Analysis of the NUDT15 gene and metabolites of azathioprine in Japanese patients with inflammatory bowel disease.

BACKGROUND: Thiopurines continue to play an important role in the treatment of inflammatory bowel disease (IBD). It is well known that thiopurines can cause several adverse reactions. Especially, hematopoietic toxicity may lead to severe agranulocytosis. In a previous prospective study, we investigated the relationship between inosine triphosphate pyrophosphatase (ITPA) c.94c > a polymorphism, 6-thioguanine nucleotide (6-TGN) concentration and toxicity. METHODS: To clarify the cause of thiopurine toxicity, we analysed nucleoside disphosphate-linked moiety X-type motif 15 (NUDT15) gene polymorphisms, i.e., R139C, V18I, and V19_V19insGV, and measured 6-mercaptopurines and 6-methylmercaptopurines (6-MMP) using the archived blood samples collected from 49 IBD patients for our previous study. RESULTS: The ITPA c.94c > a polymorphism was detected in 19 patients (38.7%, all heterozygous). The R139C polymorphism was found in 10 patients (20.4%, 1 homozygous, 9 heterozygous), V18_V19insGV in 7 patients (14.3%, all heterozygous), and V18I in 2 patients (4.08%, all heterozygous). Although R139C was more strongly associated with leukopenia than c.94c > a, there were no significant correlations with 6-TGN and 6-MMP levels, as for c.94c > a. The leukopenia incidence rates for each gene polymorphism were 0% in those with all wild-type genes, 21.4% for c.94c > a only, 42.9% for NUDT15 polymorphism (s) only, and 80.0% for both polymorphisms. CONCLUSIONS: All cases of leukopenia were associated with ITPA c.94c > a and/or polymorphism of NUDT15 and the risk of developing leukopenia was synergistically increased by ITPA and NUDT15 gene polymorphism. However, there was no association between the level of azathioprine metabolites and these polymorphisms.

The insoluble excretion of multi-matrix system mesalazine preparations in patients with ulcerative colitis.

BACKGROUND: Multi-matrix mesalazine (MMX) is an important treatment for ulcerative colitis (UC); however, it is often excreted intact, which increases the risk of relapse. This study aimed to clarify the risk factors for insoluble MMX excretion. METHODS: The subjects were 102 UC patients who were newly prescribed MMX alone to induce remission. Their stools were evaluated on the Bristol Stool Form Scale (BSFS), the presence/absence of insoluble MMX excretion was investigated in interviews, and defecation frequency at the start of treatment and disease type were retrospectively investigated by examining their medical records. RESULTS: The insoluble excretion rate (IER) was 14.7%. It tended to be higher in the patients with left-sided colitis or extensive colitis, although the differences among the disease types were not significant (p = 0.053). The mean defecation frequency of the patients that reported insoluble MMX excretion was significantly higher than that of the patients that did not report it (6.27 ± 5.28 vs. 3.69 ± 3.17, p < 0.05). The IER tended to be higher among the patients with soft stools (4.5%, 21.9%, and 23.1% in those with BSFS scores of ≤ 4, 5, and ≥ 6, respectively). In ROC analysis of defecation frequency, ≥ 3.5 defecations was found to exhibit sensitivity and specificity of 66.7% and 65.5%, respectively, for predicting insoluble MMX excretion. CONCLUSIONS: The likelihood of insoluble MMX excretion is influenced by defecation frequency and the extent of inflammation. It is important to keep the possibility of insoluble excretion in mind when prescribing MMX.

Development of Social Attention and Oxytocin Levels in Maltreated Children.

Child maltreatment (CM) is a major risk factor for various psychopathologies but also adversely affects social development. Research on oxytocin (OT) is currently drawing attention as an endocrine basis for social development. In this study, we investigated the relationship between visual attention to social cues and salivary OT levels in children exposed to CM. The results revealed that the CM group had a significantly lower percentage of gaze fixation for the human face eye area and lower salivary OT levels compared to the typical development group. Moreover, a path analysis suggested that gaze fixation for the eye area was a mediator of the relationship between salivary OT levels and social-emotional problems in the CM group. These results suggest that lower endogenous OT levels in maltreated children may lead to atypical development of their visual attention to eyes as a social cue, resulting in social-emotional problems.

Influence of block-out on retentive force of thermoplastic resin clasps: an in vitro experimental and finite element analysis.

PURPOSE: The purpose of this study was to determine the effect of block-out preparation, used to eliminate the undercut area, on the retentive force and stress distribution of resin clasps. METHODS: A total of 72 polyester and polyamide resin clasps were fabricated on a premolar abutment crown following six block-out preparations. A combination of two types of vertical block-outs and three types of horizontal block-outs (on the missing side) was used on the abutment tooth. Each clasp was subjected to an in vitro removal test using a universal testing machine. The retentive force and traces of the clasp on the abutment tooth were recorded and analyzed with one-way analysis of variance and post hoc comparisons (α=0.05). Non-linear finite element analysis was performed to assess the stress distributions of the resin clasps. RESULTS: Resin clasps with a vertical block-out of 0.75mm undercut showed significantly higher retentive force than those with the 0.5mm undercut. Resin clasps with horizontal block-out showed significantly lower retentive force than those without horizontal block-out. There was no significant difference between the two thermoplastic resins. The maximum first principal stress of the resin clasp was concentrated under the shoulder of the clasp and strongly influenced by the width of horizontal block-out in the finite element analysis. CONCLUSIONS: This in vitro experiment suggested that a horizontal block-out is necessary even for a 0.5-mm undercut. The design of the resin clasp should be considered from two aspects: retentive force and deformation risk.

FADS2 and ELOVL6 mutation frequencies in Japanese Crohn's disease patients.

Crohn's disease (CD) development is thought to involve genetic factors related to immune response as well as environmental factors, such as intestinal bacteria and diet, though no clear cause has yet been identified. In our previous study, we found that the concentrations of linoleic acid, stearic acid, and metabolites in erythrocytes differed between CD patients and healthy subjects. These factors related to lipid metabolism are controlled by Δ6 desaturase (fatty acid desaturase 2, FADS2) and elongase 6 (ELOVL6), respectively. In the present study, we analyzed the gene sequences of FADS2 and ELOVL6 in 52 Japanese CD patients, and then compared mutation frequencies with findings in healthy individuals. Nineteen FADS2 mutations and 33 ELOVL6 mutations were found. Furthermore, a new variant in the promoter region was shown in both genes, though no mutation in the coding region was found in either. For the FADS2 intron, the allele frequency of rs227784 (0.3365; 95% CI = 0.0337-0.01460) was higher than that in healthy subjects (0.0190). Furthermore, allele rs227784 had a greater association with CD (odds ratio = 4.4; 95% CI = 2.1-9.3). As compared with healthy Japanese healthy individuals, no mutations were found with a largely deviated allele frequency in the present CD group. However, the number of patients examined was small, thus the reliability of our results is limited. The present findings regarding genetic effects on CD onset and lipid metabolism may be weak.

Prevalence and clinical characteristics of cortical superficial siderosis in patients with acute stroke.

Cortical superficial siderosis (cSS) is a pathologic and radiologic diagnosis of hemosiderin deposition in subpial brain layers. However, cSS has not been fully studied in patients with acute stroke. Here, we investigated the prevalence of cSS in patients with acute stroke and analyzed the relationship between cSS and different clinical and neuroimaging characteristics. From September 2014 through June 2016, consecutive patients with acute stroke who were admitted to our department were retrospectively investigated. We analyzed the prevalence of cSS and the associations between cSS and risk factors, the topographic distribution of cerebral microbleeds (CMBs), and the severity of white matter lesions (WMLs). In total, 739 patients (589 patients with ischemic stroke/transient ischemic stroke [IS/TIA] and 150 with intracerebral hemorrhage [ICH]; mean age, 71.4 years) were enrolled. We identified cSS in six (1.0%) patients with IS/TIA and seven (4.7%) patients with ICH. The presence of cSS was associated with ICH (P < 0.0001), WMLs (P = 0.0105), and lobar and non-lobar CMBs (both P < 0.0001); no associations between cSS and age, sex, cardiovascular risk factors, IS subtype classification, or antiplatelet and anticoagulant therapy were found. In a multivariable logistic regression analysis, high numbers of lobar CMBs (≥ 2; odds ratio, 11.03; 95% confidence interval, 2.03-205.40; P = 0.0029) were independently associated with cSS. Furthermore, cSS was often located near lobar CMBs. Our results suggest that cSS is prevalent in ICH and is independently associated with lobar CMBs; however, no associations between cSS and other risk factors or comorbidities were observed.

Thrombolysis, Complete Recanalization, Diffusion Reversal, and Luxury Perfusion in Hyperacute Stroke.

A 59-year old man was admitted to our stroke care unit 1.8 hours after onset of cardioembolic stroke. Administration of issue-plasminogen activator achieved complete recanalization, and his lesion on diffusion-weighted imaging (DWI) disappeared and single photon emission computed tomography showed luxury perfusion. DWI reversal and luxury perfusion were sometimes observed in hyperacute stroke patients, especially timely reperfusion was achieved. However, the relationships between DWI reversal and luxury perfusion were not well known. Transient DWI reversal may be associated with luxury perfusion in patients treated with t-PA, via early complete recanalization achieved by thrombolysis.

Galantamine attenuates reinstatement of cue-induced methamphetamine-seeking behavior in mice.

Methamphetamine (METH) dependence is becoming a serious socioeconomic health problem worldwide. The enhancement of the cholinergic nervous system is expected to greatly alleviate drug dependence. We investigated the effect of galantamine on the reinstatement of cue-induced METH-seeking behavior using a self-administration experiment. Treatment with galantamine (1 mg/kg, p.o.) 30 minutes before exposure to the cues suppressed the reinstatement of METH-seeking behavior. However, galantamine did not affect the cue-induced reinstatement of food-seeking behavior or locomotor activity. These results suggest that galantamine may be a candidate drug for treating relapses of METH-seeking behavior.

Exposure to enriched environments during adolescence prevents abnormal behaviours associated with histone deacetylation in phencyclidine-treated mice.

Enriched environments (EEs) during development have been shown to influence adult behaviour. Environmental conditions during childhood may contribute to the onset and/or pathology of schizophrenia; however, it remains unclear whether EE might prevent the development of schizophrenia. Herein, we investigated the effects of EE during adolescence on phencyclidine (PCP)-induced abnormal behaviour, a proposed schizophrenic endophenotype. Male ICR mice (3 wk old) were exposed to an EE for 4 wk and then treated with PCP for 2 wk. The EE potentiated the acute PCP treatment-induced hyperlocomotion in the locomotor test and prevented chronic PCP treatment-induced impairments of social behaviour and recognition memory in the social interaction and novel object recognition tests. It also prevented the PCP-induced decrease of acetylated Lys9 in histone H3-positive cells and increase of the histone deacetylase (HDAC)5 level in the prefrontal cortex. To investigate whether the histone modification during adolescence might be critical for the effect of EE, 3-wk-old mice were first treated with sodium butyrate (SB; an HDAC inhibitor) for 4 wk and then treated with PCP for 2 wk. Chronic SB treatment during adolescence mimicked the effects of EE, including potentiation of hyperlocomotion induced by acute PCP treatment and prevention of social and cognitive impairments, decrease of acetylated Lys9 in histone H3-positive cells and increase of the HDAC5 level in the prefrontal cortex associated with chronic PCP treatment. Our results suggest that EEs prevent PCP-induced abnormal behaviour associated with histone deacetylation. EEs during childhood might prove to be a novel strategy for prophylaxis against schizophrenia.