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Biomedical subjects

Yutaka Honda

Publications and source records attributed to Yutaka Honda.

16 recordsLinked to original sources
PubMed2006

Genomewide association analysis of human narcolepsy and a new resistance gene.

Human narcolepsy is a hypersomnia that is affected by multiple genetic and environmental factors. One genetic factor strongly associated with narcolepsy is the HLA-DRB1*1501-DQB1*0602 haplotype in the human leukocyte antigen region on chromosome 6, whereas the other genetic factors are not clear. To discover additional candidate regions for susceptibility or resistance to human narcolepsy, we performed a genomewide association study, using 23,244 microsatellite markers. Two rounds of screening with the use of pooled DNAs yielded 96 microsatellite markers (including 16 markers on chromosome 6) with significantly different estimated frequencies in case and control pools. Markers not located on chromosome 6 were evaluated by the individual typing of 95 cases and 95 controls; 30 markers still showed significant associations. A strong association was displayed by a marker on chromosome 21 (21q22.3). The surrounding region was subjected to high-density association mapping with 14 additional microsatellite markers and 74 SNPs. One microsatellite marker (D21S0012m) and two SNPs (rs13048981 and rs13046884) showed strong associations (P < .0005; odds ratios 0.19-0.33). These polymorphisms were in a strong linkage disequilibrium, and no other polymorphism in the region showed a stronger association with narcolepsy. The region contains three predicted genes--NLC1-A, NLC1-B, and NLC1-C--tentatively named "narcolepsy candidate-region 1 genes," and NLC1-A and NLC1-C were expressed in human hypothalamus. Reporter-gene assays showed that the marker D21S0012m in the promoter region and the SNP rs13046884 in the intron of NLC1-A significantly affected expression levels. Therefore, NLC1-A is considered to be a new resistance gene for human narcolepsy.

Genetic Markers↗
PubMed2006

Characterization of peroxidase in buckwheat seed.

A peroxidase (POX)-containing fraction was purified from buckwheat seed. The POX consisted of two isozymes, POX I and POX II, that were purified 6.6- and 67.4-fold, respectively. Their molecular weights were estimated to be 46.1 kDa (POX I) and 58.1 kDa (POX II) by gel filtration. While POX I and II each oxidized quercetin, o-dianisidine, ascorbic acid and guaiacol, only POX II oxidized ABTS. Kinetic studies revealed that POX I and II had lower K(m) values for quercetin (0.071 and 0.028 mM), ABTS (0.016 mM for POX II) and ascorbic acid (0.043 and 0.029 mM) than for o-dianisidine (0.229 and 0.137 mM) and guaiacol (0.288 and 0 ). The optimum pHs of POX I and II for various substrates were almost the same, except for quercetin; pH 8.0 for POX I and pH 4.5 for II. Their optimal temperatures were 30 degrees C (POX I) and 10 degrees C (POX II), and POX I was more stable than POX II above 30 degrees C.

Ascorbic Acid↗
PubMed2006

Detection of autoantibodies against hypocretin, hcrtrl, and hcrtr2 in narcolepsy: anti-Hcrt system antibody in narcolepsy.

STUDY OBJECTIVES: The impairment of hypocretin neurotransmission system is considered to play a major role in the pathophysiology of narcolepsy. It has been hypothesized that autoimmune abnormalities underlie the etiology of narcolepsy, based on the tight association with HLA-DRB1*1501/ DQB1*0602. It remains unclear if autoantibodies against hypocretin receptors (hcrtrl and hcrtr2) are involved in narcolepsy. DESIGN: We have developed a novel radioligand binding assay to address this question. Sera from 181 patients with narcolepsy, 10 patients with other hypersomnias, and 91 control subjects were used. Human [35S]-Hcrt, hcrtrl, and hcrtr2 were synthesized by in vitro transcription/translation system. The immune complex of autoantibody and each [35S]-protein were immunoprecipitated and quantified using a radioligand-binding assay. RESULTS: We detected autoantibodies against hypocretin in 3 patients, hcrtrl in 1 patient, and hcrtr2 in 5 patients with narcolepsy. Positive reactions were also found against hcrtrl in 2 and hcrtr2 in 1 control subjects. No relationships were found between these autoantibodies and HLA-DRB1*1501/DQB1*0602 haplotypes, presence of cataplexy, presence of subjective nocturnal sleep disruption, or the score on the Epworth Sleepiness Scale. CONCLUSIONS: Although we have detected autoantibodies against the hypocretin neurotransmission system, our results do not support the hypothesis that autoantibody-mediated dysfunction in the hypocretin system underlies the pathophysiology of narcolepsy.

Autoantibodies↗
PubMed2005

Effects of lipase, lipoxygenase, peroxidase, and rutin on quality deteriorations in buckwheat flour.

To investigate the effects of changes in lipase, lipoxygenase, peroxidase (POX), and rutin concentrations on the quality of buckwheat flour, 14 buckwheat varieties were stored for 0, 4, 10, and 30 days at 5 or 20 degrees C. During the storage period, lipase activity correlated to pH (significantly negative) and water-soluble acid (WSA) (significantly positive). The lipoxygenase 1 protein concentration had a negative correlation to WSA (significant at 0 and 4 storage days at 5 degrees C and at 0 and 10 storage days at 20 degrees C). POX had significant correlation to pH and peroxide value (POV) at 5 degrees C, whereas it was not significant at 20 degrees C. The rutin concentration had negative correlations to WSA (significant at 30 days of storage at 5 degrees C and at 4 days of storage at 20 degrees C). Thus, lipase activity plays an important role that relates to lipid degradation in quality deterioration of buckwheat flour.

Fagopyrum↗
PubMed2005

Remarkable diastereomeric rearrangement of an alpha-acyloxy beta-ketosulfide to an alpha-acyloxy thioester: a novel approach to the synthesis of optically active (2S,3S) beta-amino alpha-hydroxy acids.

[reaction: see text] A novel and efficient synthetic method is described for (2S,3S)-3-amino-2-hydroxy-4-phenyl butyric acid derivatives, which are useful intermediates of enzyme inhibitors. This involves a Pummerer rearrangement of a beta-ketosulfoxide derived from l-phenylalanine followed by highly stereoselective acyl migration. From these studies, it appears that nitrogen-protecting groups exert a substantial influence over stereoselectivity. The mechanism of the rearrangement is discussed. beta-Amino alpha-hydroxy carboxylic acids are important pharmaceutical intermediates, and this method may provide a versatile synthesis from various amino acids in a few steps.

HIV Protease Inhibitors↗
PubMed2005

Overexpressed Id-1 is associated with a high risk of hepatocellular carcinoma development in patients with cirrhosis without transcriptional repression of p16.

BACKGROUND: Inhibitor of differentiation/DNA binding protein 1 (Id-1) plays a pivotal role in the regulation of cell proliferation and carcinogenesis via inhibiting basic helix-loop-helix (HLH) transcription factors. Recently, Id-1 was found to repress p16 in tumorous tissue specimens including hepatocellular carcinoma (HCC), but its relevance in precancerous liver tissues is unknown. METHODS: Id-1 expression in the liver tissue specimens of 112 patients with cirrhosis without HCC was studied by immunohistochemical analysis. Correlations were investigated between Id-1 expression and clinicopathologic features, the status of p16, and the risk of HCC occurrence. RESULTS: A high expression of Id-1 was observed in 42 patients (38%). The level of Id-1 expression was not associated with clinical standard parameters or the status of p16 in cirrhotic tissue specimens. The cumulative incidence of HCC development was significantly higher in a group of patients with high Id-1 expression (P = 0.0008). Multivariate analysis revealed that increased Id-1 expression is an independent significant factor for the risk of HCC development in patients with cirrhosis (relative risk = 2.75, P = 0.003). CONCLUSIONS: The results of the current study suggested that increased expression of Id-1 may play an important role in the early step of hepatocarcinogenesis, and might serve as a useful marker for determining patients with cirrhosis with a high risk of HCC occurrence.

Adult↗
PubMed2005

Difference in the characteristics of subjective and objective sleepiness between narcolepsy and essential hypersomnia.

The present study was conducted to investigate the difference in the characteristics of daytime sleepiness between narcolepsy and essential hypersomnia and to identify the relationship between the Epworth Sleepiness Scale (ESS) and the Multiple Sleep Latency Test (MSLT) in patients with these two disorders. Subjects consisted of 34 patients with essential hypersomnia (32.4 +/- 11.0 years old), 52 patients with narcolepsy (29.0 +/- 13.8 years old), and 45 control subjects (33.3 +/- 6.6 years old). The subjects completed the ESS and underwent MSLT following a regular sleep-wake schedule for over 2 weeks. The ESS scores were pathologically high and mean sleep latency on MSLT was short, not only in narcolepsy but also in essential hypersomnia. With respect to sleep latencies on each MSLT session, both essential hypersomnia and control subjects had the smallest value at 14:00, while narcolepsy lacked any statistical change at this time period. The correlation between ESS and mean sleep latency on MSLT was higher in essential hypersomnia than in narcolepsy, and the correlation was strongest for the session performed at 14:00. Based on the ESS and MSLT results, the severity of excessive daytime sleepiness was significantly milder in essential hypersomnia compared with that in narcolepsy. The results also indicate that diurnal variation of sleepiness was maintained, and the correlation between subjective and objective sleepiness was relatively maintained in essential hypersomnia compared to narcolepsy. It is suggested that the mild disease severity of essential hypersomnia contributed to the formation of these characteristics.

Adult↗
PubMed2004

Purification and characterization of lipase in buckwheat seed.

To obtain basic information about enzymatic deterioration of buckwheat flour, triacylglycerol lipase (LIP; EC 3.1.1.3) was purified from buckwheat seed. The LIP consisted of two isozymes, LIP I and LIP II, and they were purified with purification folds of 60 and 143 with final specific activities of 0.108 and 0.727 mumol of fatty acid released per minute per milligram of protein at 30 degrees C using triolein as a substrate. Molecular weights were estimated to be 150 (LIP I) and 28.4 kDa (LIP I) by gel filtration and 171 (LIP I) and 26.5 kDa (LIP II) by SDS-PAGE. Optimal pHs of LIP activities were 3.0 (LIP I) and 6.0 (Lip II) using triolein as a substrate. Both LIP I and II reacted in the acidic pH range. Optimal temperatures were 30 (LIP I) and 40 degrees C (LIP II), and both LIP I and II were stable below 30 degrees C when p-nitrophenyl-laurate was used as a substrate. However, they were inactivated above 60 degrees C. On the other hand, when triolein was used as a substrate, optimal temperatures were 30 degrees C for both LIP I and II, and they retained 40% of their activity after a 4 h incubation of enzymes at 70 degrees C. LIP I and II had higher activity against triolein than monoolein or tri/monopalmitin. Most of the LIP activity was distributed in the embryo.

Enzyme Stability↗
PubMed2004

New approaches to the industrial synthesis of HIV protease inhibitors.

Efficient and industrially applicable synthetic processes for precursors of HIV protease inhibitors (Amprenavir, Fosamprenavir) are described. These involve a novel and economical method for the preparation of a key intermediate, (3S)-hydroxytetrahydrofuran, from l-malic acid. Three new approaches to the assembly of Amprenavir are also discussed. Of these, a synthetic route in which an (S)-tetrahydrofuranyloxy carbonyl is attached to l-phenylalanine appears to be the most promising manufacturing process, in that it offers satisfactory stereoselectivity in fewer steps.

Carbamates↗
PubMed2003

Spectral analysis of all-night human sleep EEG in narcoleptic patients and normal subjects.

To investigate the pathophysiology of narcoleptic patients' sleep in detail, we analysed and compared the whole-night polysomnograms of narcoleptic patients and normal human subjects. Eight drug-naive narcoleptic patients and eight age-matched normal volunteers underwent polysomnography (PSG) on two consecutive nights. In addition to conventional visual scoring of the polysomnograms, rapid eye movement (REM)-density and electroencephalograph (EEG) power spectra analyses were also performed. Sleep onset REM periods and fragmented nocturnal sleep were observed as expected in our narcoleptic patients. In the narcoleptic patients, REM period duration across the night did not show the significant increasing trend that is usually observed in normal subjects. In all narcoleptic patient REM periods, eye movement densities were significantly increased. The power spectra of narcoleptic REM sleep significantly increased between 0.3 and 0.9 Hz and decreased between 1.0 and 5.4 Hz. Further analysis revealed that non-rapid eye movement (NREM) period duration and the declining trend of delta power density in the narcoleptic patients were not significantly different from the normal subjects. Compared with normal subjects, the power spectra of narcoleptic NREM sleep increased in the 1.0-1.4 Hz and 11.0-11.9 Hz frequency bands, and decreased in a 24.0-26.9 Hz frequency band. Thus, increased EEG delta and decreased beta power densities were commonly observed in both the NREM and REM sleep of the narcoleptic patients, although the decrease in beta power during REM sleep was not statistically significant. Our visual analysis revealed fragmented nocturnal sleep and increased phasic REM components in the narcoleptic patients, which suggest the disturbance of sleep maintenance mechanism(s) and excessive effects of the mechanism(s) underlying eye movement activities during REM sleep in narcolepsy. Spectral analysis revealed significant increases in delta components and decreases in beta components, which suggest decreased activity in central arousal mechanisms. These characteristics lead us to hypothesize that two countervailing mechanisms underlie narcoleptic sleep pathology.

Adult↗
PubMed2002

Significant association of the arylalkylamine N-acetyltransferase ( AA-NAT) gene with delayed sleep phase syndrome.

Arylalkylamine N-acetyltransferase (AA-NAT) is a rate-limiting enzyme in melatonin hormone synthesis and participates in daily oscillations of the melatonin level. We studied the association between the AA-NAT gene and delayed sleep phase syndrome (DSPS). Results indicate that there is a significant difference in allele positivity at the single nucleotide polymorphism involved in an amino acid substitution from alanine to threonine at position 129 between patients with DSPS and healthy controls. The frequency of the 129 threonine allele is significantly higher in the patients than in the controls ( P=0.0029). The data suggest that AA-NAT could be a susceptibility gene for DSPS.

Alleles↗
PubMed2002

Synthesis of optically active alpha-aminoalkyl alpha'-halomethyl ketone: a cross-Claisen condensation approach.

A simple and versatile method was developed for the synthesis of alpha-aminoalkyl alpha'-halomethyl ketone derivatives, which are useful intermediates of protease inhibitors. It involves selective halogenation of the alpha-position on a beta-ketoester, which is prepared by cross-Claisen condensation using N-protected amino acid ester. The title compound is obtained in high yield after decarboxylation of the alpha-halo-beta-ketoester.

Journal Article↗
PubMed2002

Clinical significance of sleep-related breathing disorder in narcolepsy.

Both the influence of comorbid obstructive sleep apnea-hypopnea syndrome (OSAHS) on daytime sleepiness and its pathological mechanism in 10 narcoleptic patients was studied. Mild elevation of esophageal negative pressure and obstruction in the velopharyngeal area, as observed by upper airway magnetic resonance imaging, during apneic episodes was observed in the subjects. Severity of the disorder was correlated positively with body mass index, and the latencies of the multiple sleep latency tests were not improved with nasal continuous positive airway pressure treatment in subjects. Pathogenesis of OSAHS in narcolepsy was thought to be almost similar to typical OSAHS, and that the disorder seemed to lack a pathological influence on daytime sleepiness.

Adult↗
PubMed2002

Subjective sleep quality and suggested immobilization test in restless leg syndrome and periodic limb movement disorder.

The severity of restless leg syndrome (RLS) and/or periodic limb movement disorder (PLMD) was investigated by using a suggested immobilization test (SIT) and by measuring the influence of these disorders on the subjective sleep quality as assessed by the Pittsburgh Sleep Quality Index (PSQI). Patients with RLS and those with both RLS and PLMD showed remarkably high values for PSQI and SIT, whereas patients with PLMD only showed normal values for PSQI. These findings suggest that there is only a small pathological significance for periodic limb movements, and demonstrate the efficacy of SIT and PSQI for evaluating the severity of these disorders.

Electromyography↗
PubMed2002

Clinical significance of cataplexy and HLADR1501 in narcolepsy.

Clinical symptoms and multiple sleep latency test (MSLT) measures among narcoleptic patients with both cataplexy and HLADR1501 were compared with cataplexy-free narcoleptic patients with a positive finding of HLADR1501 and cataplexy-free patients without HLADR1501. Both mean sleep onset latencies and rapid eye movement (REM) latencies on MSLT were shorter in the patients with cataplexy compared with the cataplexy-free patients. In four cataplexy-free patients without HLADR1501, nocturnal sleep was remarkably long and their excessive daytime sleepiness did not respond to treatment. The findings suggest that the severity and disease mechanism of narcolepsy might become heterogenous when cataplexy and HLADR1501 are considered.

Analysis of Variance↗