data did not provide evidence for a contribution of the FN1 gene to susceptibility to schizophrenia. © 2002 Wiley-Liss, Inc.

To examine the cannabinoid hypothesis for pathogenesis of schizophrenia, we examined two kinds of polymorphisms of the CNR1 gene, which encodes human CB1 receptor, a subclass of central cannabinoid receptors, in schizophrenics and age-matched controls in the Japanese population. Allelic and genotypic distributions of polymorphism 1359G/A at codon 453 in the coding region and AAT triplet repeats in the 3' flanking region in the Japanese population were quite different from those in Caucasians. Although the polymorphism 1359G/A was not associated with schizophrenia, the triplet repeat polymorphism of the CNR1 gene was significantly associated with schizophrenia, especially the hebephrenic subtype (P = 0.0028). Hebephrenic schizophrenia showed significantly increased rate of the 9 repeat allele (P = 0.032, OR = 2.30, 95% CI (1.91-2.69)), and decreased rate of the 17 repeat allele (P = 0.011, OR = 0.208, 95% CI (0.098-0.439)). The present findings indicated that certain alleles or genotypes of the CNR1 gene may confer a susceptibility of schizophrenia, especially of the hebephrenic type.

The NOTCH4 gene is located at 6p21.3, a site which several studies have shown to have significant linkage with schizophrenia. Recently, an exceptionally strong association was reported between NOTCH4 gene polymorphisms and schizophrenia in British patients. We re-examined their findings using a Japanese population. We genotyped three kinds of polymorphisms, SNP1 in the 5' flanking region, SNP2 in the promoter region and CTG repeats in exon 1 of the NOTCH4 gene of schizophrenics (N=188), patients with schizoaffective disorder (N=39) and controls (N=143). Genotypic distributions and allelic frequencies of SNP1, SNP2 and CTG repeats of the NOTCH4 gene did not show significant associations with schizophrenia or schizoaffective disorder. Neither they showed association with schizophrenia subcategories, hebephrenic and paranoid type schizophrenia, nor with subgroups of schizophrenia with and without positive family history of psychoses. The present study found that the NOTCH4 gene does not confer susceptibility to schizophrenia and schizoaffective disorders, at least in Japanese subjects, in contrast to the findings in British subjects.

Background Several lines of evidence have supported possible roles of the sigma receptors in the etiology of schizophrenia and mechanisms of antipsychotic efficacy. An association study provided genetic evidence that the sigma receptor type 1 gene (SIGMAR1) was a possible susceptibility factor for schizophrenia, however, it was not replicated by a subsequent study. It is necessary to evaluate further the possibility that the SIGMAR1 gene is associated with susceptibility to schizophrenia. Methods A case-control association study between two polymorphisms of the SIGMAR1 gene, G-241T/C-240T and Gln2Pro, and schizophrenia in Japanese population, and meta-analysis including present and previous studies. Results There was no significant association of any allele or genotype of the polymorphisms with schizophrenia. Neither significant association was observed with hebephrenic or paranoid subtype of schizophrenia. Furthermore, a meta-analysis including the present and previous studies comprising 779 controls and 636 schizophrenics also revealed no significant association between the SIGMAR1 gene and schizophrenia. Conclusion In view of this evidence, it is likely that the SIGMAR1 gene does not confer susceptibility to schizophrenia.