Comparison of uninterrupted anticoagulation with dabigatran etexilate or warfarin in the periprocedural period for atrial fibrillation catheter ablation: Results of the Japanese subgroup of the RE-CIRCUIT trial.

Background: There are limited data on uninterrupted anticoagulation with direct oral anticoagulants during catheter ablation for atrial fibrillation (AF), particularly in Japan. We planned a subgroup analysis of the RE-CIRCUIT study, comparing the use of uninterrupted dabigatran therapy with warfarin therapy during catheter ablation among the Japanese subgroup and with that in the total population. Methods: The RE-CIRCUIT study utilized a prospective, randomized, open-label, blinded endpoint design, and the primary endpoint was the incidence of major bleeding events (MBEs). Patients were randomized to uninterrupted dabigatran 150 mg twice daily or warfarin. In this study, we analyzed the results in Japanese patients. Results: Of 704 enrolled patients in the study, 112 Japanese patients were randomized to dabigatran (n = 65) or warfarin (n = 47). MBEs were experienced by two patients: one in the dabigatran group (1.6%, cardiac tamponade) and one in the warfarin group (2.2%, groin hematoma) (risk difference vs warfarin -0.6%; 95% CI -5.8, 4.7). Within the Japanese subgroup, there were no thromboembolic events in both groups. Conclusion: While not designed to show statistical difference between two treatment groups, our results from the Japanese subgroup supported those from the overall population. Furthermore, this study provided clinical information regarding MBE, especially cardiac tamponade, in Japanese patients.

Impaired CNS leptin action is implicated in depression associated with obesity.

Recent epidemiological studies indicate that obesity increases the incidence of depression. We examined the implication of leptin for obesity-associated depression. Leptin induced antidepressive behavior in normal mice in a forced swimming test (FST), and leptin-overexpressing transgenic mice with hyperleptinemia exhibited more antidepressive behavior in the FST than nontransgenic mice. In contrast, leptin-deficient ob/ob mice showed more severe depressive behavior in the FST than normal mice, and leptin administration substantially ameliorated this depressive behavior. Diet-induced obese (DIO) mice fed a high-fat diet showed more depressive behavior in the FST and in a sucrose preference test compared with mice fed a control diet (CD). In DIO mice, leptin induced neither antidepressive action nor increment of the number of c-Fos immunoreactive cells in the hippocampus. Diet substitution from high-fat diet to CD in DIO mice ameliorated the depressive behavior and restored leptin-induced antidepressive action. Brain-derived neurotrophic factor concentrations in the hippocampus were significantly lower in DIO mice than in CD mice. Leptin administration significantly increased hippocampal brain-derived neurotrophic factor concentrations in CD mice but not in DIO mice. The antidepressant activity of leptin in CD mice was significantly attenuated by treatment with K252a. These findings demonstrated that leptin induces an antidepressive state, and DIO mice, which exhibit severe depressive behavior, did not respond to leptin in both the FST and the biochemical changes in the hippocampus. Thus, depression associated with obesity is due, at least in part, to impaired leptin activity in the hippocampus.

C-type natriuretic peptide as a new regulator of food intake and energy expenditure.

The physiological implication of C-type natriuretic peptide (CNP) including energy metabolism has not been elucidated, because of markedly short stature in CNP-null mice. In the present study we analyzed food intake and energy expenditure of CNP-null mice with chondrocyte-targeted CNP expression (CNP-Tg/Nppc(-/-) mice), in which marked skeletal dysplasia was rescued, to investigate the significance of CNP under minimal influences of skeletal phenotypes. In CNP-Tg/Nppc(-/-) mice, body weight and body fat ratio were reduced by 24% and 32%, respectively, at 20 wk of age, and decreases of blood glucose levels during insulin tolerance tests were 2-fold exaggerated at 17 wk of age, as compared with CNP-Tg/Nppc(+/+) mice. Urinary noradrenalin excretion of CNP-Tg/Nppc(-/-) mice was greater than that of CNP-Tg/Nppc(+/+) mice by 28%. In CNP-Tg/Nppc(-/-) mice, rectal temperature at 1600 h was higher by 1.1 C, and uncoupling protein-1 mRNA expression in the brown adipose tissue was 2-fold increased, which was canceled by propranolol administration, as compared with CNP-Tg/Nppc(+/+) mice. Oxygen consumption was significantly increased in CNP-Tg/Nppc(-/-) mice compared with that in CNP-Tg/Nppc(+/+) mice. Food intake of CNP-Tg/Nppc(-/-) mice upon ad libitum feeding and refeeding after 48 h starvation were reduced by 21% and 61%, respectively, as compared with CNP-Tg/Nppc(+/+) mice. This study unveiled a new aspect of CNP as a molecule regulating food intake and energy expenditure. Further analyses on precise mechanisms of CNP actions would lead to the better understanding of the significance of the CNP/guanylyl cyclase-B system in food intake and energy expenditure.

Orexins increase mRNA expressions of neurotrophin-3 in rat primary cortical neuron cultures.

Orexins and melanin-concentrating hormone (MCH) as orexigenic neuropeptides are present in the lateral hypothalamus, and their receptors are distributed in the cerebral cortex and hippocampus. In the present study, the regulatory effects of orexin-A, orexin-B and MCH on neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) expressions were examined in primary cortical neuron cultures using quantitative real-time PCR. Both orexin-A and orexin-B on 6-day exposure significantly increased the NT-3 mRNA at concentrations of 0.01, 0.1 and 1microM. Orexin-A and B at 1microM led to an increase of twofold or more over the control. However, no such NT-s mRNA increase occurred with exposure to MCH at the same concentrations as orexins. The mRNA expression of BDNF was significantly increased only by orexin-B at 1microM. These findings suggest that orexins, but not MCH, may be an inducer of NT-3 in the cerebral cortex.

Orexin decreases mRNA expressions of NMDA and AMPA receptor subunits in rat primary neuron cultures.

Orexin is one of the orexigenic neuropeptides in the hypothalamus. Orexin neurons in the lateral hypothalamus (LH) project into the cerebral cortex and hippocampus in which the receptors are distributed in high concentrations. Therefore, to elucidate the actions of orexin in the cerebral cortex, we examined its effects on the mRNA expressions of N-methyl-d-aspartate (NMDA) receptor subunits (NR1, NR2A, NR2B) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunits (GluR1, GluR2) following 6-day application of orexin-A or orexin-B to rat primary cortical neuron cultures. The mRNAs of NR1 and NR2A subunits were significantly decreased by orexin-A and orexin-B at concentrations over 0.1 microM and 0.01 microM, respectively. The mRNA expression of NR2B subunit was also significantly decreased by orexin-A and orexin-B only at the concentration of 1 microM. Moreover, orexin-A and orexin-B at concentrations over 0.01 microM significantly decreased the mRNA expressions of AMPA receptor subunits, GluR1 and GluR2. The present study demonstrated that orexins significantly suppressed RNA expressions of NMDA and AMPA receptor subunits in cortical neuron cultures, suggesting that orexin may regulate the higher functions of the cerebral cortex as well as be involved in energy regulation in the hypothalamus.

Tumor suppressor candidate 5 (TUSC5) is expressed in brown adipocytes.

Rat brain endothelial cell derived gene-1 (BEC-1) had considerable homology with tumor suppressor candidate 5 (TUSC5). TUSC5 was expressed abundantly, and its mRNA was inhibited by cold exposure in rat brown adipose tissue (BAT). In the present study, we investigated its regulatory mechanism using primary cultured rat brown preadipocytes (RBPA) and Zucker lean rats (ZL). We found that: (1) TUSC5 mRNA began to increase in a manner similar to C/EBP-alpha, PPAR-gamma, and adiponectin during differentiation in RBPA; (2) neither beta3-adrenoceptor agonist BRL 37344 nor dexamethasone affected TUSC5 mRNA in RBPA; (3) propranolol did not block the decrease of TUSC5 mRNA by cold exposure in ZL; (4) BRL 37344 did not influence TUSC5 mRNA in ZL; and (5) dexamethasone inhibited TUSC5 mRNA in a dose-dependent manner similar to UCP-1 in ZL. These data suggested that TUSC5 is involved in the differentiation, and its expression is regulated independently of the beta-adrenergic pathway in BAT.