A genome-wide association study of coping behaviors suggests FBXO45 is associated with emotional expression.

Individuals use coping behaviors to deal with unpleasant daily events. Such behaviors can moderate or mediate the pathway between psychosocial stress and health-related outcomes. However, few studies have examined the associations between coping behaviors and genetic variants. We conducted a genome-wide association study (GWAS) on coping behaviors in 14088 participants aged 35 to 69 years as part of the Japan Multi-Institutional Collaborative Cohort Study. Five coping behaviors (emotional expression, emotional support seeking, positive reappraisal, problem solving and disengagement) were measured and analyzed. A GWAS analysis was performed using a mixed linear model adjusted for study area, age and sex. Variants with suggestive significance in the discovery phase (N = 6403) were further examined in the replication phase (N = 7685). We then combined variant-level association evidence into gene-level evidence using a gene-based analysis. The results showed a significant genetic contribution to emotional expression and disengagement, with an estimation that the 19.5% and 6.6% variance in the liability-scale was explained by common variants. In the discovery phase, 12 variants met suggestive significance (P < 1 × 10-6 ) for association with the coping behaviors and perceived stress. However, none of these associations were confirmed in the replication stage. In gene-based analysis, FBXO45, a gene with regulatory roles in synapse maturation, was significantly associated with emotional expression after multiple corrections (P < 3.1 × 10-6 ). In conclusion, our results showed the existence of up to 20% genetic contribution to coping behaviors. Moreover, our gene-based analysis using GWAS data suggests that genetic variations in FBXO45 are associated with emotional expression.

The relationship of brachial-ankle pulse wave velocity to future cardiovascular disease events in the general Japanese population: the Takashima Study.

Brachial-ankle pulse wave velocity (baPWV) is a non-invasive measure of arterial stiffness obtained using an automated system. Although baPWVs have been widely used as a non-invasive marker for evaluation of arterial stiffness, evidence for the prognostic value of baPWV in the general population is scarce. In this study, we assessed the association between baPWV and future cardiovascular disease (CVD) incidence in a Japanese population. From 2002 to 2009, baPWV was measured in a total of 4164 men and women without a history of CVD, and they were followed up until the end of 2009 with a median follow-up period of 6.5 years. Hazard ratios (HRs) for CVD incidence according to baPWV levels were calculated using a Cox proportional hazards model adjusted for potential confounding factors, including seated or supine blood pressure (BP). During the follow-up period, we observed 40 incident cases of CVD. In multivariable-adjusted model, baPWV as a continuous variable was not significantly associated with future CVD risk after adjustment for supine BP. However, compared with lower baPWV category (<18 m s(-1)), higher baPWV (< or = 18.0 m s(-1)) was significantly associated with an increased CVD risk (HR: 2.70, 95% confidence interval: 1.18-6.19). Higher baPWV (< or = 18.0 m s(-1)) would be an independent predictor of future CVD event in the general Japanese population.

Is there any circadian variation consequence on acute case fatality of stroke? Takashima Stroke Registry, Japan (1990-2003).

BACKGROUND: Circadian periodicity in the onset of stroke has been reported. However, it is unclear whether this variation affects the acute stroke case fatality. Time of the day variation in stroke case fatality was examined using population-based stroke registration data. METHODS: Stroke event data were acquired from the Takashima Stroke Registry, which covers a stable population of approximately 55,000 in Takashima County in central Japan. During the period of 1990-2003, there were 1080 (549 men and 531 women) cases with classifiable stroke onset time. Stroke incidence was categorized as occurring at night (midnight-6 a.m.), morning (6 a.m.-noon), afternoon (noon-6 p.m.), and evening (6 p.m.-midnight). The 28-day case fatality rates and 95% confidence intervals (95% CI) were calculated by gender, age, and stroke subtype across the time blocks. After adjusting for gender, age at onset, and stroke severity at onset, the hazard ratios for fatal strokes in evening, night, and morning were calculated, with afternoon serving as the reference. RESULTS: For all strokes, the 28-day case fatality rate was 23.3% (95% CI:19.4-27.6) for morning onset, 16.9% (95% CI:13.1-21.6) for afternoon onset, 18.3% (95% CI:13.6-24.1) for evening onset, and 21.0% (95% CI:15.0-28.5) for the night onset stroke. The case fatality for strokes during the morning was higher than the case fatality for strokes during afternoon. This fatality risk excess for morning strokes persisted even after adjusting for age, gender, and stroke severity on onset in multivariate analysis. CONCLUSION: In the examination of circadian variation of stroke case fatality, 28-day case fatality rate tended to be higher for the morning strokes.

Morning surge in circadian periodicity of ischaemic stroke is independent of conventional risk factor status: findings from the Takashima Stroke Registry 1990-2003.

BACKGROUND: We examined the circadian periodicity of ischaemic stroke (IS) onset and its relationship with conventional risk factors using 14-year stroke registration data. METHODS: Ischaemic stroke event data were acquired from the Takashima Stroke Registry, which covers a stable population of approximately 55,000 in Takashima County in central Japan. During 1990-2003 there were 637 (353 men and 284 women) cases with classifiable onset time. IS incidence was categorized as occurring at night (midnight to 6 am), morning (6 am to noon), afternoon (noon to 6 pm), and evening (6 pm to midnight). The OR (with 95% CI) of having an IS in the morning, afternoon, and evening were calculated, with night serving as reference. RESULTS: There was significant diurnal variation in IS incidence (P < 0.001). The proportion of events was highest in the morning (40.7; 95% CI: 36.9-44.5), and lowest in the night (14.0; 95% CI: 11.5-16.9). In the morning an excess incidence of IS was observed in both genders, in subjects <65 years and > or =65 years, and in all IS subtypes. The morning excess of IS incidence was similar across seasons and days of the week. For all IS, morning excess was higher (odds ratio: 2.91; 95% CI: 2.29-3.70) compared to the night period. Similar trends persisted after adjusting for age, gender, and risk factors. CONCLUSION: In the examination of circadian variation of IS onset, a predominant morning peak independent of conventional risk factors was observed in a Japanese population with similar pattern across seasons of the year and days of the week.

High blood pressure in middle age is associated with a future decline in activities of daily living. NIPPON DATA80.

Although several studies have reported on the relation between high blood pressure (BP) and impaired activities of daily living (ADL), only a few studies have reported on the relation of high BP in middle-aged subjects with future impaired ADL. Furthermore, no studies reported an excess impaired ADL due to non-normal BP. Using ADL 1999 data, we compared data from NIPPON DATA80 survivors without impaired ADL (N=1816) with those with impaired ADL (N=75) using baseline BP information collected in 1980. We analysed participants who were aged 47-59 years at baseline. Multiple adjusted logistic regression analyses were used to estimate the risk of impaired ADL, according to baseline BP categories using Joint National Committee 7 guidelines (normal BP, prehypertension, stage 1 hypertension (HT) and stage 2 HT). Subjects who used antihypertensive medications were classified as having stage 2 HT. We calculated excess impaired ADL due to non-normal BP. Compared with normal BP categories, the adjusted odds ratio (OR) and 95% confidence interval (CI) of having impaired ADL was higher in subjects with prehypertension (OR=1.50, 95% CI: 0.55-4.09), stage 1 HT (OR=1.56, 95% CI: 0.56-4.32) and stage 2 HT (OR=2.96, 95% CI: 1.09-8.05). Non-normal BP explained 45% (33.7/75) of impaired ADL. A positive relation of BP categories with the composite end point of mortality and impaired ADL was also observed. In conclusion, controlling BP in middle age may prevent deaths and future ADL decline.

Gene expression profiling of the response of esophageal carcinoma cells to cisplatin.

Cisplatin is the most common chemotherapeutic agent used in esophageal cancer. However, sensitivity to cisplatin varies greatly between patients. It is important to identify the gene(s) that are related to the sensitivity to cisplatin in esophageal cancer patients. The IC50 for cisplatin was measured for 15 esophageal cancer cell lines (TE1-5, TE8-15, KYSE140, and KYSE150). RNA was extracted from each of these cell lines and a normal esophageal epithelial cell line, namely, Het1A, and gene expression profiles were analyzed using an oligonucleotide microarray consisting of 34 594 genes. TE4 was highly resistant and TE12, 14, and 15 were sensitive to cisplatin. Thirty-seven genes were differentially expressed in the cisplatin-resistant esophageal cancer cell line. Our investigation provides a list of candidate genes that may be associated with resistance to cisplatin in esophageal cancer cells, which may serve as a basis for additional functional studies.

Decreased expression of NDRG1 is correlated with tumor progression and poor prognosis in patients with esophageal squamous cell carcinoma.

NDRG1 (N-myc downstream regulated gene-1) was reported to be necessary for p53-mediated apoptosis and to be regulated by PTEN (phosphatase and tensin homolog). In several cancers, it was suggested to be a tumor suppressor gene. Its significance in esophageal squamous cell carcinoma (ESCC) has not been studied. The objective of this study was to clarify the relation between clinicopathological and biologic factors in esophageal carcinoma and to determine the prognostic significance of the expression of NDRG1. Expression of NDRG1 mRNA was quantified by real-time reverse transcription polymerase chain reaction using a Lightcycler in 47 esophageal ESCC specimens. The data were analyzed with reference to clinicopathological factors. Among the esophageal cancer tissues, NDRG1 mRNA expression was significantly lower in tumors of more advanced pathological stage (0-I vs. II-IV; P = 0.0027) and local tumor invasion (T1-2 vs. T3-4; P = 0.0136). Patients who had low NDRG1 mRNA expression had a significantly shorter survival after surgery compared with patients who had high NDRG1 mRNA expression (log-rank test, P = 0.0478). Impaired NDRG1 expression may lead to more aggressive invasion of ESCC.

Expression of the Per1 gene in the hamster: brain atlas and circadian characteristics in the suprachiasmatic nucleus.

Recent progress in study on the molecular component of mammalian clocks has claimed that mammals and Drosophila share the similar fundamental clock oscillating system. In the present study, we investigated expression of Per1, the first gene of the mammalian homolog of the Drosophila clock gene period, in the hamster brain, and we also examined its circadian expression pattern in the mammalian clock center, the suprachiasmatic nucleus (SCN). In situ hybridization using isotope-labeled cRNA probes revealed a wide and region-specific distribution of Per1 in the hamster brain and spinal cord. High levels of Per1 were found in the internal granular layer of the granular cells of the olfactory bulb, anterior olfactory nuclei, tenia tecta, olfactory tubercle, piriform cortex, suprachiasmatic nucleus, and gyrus dentatus of hippocampus. Moderate levels of expression were detected in many brain regions including the granular layer of the cerebellum, anterior paraventricular thalamic nucleus, caudate-putamen, inferior colliculus, pontine nuclei, inferior olive, and nucleus of the solitary tract. We examined the circadian profile of hamster Per1 mRNA in the SCN in constant darkness and found that Per1 expression showed a peak at subjective day (circadian time [CT] 4) and formed a trough at subjective night (CT16-CT20). A brief exposure of light at CT16 could acutely induce large quantities of Per1 mRNA in the hamster SCN, except for its dorsomedial subdivision. These findings suggest that the characteristics of Per1 gene expression in the mammalian circadian center (showing a peak in the daytime and a trough in the nighttime and a rapid inducibility by light) are common among mammalian species. Lastly, in hamster brain, Per1 gene is also inducible in extra-SCN brain nuclei, since light at night also elicited Per1 mRNA in neurons of the hypothalamic paraventricular nucleus.

A light-independent oscillatory gene mPer3 in mouse SCN and OVLT.

A new member of the mammalian period gene family, mPer3, was isolated and its expression pattern characterized in the mouse brain. Like mPer1, mPer2 and Drosophila period, mPer3 has a dimerization PAS domain and a cytoplasmic localization domain. mPer3 transcripts showed a clear circadian rhythm in the suprachiasmatic nucleus (SCN). Expression of mPer3 was not induced by exposure to light at any phase of the clock, distinguishing this gene from mPer1 and mPer2. Cycling expression of mPer3 was also found outside the SCN in the organum vasculosum lamina terminalis (OVLT), a potentially key region regulating rhythmic gonadotropin production and pyrogen-induced febrile phenomena. Thus, mPer3 may contribute to pacemaker functions both inside and outside the SCN.

A new mammalian period gene predominantly expressed in the suprachiasmatic nucleus.

BACKGROUND: In mammals, two possible clock genes (Clock, Per1) have very recently been reported. mPer1 (the first identified mouse period gene), in particular, shows a circadian expression in suprachiasmatic nuclei (SCN), the mammalian circadian centre. However, only mPer1 and Clock as clock components may not be sufficient to understand all the events in circadian oscillation and entrainment. RESULTS: A mammalian period complementary DNA, mPer2, has been isolated from the mouse brain. The amino acid sequence of mPer2 is similar to mPer1 and Drosophila Period (dPer), indicating that mPer2 is a member of the family which contains mPer1, itself a homologue of dPer. mPer2 mRNA is predominantly expressed in SCN. A robust circadian rhythmic expression in the SCN supports the view that mPer2 is a clock gene. mPer2 is strongly expressed at the subjective afternoon in constant darkness, distinct from a morning-phase clock mPer1. Our precise quantitative in situ hybridizations have revealed that the peak expression of mPer2 transcripts is delayed by 8 h in LD (light-dark) or 4 h in DD (dark-dark) conditions when compared to mPer1. A short brief light exposure at the early subjective night, prompting a phase-shift in locomotor rhythms, induces a transient increase of mPer2 transcripts with delayed onset, as compared to mPer1 mRNA induction. Furthermore, mPer2 is co-expressed with mPer1 in single SCN cells. CONCLUSIONS: Mammalian period genes show molecular heterogeneity, each of which is composed of a different oscillator, and may serve to establish stable circadian rhythms in mammalian oscillating cells.

Significance of glomerular deposition of apolipoprotein (a) in various glomerulopathies.

Apolipoprotein (a) [apo(a)] may interfere with the fibrinolytic system because of its structural similarity to plasminogen. In the present study, we evaluated the effect of glomerular deposition of apo(a) on coagulation and fibrinolysis in patients with glomerular diseases. Twenty-four patients (13 males and 11 females) with various glomerulopathies were studied. We examined renal biopsy specimens for the presence of apo(a), and investigated the relationship between the glomerular deposition of apo(a) and coagulation and fibrinolysis within the glomeruli. The patients who exhibited the deposition of apo(a) (group A) had a significantly higher incidence of deposition of apo B-100 and low-density lipoprotein (LDL) receptor, and a significantly lower incidence of deposition of plasmin-alpha 2-plasmin inhibitor complexes (PIC) and tissue-type plasminogen activator than did patients without apo(a) deposition (group B). Patients in group A had a significantly higher level of serum total cholesterol and lipoprotein (a) than did patients in group B. Plasma levels of PIC and D-dimer in group A were significantly lower than those in group B. The plasma level of thrombin-antithrombin III complexes in group A was significantly higher than that in group B. These findings suggest that glomerular apo(a) deposition plays a part in coagulation and fibrinolysis within the glomeruli in patients with glomerular diseases.

Gel chromatographic analysis of cyclosporin and its metabolites in human blood compartments.

Gel chromatography combined with specific and non-specific cyclosporin radioimmunoassays was adopted for quantitative analysis of cyclosporin and metabolites in free and protein-bound forms in blood compartments of kidney transplant patients. The analytical method was proved to be useful for the purpose, although plasma protein-bound forms of neither cyclosporin nor metabolites could be quantitated in the system. The present study also provided, by gel chromatographic analysis, additional examples to prove that concentrations of cyclosporin metabolites in blood compartments may not be deduced or inferred simply from those of cyclosporin.

Visceral epithelial cells in rat glomerular cell culture.

The purpose of this study was to identify and characterize visceral epithelial cells (VECs) of renal glomeruli in culture. Such cells have been described variably as regular, polygonal cells showing a high rate of replication and a cobblestone-like appearance at confluence and also as irregular, arborized and often multinucleated cells showing a very limited proliferative capacity. We examined early outgrowths from the glomeruli by immunofluorescence microscopy using antibodies specific for VECs (anti-podocalyxin(1A), anti-pp44 and 5-1-6), for endothelial cells (anti-von Willebrand factor (vWF) and RECA-1) and for mesangial cells (anti-Thy-1). 1A and anti-pp44 reacted with several types of irregular, arborized cells, but never with regular, polygonal cells. 5-1-6 did not react with any of the cells. Neither the 1A- nor anti-pp44-positive cells (1A/pp44(+) cells) stained with anti-vWF, RECA-1 or anti-Thy-1. However, all the 1A/pp44(+) cells expressed desmin and vimentin but not cytokeratin. These results show that the 1A/pp44(+) cells are derived from VECs, supporting the idea that most polygonal cells in glomerular cultures are of parietal epithelial origin.

[Clinical effects of FUT-187 in reflux esophagitis after gastrectomy].

FUT-187 was orally administered to 38 patients with postgastrectomy reflux esophagitis for 4 weeks. The drug reduced the chief subjective symptoms of reflux esophagitis, such as heartburn, chest pain, precordial pain, and dysphagia for solids in 78.1% of patients. Redness, edema and erosion were also reduced in 53.3% of patients as determined endoscopically. Overall, FUT-187 exhibited an excellent therapeutic effect on the reflux esophagitis which was refractory to conventional treatments.

Effect of traditional Chinese medicine (sairei-to) on monoclonal antibody-induced proteinuria in rats.

The effects of traditional Chinese medicine (Sairei-to) on monoclonal antibody (mAb) inducing proteinuria were examined. Four hundred, 200 and 100 mg/kg body weight (BW) of Sairei-to and phosphate-buffered saline (PBS) as a control were injected intraperitoneally into four groups of female Wistar rats every day from 5 days before intravenous injection of mAb to the end of the experimental period. The amount of urinary protein excretion was significantly suppressed in roughly a dose-dependent manner. For example, 116.6 +/- 89.7 mg/day of proteinuria was observed in control groups compared to 4.2 +/- 15.2 mg/day in the 400 mg/kg BW of Sairei-to treated group 2 days after mAb injection (P < 0.01). Statistically significant (P < 0.01) differences were again observed in a repeat experiment (122.1 +/- 53.7 vs 10.2 +/- 10.1 mg/day on the 2nd day) without affecting the glomerular filtration rate. No significant difference was recognized between the total amount of mAb bound to glomeruli 1 h after mAb injection in Sairei-to-treated and non-treated rats, indicating that Sairei-to pretreatment has no effects on the number or quality of antigenic molecules. The effect of Sairei-to on a non-immunological model of proteinuria was also examined. No significant reduction of proteinuria by similar Sairei-to treatment was observed in aminonucleoside of puromycin nephropathy. The authors conclude that mAb-induced proteinuria in rats is significantly suppressed by the traditional Chinese medicine, Sairei-to.

Change in fibrinolytic activity as a parameter for assessing local mechanical stimulation during physical exercise.

The influences of mechanical force during physical exercise on blood coagulation and fibrinolysis were investigated and the effects of sports equipment, especially shoes were also examined. As an experimental model, local mechanical vibration was applied to the palm of the hand. General coagulation parameters did not change, but fibrinolytic activity was elevated due to the tissue plasminogen activator (t-PA) released from vascular endothelial cells stimulated by vibration. The influence of mechanical stimulation by repeated side-jumping with bare feet was examined on the sole of the foot. As with t-PA, the von Willebrand Factor antigen (vWF:Ag) derived from vascular endothelial cells also tended to increase, but not as much as when wearing sports shoes. Sports shoes protected the blood vessels of the feet from damage by mechanical force during physical exercise. Changes in fibrinolytic activity and t-PA could be useful for assessing local mechanical stimulation during physical exercise and also as indexes for the development of new sports equipment and its improvement.

Significance of glomerular deposition of plasmin-alpha 2-plasmin inhibitor complexes in various glomerulopathies.

To elucidate the relationship between glomerular deposition of plasmin-alpha 2-plasmin inhibitor complexes (PIC) and renal lesions or dysfunction, 25 patients with various glomerulopathies and various degrees of renal injuries were examined. Glomerular PIC deposition was found in eight patients (group A), and other 17 patients showed no deposition (group B). PIC was found mainly in the mesangium and along the capillary loops. Group A showed significantly more severe hematuria (p < 0.05) than group B. Group A showed a significant decrease in glomerular filtration rate (GFR; p < 0.05): the mean values being 60.8 +/- 39 in group A and 94.5 +/- 32 ml/min in group B. Group A showed a significant decrease in the phenolsulfonphthalein excretion test (p < 0.05). There was no significant difference in the mean values of plasma PIC, D-dimer, and thrombin-antithrombin III complexes (TAT) between two groups. Histologically, group A showed a significantly high incidence of adhesion (p < 0.05), crescentic formation (p < 0.05), endothelial swelling and/or detachment (p < 0.01), tubulointerstitial changes (p < 0.01), and glomerular deposition of platelet factor 4 (p < 0.01). The present study demonstrates that glomerular PIC deposition reflects the existence of activation of coagulation and fibrinolysis within the glomeruli and suggests that glomerular PIC deposition plays a part in the progression of renal injuries in various glomerulopathies.

Comparative free radical scavenging action of angiotensin-converting enzyme inhibitors with and without the sulfhydryl radical.

The free radical scavenging effects of an angiotensin-converting enzyme (ACE) inhibitor containing sulfhydryl (SH; captopril) were compared with those of ACE inhibitors not containing SH (enalapril, enalaprilat, delapril and its de-esterified products). Electron spin resonance (ESR) using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as the spin trap showed that enalapril and delapril (0.6-4.8 mmol/l) inhibited hydroxyl radicals concentration-dependently. Captopril (2.4-10 mmol/l), enalaprilat and the de-esterified product of delapril (1.2-4.8 mmol/l) also inhibited hydroxyl radicals in a concentration-dependent manner. The effects of captopril and enalapril (2.4-4.8 mmol/l) on the scavenging of superoxide anion radical were also concentration-dependent. Delapril, its de-esterified product, and enalaprilat weakly inhibited superoxide anion radical. These results indicate that both SH- and non-SH-containing ACE inhibitors scavenge hydroxyl radical more strongly than the superoxide anion radical and that the free radical scavenging action of ACE inhibitors is probably not related only to the presence of the SH radical.