NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD.

The efficacy of thiopurines, including azathioprine (AZA) and 6-mercaptopurine (6MP), has been demonstrated for the treatment of inflammatory bowel disease (IBD). The most common and serious adverse event of treatment with thiopurines altered by doctors is leukopenia. Hair loss is also a serious event that could be a critical reason for patients to decline thiopurine treatment. Thiopurine-induced severe hair loss causes cosmetic problems, and it takes a long time to recover. In a recent study, NUDT15 R139C was strongly associated with thiopurine-induced leukopenia in Korean and Caucasian populations. In this study, we performed an association study to investigate and replicate the association of R139C with adverse events of thiopurines in Japanese patients. A total of 142 Japanese patients with IBD, with histories of thiopurine treatment, were examined. NUDT15 R139C was genotyped using a custom TaqMan genotyping assay. Adverse events including leukopenia were reviewed from medical records. The 6MP dose was adjusted to AZA equivalents by multiplying with 2 as a thiopurine dose. Five patients developed severe hair loss and all of them were risk homozygous (T/T) for R139C. No early severe hair loss was observed in patients with the C/T or C/C genotype (P=3.82 × 10(-16), odds ratio=212). The association of R139C with early (<8 weeks) leukopenia (white blood cells<3000 mm(-3)), which was previously reported in Korean patients, was replicated in our Japanese IBD cohort (P=1.92 × 10(-16), odds ratio=28.4). However, we could not confirm the association with late leukopenia in the Japanese subjects. Patients with the C/T genotype discontinued treatment or required thiopurine dose reduction significantly earlier than patients with the C/C genotype (P=1.45 × 10(-4)); however, on manipulating the doses, there was no significant difference in the thiopurine continuation rates between the groups. In the maintenance period, the frequencies of 6MP usage were higher, and the doses of thiopurines were significantly lower in patients with the C/T genotype than in those with the C/C genotype (0.574±0.316 mg kg(-1) per day vs 1.03±0.425 mg kg(-1) per day, P=6.21 × 10(-4)). NUDT R139C was significantly associated with early severe hair loss in Japanese patients with IBD. We also verified the previously reported association of R139C with early leukopenia in a different East Asian population. It is recommended that treatment with thiopurines should be avoided for patients with the T/T genotype. Low-dose 6MP (0.2-0.3 mg kg(-1) per day) could be used rather than AZA for the patients with C/T genotype to continue thiopurine treatments. However, late leukopenia and other several adverse events could not be completely predicted by R139C genotypes.

High frequency region of the snore spectra carry important information on the disease of sleep apnoea.

Snoring is the most common symptom of obstructive sleep apnoea (OSA). Several researchers have reported differences between the power spectra of non-OSA and OSA snorers. The traditional approach over the years has been to record snore sounds at a bandwidth of < 5 kHz. Narrowing of the upper airways during OSA events and the resulting upward shift of snore frequencies also lend support to the idea of examining snore sounds beyond 5 kHz. In this paper, we compute the power spectra of snores in three different bands defined as: low-frequency band (LFB: < 5 kHz); middle-frequency band (MFB: 5-10 kHz) and high-frequency band (HFB: 10-20 kHz). We illustrate that there is a significant difference between non-OSA snorers (Apnoea Hypopnoea Index (AHI) < 10) and OSA snorers (AHI > 10) in the region > 5 kHz. We then develop a feature to diagnose OSA based on the spectral differences in the high frequency region and evaluate its performance on a database of 20 subjects. Our results strongly suggest that the high-frequency region of the snore sounds carry information, hitherto disregarded, on the disease of sleep apnoea.

HLA-B is the best candidate of susceptibility genes in HLA for Japanese ulcerative colitis.

Recently, a genome-wide association study for ulcerative colitis (UC) in the UK population was reported, and several susceptibility loci including the human leukocyte antigen (HLA) region were identified. The strongest association in the HLA region was found at a 400 kb haplotype block containing HLA-DRB1. In Japanese population, previous study suggested the association between UC and HLA-B*52; however, HLA typing was determined using serotyping with the small sample size. The purpose of this study was to perform an association study in HLA-B by genotyping. A total of 320 patients with UC and 322 healthy controls were recruited in this case-control study. All subjects were Japanese. Genotyping of HLA-B was performed by polymerase chain reaction using a sequence-specific primer. When the allele frequencies were compared, significant associations were found with B*52 [odds ratio (OR) = 3.65, P = 1.6 x 10(-17), P(c) = 3.7 x 10(-16)] and B*4002 (OR = 0.52, P = 0.00030, P(c) = 0.0068). The allele frequency of B*52 was significantly higher in patients diagnosed before 40 years of age than in those diagnosed after 40 years (OR = 1.79, P = 0.010, P(c) = 0.020). A combination association map of Japanese UC using our current and previous studies showed two equal peaks of association on HLA-DRB1 and HLA-B, indicating the possible existence of two casual variants in the HLA region inside and outside the 400 kb block found in UK. We conclude that HLA-B contributes to the susceptibility to Japanese UC, especially cases with younger age of onset. The strength of association for HLA-B was equal to that for HLA-DRB1 in Japanese UC, in contrast to the UK population.

Quality of life of patients and medical cost of "half elemental diet" as maintenance therapy for Crohn's disease: secondary outcomes of a randomised controlled trial.

BACKGROUND/AIM: Quality of life (QOL) of the patients and medical costs are important in current medical treatments, especially those for chronic diseases. We have reported the effectiveness of 'half elemental diet (ED)' as maintenance therapy for patients with Crohn's disease (CD). The aim of this study was to evaluate the QOL of CD patients and medical costs of half-ED. METHODS: Fifty-one CD patients in remission were randomly assigned to a half-ED group (n=26) or a free diet group (n=25). The primary outcome measure was the occurrence of relapse during a 2-year period. This time, we investigated the QOL of the patients and medical costs of half-ED, as secondary outcomes. QOL was evaluated using the Japanese version of the IBDQ scoring system, and medical costs were calculated monthly from the receipts. RESULTS: IBDQ score was not significantly different between the two groups at 1 and 13 months after the start of maintenance treatment. Medical costs were not significantly different between them either. This study showed that half-ED therapy did not affect the treatment of CD patients, neither regarding their QOL nor medical costs. CONCLUSION: This study has confirmed this half-ED therapy is beneficial for patients with Crohn's disease.

HLA-DRB1 alleles influence clinical phenotypes in Japanese patients with ulcerative colitis.

The human leukocyte antigen (HLA) region has been implicated in the disease susceptibility of inflammatory bowel disease by several linkage and association studies. In Caucasians, HLA-DRB1 has been reported to determine the clinical phenotypes of ulcerative colitis (UC). Others and we previously reported that HLA-DRB1*1502 was strongly associated with UC in the Japanese population. However, the contribution of HLA-DRB1 to the clinical phenotypes in Japanese UC has not been elucidated yet. The aim of this study was to determine whether HLA-DRB1 alleles were associated with the clinical phenotypes in Japanese patients with UC. A total of 353 patients with UC were recruited. Patients were classified into subgroups by sex, age at diagnosis, disease extent, need for steroid therapy or need for surgical treatment. The allele frequency of HLA-DRB1*08 was significantly higher in patients whose disease extended beyond the rectum (left-sided and extensive UC) than in those with proctitis [odds ratio (OR)=2.20, Pc=0.043). The allele frequency of HLA-DRB1*09 was significantly higher in patients with UC diagnosed at the age of 40 years or older than in those with UC diagnosed before the age of 40 years (OR=2.31, Pc=0.022). Besides these positive associations, no significant differences were found in the allele frequencies between the other subgroups. We conclude that HLA-DRB1*09 is associated with the age at diagnosis and HLA-DRB1*08 is associated with the disease extent of UC in Japanese. These results indicate that HLA-DRB1 is not only associated with the overall UC susceptibility but also associated with the clinical phenotypes in Japanese.

Comparison and evaluation of leakage flux on various types of dental magnetic attachment.

A dental magnetic attachment is a device to retain dental prostheses such as overdentures by magnetic attraction. As compared with mechanical attachments, the dental magnetic attachment has superior characteristics such as easy insertion, good esthetics and less lateral pressure to its abutment tooth. As a result, it has come to be used widely. There are various types of dental magnetic attachments. There are a cup type and a sandwich type in Japan, and several types of dental magnetic attachments in other countries. They are used for a long term in the mouth, it is necessary to clarify those leakage magnetic fields. Therefore, in this paper, we evaluate the leakage magnetic fields leaking out of sandwich type and open magnetic circuit type of dental magnetic attachment.

New water disinfection system using UVA light-emitting diodes.

AIM: To evaluate the ability of high-energy ultraviolet A (UVA) light-emitting diode (LED) to inactivate bacteria in water and investigate the inactivating mechanism of UVA irradiation. METHODS AND RESULTS: We developed a new disinfection device equipped with high-energy UVA-LED. Inactivation of bacteria was determined by colony-forming assay. Vibrio parahaemolyticus, enteropathogenic Escherichia coli, Staphylococcus aureus and Escherichia coli DH5alpha were reduced by greater than 5-log(10) stages within 75 min at 315 J cm(-2) of UVA. Salmonella enteritidis was reduced greater than 4-log(10) stages within 160 min at 672 J cm(-2) of UVA. The formation of 8-hydroxy-2'-deoxyguanosine in UVA-LED irradiated bacteria was 2.6-fold higher than that of UVC-irradiated bacteria at the same inactivation level. Addition of mannitol, a scavenger of hydroxyl radicals (OH(*)), or catalase, an enzyme scavenging hydrogen peroxide (H(2)O(2)) to bacterial suspensions significantly suppressed disinfection effect of UVA-LED. CONCLUSION: This disinfection system has enough ability to inactivate bacteria and OH(*) and H(2)O(2) participates in the disinfection mechanism of UVA irradiation. SIGNIFICANCE AND IMPACT OF THE STUDY: We newly developed UVA irradiation system and found that UVA alone was able to disinfect the water efficiently. This will become a useful disinfection system.

Evaluation of leakage flux out of a dental magnetic attachment.

A dental magnetic attachment is a device to retain dental prostheses such as overdentures by magnetic attraction. As compared with mechanical attachments, the magnetic attachment has a superior retention properties due to less lateral pressure to its abutment tooth, and hence it has come to be widely used, particularly for retaining overdentures. Because the dental magnetic attachments are a device used in the mouth, the tissues in the mouth are exposed to the magnetic fields leaking out of the magnetic attachments for a long time. It may therefore be important to discuss biological effects of the leakage magnetic fields. It is required at first to evaluate the strength of the leakage magnetic fields.

Feature extraction for snore sound via neural network processing.

Snore sound (SS) is the earliest and the most common symptom of Obstructive Sleep Apnea (OSA) which is a serious disease caused by the collapse of upper airways during sleep. SS should carry vital information on the state of the upper airways and is simple to acquire and rich in features but their analysis is complicated. In this study we use neural network (NN) based method to model SS via a simple second order one-step predictor. We show that the some hidden information/feature of a SS can be conveniently captured in the connection-weight-space (CWS) of the NN, after a process of supervised training. The availability of the proposed method is investigated by performing independent component analysis (ICA) on CWS.

Butyrophilin-like 2 gene is associated with ulcerative colitis in the Japanese under strong linkage disequilibrium with HLA-DRB1*1502.

The human leukocyte antigen (HLA) region has been implicated in the pathogenesis of inflammatory bowel disease (IBD), which is classified into Crohn's disease (CD) and ulcerative colitis (UC). Recently, an association between sarcoidosis and the butyrophilin-like 2 (BTNL2) gene was reported. BTNL2 is located in the HLA region and its messenger RNA is expressed most abundantly in the intestine. In this study, we performed a case-control association study of BTNL2 in the Japanese patients with IBD and performed linkage disequilibrium (LD) analysis between BTNL2 and HLA-DRB1. We analyzed eight polymorphisms selected after direct sequencing and found that none of the polymorphisms were associated with the Japanese CD cohort. In contrast, five polymorphisms were significantly associated with UC, especially three single nucleotide polymorphisms (BTNL2_19, BTNL2_22 and BTNL2_23) were associated as a haplotype. The most frequent haplotype (GGC haplotype) was a low-risk haplotype (P= 0.000052), whereas the other TCT haplotype was a high-risk haplotype (P= 0.0000085). Among the eight polymorphisms, the strongest association with UC was found in BTNL2_19 (OR = 1.92, P= 0.0000035). As expected, the BTNL2_19-T allele showed strong LD with DRB1*1502 (D'= 0.92). When BTNL2_19 was tested as conditional on the DRB1*1502 carrier status, the significant association disappeared, suggesting that the association was because of its strong LD with DRB1*1502. We conclude that BTNL2 does not contribute to the susceptibility to Japanese CD but is associated with Japanese UC because of the strong LD with HLA-DRB1*1502. The strong LD between BTNL2 and HLA-DRB1 raises another issue about the potential role of BTNL2 in other diseases associated with HLA-DRB1.

Effectiveness of an 'half elemental diet' as maintenance therapy for Crohn's disease: A randomized-controlled trial.

BACKGROUND: Although thiopurines have a proven role in maintenance therapy for Crohn's disease, an alternative therapy is needed for patients intolerant or resistant to thiopurines. AIM: To evaluate the effectiveness of home enteral nutrition as a maintenance therapy regimen in which half of the daily calorie requirement is provided by an elemental diet and the remaining half by a free diet. We refer to this home enteral nutrition therapy as 'half elemental diet'. METHODS: Between 2002 and 2005, 51 patients in remission from two hospitals were randomly assigned to a half elemental diet group (n = 26) or a free diet group (n = 25). The primary outcome measure of this study was the occurrence of relapse over the 2-year period. RESULTS: The relapse rate in the half elemental diet group was significantly lower [34.6% vs. 64.0%; multivariate hazard ratio 0.40 (95% CI: 0.16-0.98)] than that in the free diet group after a mean follow-up of 11.9 months. Compliance was similar in the two groups. No adverse event occurred in any of the patients throughout the study. CONCLUSION: This randomized-controlled trial shows the effectiveness of an half elemental diet, which is a promising maintenance therapy for Crohn's disease patients.

Tracking the states of a nonlinear and nonstationary system in the weight-space of artificial neural networks.

We propose a novel interpretation and usage of Neural Network (NN) in modeling physiological signals, which are allowed to be nonlinear and/or nonstationary. The method consists of training a NN for the k-step prediction of a physiological signal, and then examining the connection-weight-space (CWS) of the NN to extract information about the signal generator mechanism. We define a novel feature, Normalized Vector Separation (gamma(ij)), to measure the separation of two arbitrary states "i" and "j" in the CWS and use it to track the state changes of the generating system. The performance of the method is examined via synthetic signals and clinical EEG. Synthetic data indicates that gamma(ij) can track the system down to a SNR of 3.5 dB. Clinical data obtained from three patients undergoing carotid endarterectomy of the brain showed that EEG could be modeled (within a root-means-squared-error of 0.01) by the proposed method, and the blood perfusion state of the brain could be monitored via gamma(ij), with small NNs having no more than 21 connection weight altogether.

Significance of colonoscopy in patients with intestinal graft-versus-host disease after hematopoietic stem cell transplantation.

BACKGROUND AND STUDY AIMS: Patients with intestinal graft-versus-host disease (GVHD) are generally in poor clinical condition. In this study we aimed to establish the clinical significance of endoscopic diagnosis of this condition, observing only the distal section of the large intestine. PATIENTS AND METHODS: Endoscopic and pathological findings at colonoscopy were evaluated retrospectively in 12 patients who were diagnosed with intestinal GVHD after undergoing hematopoietic stem cell transplantation. RESULTS: The main mucosal changes observed at endoscopy were granular change, edema, "spotty redness", and sloughing. These were clearly displayed after enhancement with Indigo carmine staining, and with insertion of the colonoscope only as far as the distal section of the large intestine. A histological diagnosis of intestinal GVHD was made in 50 % of the patients, whose intestinal epithelium specimens showed numerous apoptotic bodies. It was possible to perform total colonoscopy in two patients who were in relatively good condition clinically, but there were no remarkable differences in the endoscopic findings throughout the large intestine, from the terminal ileum to the rectum. In terms of clinical outcomes of the 12 patients, their prognosis was poor in that they all either went on to suffer from chronic GVHD or died. CONCLUSIONS: Endoscopic and histological findings on distal colonoscopy are clinically significant in the diagnosis of intestinal GVHD, and limiting this examination to the distal section of the large intestine avoids causing further clinical deterioration in patients who are already in very poor general condition and the possibility of causing endoscopy-related complications.

Systematic identification for inert region of a brain from EEG.

Evaluation of biomedical signals is important in the diagnosis of neurology diseases, such as dementia, in neurology through the use of electroencephalograms (EEG). While automated techniques exist for EEG analysis, it is likely that additional information can be extracted from EEG signal through the use of new methods. We describe a method for identifying inert region from EEG. This method uses EEG as input to an artificial neural network with five outputs: activity in whole regoin and inert region separated by four regions.