Tatsuya Kurihara

MAOA, MTHFR, and TNF-β genes polymorphisms and personality traits in the pathogenesis of migraine

Migraine is a multifactorial disease with various factors, such as genetic polymorphisms and personality traits, but the contribution of those factors is not clear. To clarify the pathogenesis of migraine, the contributions of genetic polymorphisms and personality traits were simultaneously investigated using multivariate analysis. Ninety-one migraine patients and 119 non-headache healthy volunteers were enrolled. The 12 gene polymorphisms analysis and NEO-FFI personality test were performed. At first, the univariate analysis was performed to extract the contributing factors to pathogenesis of migraine. We then extracted the factors that independently contributed to the pathogenesis of migraine using multivariate stepwise logistic regression analysis. Using the multivariate analysis, three gene polymorphisms including monoamine oxidase A (MAOA) T941G, methylenetetrahydrofolate reductase (MTHFR) C677T, and tumor necrosis factor beta (TNF-β) G252Α, and the neuroticism and conscientiousness scores in NEO-FFI were selected as significant factors that independently contributed to the pathogenesis of migraine. Their odds ratios were 1.099 (per point of neuroticism score), 1.080 (per point of conscientiousness score), 2.272 (T and T/T or T/G vs G and G/G genotype of MAOA), 1.939 (C/T or T/T vs C/C genotype of MTHFR), and 2.748 (G/A or A/A vs G/G genotype of TNF-β), respectively. We suggested that multiple factors, such as gene polymorphisms and personality traits, contribute to the pathogenesis of migraine. The contribution of polymorphisms, such as MAOA T941G, MTHFR C677T, and TNF-β G252A, were more important than personality traits in the pathogenesis of migraine, a multifactorial disorder.

Effect of clonazepam and clonidine on primary sleep bruxism: a double-blind, crossover, placebo-controlled trial

The aim of this study was to assess the acute effects of clonazepam and clonidine on rhythmic masticatory muscle activity in young adults with primary sleep bruxism, as well as accompanying effects on sleep architecture and cardiac activity. This study used a double‐blind, crossover, placebo‐controlled design. Polysomnography was performed on 19 subjects [nine men and 10 women; mean age (±SE): 25.4 ± 2.7 years] for 5 nights. The first 2 nights were used for the habituation and diagnosis of sleep bruxism. The other 3 nights were randomly assigned for clonazepam (1.0 mg), clonidine (0.15 mg) or placebo (all administered 30 min before bedtime). Sleep, oromotor activity and cardiac activity variables were assessed and compared among the three drug conditions. Clonidine significantly reduced the median percentage of time spent in the rapid eye movement sleep stage compared with placebo and clonazepam. The number of rhythmic masticatory muscle activity episodes was reduced with clonidine by >30% compared with placebo and clonazepam. The reduction of rhythmic masticatory muscle activity index by clonidine was associated with an increase of mean RR intervals (slower heart rate) during quiet sleep periods and during a 70‐s period before the onset of rhythmic masticatory muscle activity episodes. However, no changes in cardiac activity variables were observed for clonazepam. In young adults with primary sleep bruxism, clonidine was significantly more effective in suppressing sleep bruxism than clonazepam. The acute effects of clonidine on rhythmic masticatory muscle activity episodes may be mediated by suppression of autonomic nervous system activity and non‐rapid eye movement–rapid eye movement sleep processes.

A Cyclooxygenase 2 Gene Polymorphism is a Risk Factor for the Complication of Medication Overuse Headaches in Patients with Migraines

We determined whether cyclooxygenase-2 (COX-2) gene polymorphisms were involved in the aggravation of migraines due to the overuse of medication. Polymorphisms in the COX-2 (rs20417, rs689466) gene were examined. Forty-seven patients with migraine (6 males and 41 females; 5 with migraines with aura (MA), 36 with migraines without aura (MO), 6 with MA + MO; 1 with MA and 21 with MO; 36.4 ± 10.3 years) and 22 patients with medication overuse headache (MOH) (1 male and 21 females; 39.6 ± 9.9 years) who had migraines participated in this study. The genotypes of each polymorphism were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) methods. No significant differences were observed in the genotypic distributions of rs20417 (C/C + G/C vs. G/G, p=0.220) between migraine patients and MOH patients. The frequencies of the rs689466 G/G genotype were significantly higher in patients with MOH than in patients with migraines (G/G vs. A/A+A/G, p=0.008). Furthermore, the frequencies of the rs689466 G/G genotype were significantly higher in patients with MOH who had migraines without aura (MO) than in patients with MO (G/G vs. A/A+A/G, p=0.001). The results of this study showed that the COX-2 polymorphism (rs689466) was independently related with the complication of MOH in patients with MO.

Characteristics of inconsistent responders to prophylaxis therapy with lomerizine in patients with migraine: A retrospective study in Japan

Although lomerizine is used as a first-line prophylactic drug for migraines in Japan, approximately 30% of patients fail to respond to this treatment. On the basis of medical records, we investigated the involvement of clinical factors in response to lomerizine used in patients with migraine as primary headache and established a scoring system for predicting clinical responses to prophylactic therapy. Ninety-four consistent responders and 33 inconsistent responders to lomerizine were enrolled in this study. Multivariate stepwise logistic regression analysis revealed that migraine plus tension-type headache as primary headache and frequency of headache attacks were significant factors that contributed independently to negative response [odds ratio, 3.817 (no vs. yes; 95% confidence interval (CI), 1.264-11.628) and 5.814 (>15 episode days/month vs. 0-14 episode days/month; 95% CI, 2.381-14.286), respectively]. The predictive index (PI) of clinical responses to lomerizine in patients with migraine was calculated using the regression coefficients of two factors as an integer, where the score for inconsistent responders (1.00±0.71) was significantly higher than that for consistent responders (0.37±0.53, p<0.001). Sensibility of the low-scoring group (PI=0) was 75.8%, and specificity of the high-scoring group (PI=2) was 97.9%. Groups scoring low, intermediated and high included 11.6%, 35.4% and 80.0% of inconsistent responders, respectively. The PI value obtained might represent an appropriate scoring system to predict responses in these patients.

Decreased cardiac mitochondrial tetrahydrobiopterin in a rat model of pressure overload

Sustained cardiac pressure overload induces mitochondrial dysfunction and apoptosis of cardiomyocytes leading to pathological cardiac hypertrophy and dysfunction. Mitochondrial nitric oxide synthase (NOS) appears to cause uncoupling, which produces reactive oxygen species (ROS) instead of nitric oxide (NO), by a decrease in the cofactor tetrahydrobiopterin (BH4). This study focused on examining the changes in mitochondrial BH4 levels during cardiac pressure overload. Chronic cardiac pressure overload was generated by abdominal aortic banding in rats. Levels of BH4 and its oxidized form were measured in the mitochondria isolated from the left ventricle (LV) and the post-mitochondrial supernatants. Chronic aortic banding increased blood pressure, and induced cardiac hypertrophy and fibrosis. Notably, the BH4 levels were decreased while its oxidized forms were increased in LV mitochondria, but not in the post-mitochondrial supernatants containing the cytosol and microsome. Anti-neuronal NOS antibody-sensitive protein was detected in the cardiac mitochondria. Moreover, continuous administration of BH4 to rats with pressure overload increased mitochondrial BH4 levels and reduced cardiac fibrosis and matrix metallopeptidase activity, but not cardiac hypertrophy. These findings show the possibility that NOS uncoupling by decreased cardiac mitochondrial BH4 levels is implicated, at least in part, in the development of cardiac fibrosis, leading to cardiac dysfunction induced by pressure overload.

Factors involved in resistance to early treatment of acute cholangitis patients.

BACKGROUND/AIMS Severity-based treatment is not homogenously effective for acute cholangitis patients and some are resistant to early treatment. We performed a retrospective cohort study involving acute cholangitis patients and analyzed factors strongly associated with resistance to early treatment. METHODOLOGY The subjects were 94 patients admitted to the Department of Gastroenterology, Showa University Hospital and diagnosed with acute cholangitis. The endpoint was set as the presence or absence of resistance to early treatment. Background and blood test results of the patients immediately after admission were surveyed and significant factors independently contributing to resistance to early treatment were extracted from the surveyed factors employing a logistic regression model. RESULTS The mean age of the patients was 73.2 ± 11.6 years and 58 were male (61.7%). Jaundice, fever and abdominal pain were observed in 46 (48.9%), 66 (70.2%) and 85 patients (90.4%), respectively. Twenty-eight patients (29.8%) were resistant to early treatment. On multivariate analysis, 3 factors (fever, serum amylase level and systolic blood pressure (below 100 mm Hg)) were extracted as significant factors independently contributing to resistance to early treatment (p<0.05). CONCLUSIONS If such resistance can be predicted before treatment, appropriate treatment may be selected to shorten the persistence of symptoms, improving the patients QOL.

Factors predicting the appearance of neutropenia in patients with advanced pancreatic cancer undergoing gemcitabine therapy.

BACKGROUND/AIM Factors predicting the appearance of neutropenia were evaluated in patients with advanced pancreatic cancer undergoing gemcitabine hydrochloride (GEM) therapy. METHODOLOGY The subjects were 92 patients who were diagnosed with unresectable advanced pancreatic cancer and underwent GEM therapy. Mono- and multivariate analyses were performed concerning each evaluated factor. The toxicity index (TI) was also prepared by combining the extracted predictive factors. RESULTS Severe neutropenia occurred in 26 patients (28.2%). As a result of multivariate analysis, the white blood cell count (WBC), CA19-9 and liver metastasis were extracted as factors independently and significantly contributing to the appearance of severe neutropenia (p<0.05). The TI was prepared by combining these 3 factors and their regression coefficients: TI = 4.777-0.605xWBC (x103/microL)-0.511xlog (CA19-9)-1.285xliver metastasis. CONCLUSIONS The WBC, CA19-9 and liver metastasis before treatment were shown to be related to the appearance of severe neutropenia after GEM therapy.

Clinical Response to Valproate in Patients with Migraine

Background and Purpose Valproate is used as a prophylactic drug for migraine, but it is not be effective in all patients. We used medical records to investigate which clinical factors affected the response to valproate in patients with migraine as an original headache, and established a scoring system for predicting the clinical response to prophylactic therapy. Methods We investigated clinical factors from the medical records of 95 consistent responders (CRs) and 24 inconsistent responders (IRs) to valproate. Results Multivariate stepwise logistic regression analysis revealed that a history of hyperlipidemia and hay fever and the complication of depression or other psychiatric disorder were significant factors that independently contributed to a negative response, with odds ratios of 6.024 [no vs. yes; 95% confidence interval (CI)=1.616–22.222], 2.825 (no vs. yes; 95% CI=1.046–7.634), and 2.825 (no vs. yes; 95% CI=1.052–7.576), respectively. A predictive index (PI) of the clinical response to valproate in patients with migraine was calculated using the regression coefficients of these three factors as an integer, and the index was significantly higher for IRs than for CRs (1.46±1.10 vs. 0.69±0.74, mean±SD, p<0.001). Conclusions The obtained PI may represent an appropriate scoring system for predicting the responses in these patients.

Prognostic Index for Survival in Patients with Advanced Non-Small-Cell Lung Cancer Treated with Third-Generation Agents

We retrospectively evaluated clinical data from patients with advanced non-small-cell lung cancer (NSCLC) treated with third-generation chemotherapy agents prior to treatment, to determine a reliable method for predicting prognosis in such patients. We analyzed 100 patients who received third-generation agents (paclitaxel, docetaxel, gemcitabine, irinotecan, and vinorelbine) for the treatment of advanced NSCLC. Factors significantly related to prognosis were evaluated using the Cox regression model, and the prognostic index (PI) was determined by combining these factors. The mean follow-up duration was 12.6 months (0.2-67.0 months). Multivariate analysis identified pleural effusion, absolute neutrophil count (ANC), and C-reactive protein (CRP) level as significant factors that independently contribute to prognosis in patients with advanced NSCLC treated with third-generation agents (p < 0.05). The PI was calculated using these 3 factors, according to the following formula: PI = 0.581 × pleural effusion + 0.125 × ANC + 0.105 × CRP. The death rate in the group with the highest PI scores was significantly higher than in the group with the lowest scores (p < 0.001). Pleural effusion, ANC, and CRP level were the most important factors that contributed to prognosis following chemotherapy with third-generation agents in patients with advanced NSCLC. The PI is suggested to be an appropriate index to predict the prognosis of patients with NSCLC.