Mortality risk after use of a paclitaxel-coated stent in femoropopliteal peripheral artery disease.

Although paclitaxel-based devices which demonstrated improved outcomes in the treatment of lower-extremity peripheral artery disease (PAD) have been used worldwide, Katsanos et al. reported a systematic review and summary-level meta-analysis of RCTs in which application of paclitaxel-based devices in the femoropopliteal artery was associated with an increased mortality risk. The purpose of this study was to describe the safety of endovascular therapy (EVT) using paclitaxel-coated stents for femoropopliteal disease by evaluating the mortality risk compared with patients treated with paclitaxel-free devices. A retrospective, multicenter, non-randomized study examined 481 de-novo symptomatic PAD patients treated in 13 Japanese medical centers from January 2011 to December 2015. The risk of all-cause mortality was analyzed between the 65 patients treated with a paclitaxel-coated stent (PTX-coated group) and 416 patients treated with an uncoated balloon or bare nitinol stent (PTX-free group). Overall survival of the PTX-coated group and the PTX-free group were compared after propensity score matching. The 2-year overall survival estimates were 87.7% in the PTX-coated group vs 88.7% in the PTX-free group. There were no significant differences in the mortality risk between the groups through a full follow-up of 2 years (p = 0.80). The multivariate cox proportional hazards model identified three significant predictors of mortality; age (HR, 1.08; 95% CI, 1.03-1.13; p = 0.002), hemodialysis (HR, 3.16; 95% CI, 1.34-7.42; p = 0.008), and albumin (g/dl) (HR, 0.46; 95% CI, 0.25-0.85; p = 0.01).

The effect of electroconvulsive seizure on survival, neuronal differentiation, and expression of the maturation marker in the adult mouse hippocampus.

Electroconvulsive seizure (ECS), a model of electroconvulsive therapy in rodents, strongly increases neurogenesis in the adult hippocampus. Neurogenesis is a multi-step process that spans proliferation, survival, neuronal differentiation, and functional maturation. Our previous study demonstrated that ECS stimulates the proliferation of neural stem-like cells. However, the contribution of ECS to survival, neuronal differentiation, and maturation in newborn cells remains unknown. To evaluate the effect of ECS on these processes, we labeled newborn cells with bromodeoxyuridine (BrdU) before ECS treatment to determine the cell age and examined the survival rate and expression of cellular markers in the BrdU-labeled cells. Our results revealed that exposure to ECS (11 repetitions) during the differentiation phase significantly increased survival and promoted neuronal differentiation of newborn cells in the dentate gyrus. Four of ECS repetitions during the early differentiation phase were sufficient to promote dendritic outgrowth in immature neurons and enhance the expression of the immature neuronal marker, calretinin, in newborn cells. In contrast, exposure to ECS (11 repetitions) during the late maturation phase significantly suppressed the expression of the mature neuronal marker, calbindin, in newborn neurons. These results demonstrate that ECS during the differentiation phase promoted survival and neuronal differentiation and, in contrast, suppressed mature marker expression during the late maturation phase, suggesting that ECS has multiple effects on the different stages of adult neurogenesis.

The Innate Immune Receptors TLR2/4 Mediate Repeated Social Defeat Stress-Induced Social Avoidance through Prefrontal Microglial Activation.

Repeated environmental stress has been proposed to induce neural inflammation together with depression and anxiety. Innate immune receptors, such as Toll-like receptors (TLRs), are activated by exogenous or endogenous ligands to evoke inflammation. Here we show that the loss of TLR2 and TLR4 (TLR2/4) abolished repeated social defeat stress (R-SDS)-induced social avoidance and anxiety in mice. TLR2/4 deficiency mitigated R-SDS-induced neuronal response attenuation, dendritic atrophy, and microglial activation in the medial prefrontal cortex (mPFC). Furthermore, mPFC microglia-specific TLR2/4 knockdown blocked social avoidance. Transcriptome analyses revealed that R-SDS induced IL-1α and TNF-α in mPFC microglia in a TLR2/4-dependent manner, and antibody blockade of these cytokines in the mPFC suppressed R-SDS-induced social avoidance. These results identify TLR2/4 as crucial mediators of R-SDS-induced microglial activation in the mPFC, which leads to neuronal and behavioral changes through inflammation-related cytokines, highlighting unexpected pivotal roles of innate immunity in the mPFC in repeated environmental stress-induced behavioral changes. VIDEO ABSTRACT.

Prolonged Inflation Technique Using a Scoring Balloon for Severe Calcified Lesion.

Percutaneous coronary intervention for the treatment of a severe calcified lesion is still one of the most technically challenging areas of interventional cardiology. Calcified lesions are a cause of stent underexpansion, which significantly increases the subsequent risks of in-stent restenosis and thrombosis, even when drug-eluting stents are used. In this report, we describe the usefulness of prolonged inflations using a scoring balloon catheter (Scoreflex) for severe calcified lesions. Prolonged inflation using a scoring balloon enables an adequate dilation for treatment of a severe calcified plaque that was unresponsive to conventional technique with or without rotational atherectomy.

A left atrial appendage thrombus that developed during prophylactic low-dose dabigatran treatment resolved after switching to apixaban.

We describe a case of atrial fibrillation in which an intracardiac thrombus that could not be prevented with "low-dose" dabigatran treatment was resolved by switching to apixaban treatment. Thrombolysis using direct oral anticoagulants (DOACs) could be a therapeutic option for patients with intracardiac thrombi, although the efficacies of different DOACs seem to differ and need further examination.

Rapid and stable changes in maturation-related phenotypes of the adult hippocampal neurons by electroconvulsive treatment.

Electroconvulsive therapy (ECT) is a highly effective and fast-acting treatment for depression. Despite a long history of clinical use, its mechanism of action remains poorly understood. Recently, a novel cellular mechanism of antidepressant action has been proposed: the phenotype of mature brain neurons is transformed to immature-like one by antidepressant drug treatments. We show here that electroconvulsive stimulation (ECS), an animal model of ECT, causes profound changes in maturation-related phenotypes of neurons in the hippocampal dentate gyrus of adult mice. Single ECS immediately reduced expression of mature neuronal markers in almost entire population of dentate granule cells. After ECS treatments, granule cells showed some of physiological properties characteristic of immature granule cells such as higher somatic intrinsic excitability and smaller frequency facilitation at the detate-to-CA3 synapse. The rapid downregulation of maturation markers was suppressed by antagonizing glutamate NMDA receptors, but not by perturbing the serotonergic system. While single ECS caused short-lasting effects, repeated ECS induced stable changes in the maturation-related phenotypes lasting more than 2 weeks along with enhancement of synaptic excitation of granule cells. Augmentation of synaptic inhibition or blockade of NMDA receptors after repeated ECS facilitated regaining the initial mature phenotype, suggesting a role for endogenous neuronal excitation in maintaining the altered maturation-related phenotype probably via NMDA receptor activation. These results suggest that brief neuronal activation by ECS induces "dematuration" of the mature granule cells and that enhanced endogenous excitability is likely to support maintenance of such a demature state. The global increase in neuronal excitability accompanying this process may be relevant to the high efficacy of ECT.

Rapid and lasting enhancement of dopaminergic modulation at the hippocampal mossy fiber synapse by electroconvulsive treatment.

Electroconvulsive therapy (ECT) is an established effective treatment for medication-resistant depression with the rapid onset of action. However, its cellular mechanism of action has not been revealed. We have previously shown that chronic antidepressant drug treatments enhance dopamine D1-like receptor-dependent synaptic potentiation at the hippocampal mossy fiber (MF)-CA3 excitatory synapse. In this study we show that ECT-like treatments in mice also have marked effects on the dopaminergic synaptic modulation. Repeated electroconvulsive stimulation (ECS), an animal model of ECT, strongly enhanced the dopamine-induced synaptic potentiation at the MF synapse in hippocampal slices. Significant enhancement was detectable after the second ECS, and further repetition of ECS up to 11 times monotonously increased the magnitude of enhancement. After repeated ECS, the dopamine-induced synaptic potentiation remained enhanced for more than 4 wk. These synaptic effects of ECS were accompanied by increased expression of the dopamine D1 receptor gene. Our results demonstrate that robust neuronal activation by ECS induces rapid and long-lasting enhancement of dopamine-induced synaptic potentiation at the MF synapse, likely via increased expression of the D1 receptor, at least in part. This rapid enhancement of dopamine-induced potentiation at the excitatory synapse may be relevant to the fast-acting antidepressant effect of ECT. NEW & NOTEWORTHY: We show that electroconvulsive therapy (ECT)-like stimulation greatly enhances synaptic potentiation induced by dopamine at the excitatory synapse formed by the hippocampal mossy fiber in mice. The effect of ECT-like stimulation on the dopaminergic modulation was rapidly induced, maintained for more than 4 wk after repeated treatments, and most likely mediated by increased expression of the dopamine D1 receptor. These effects may be relevant to fast-acting strong antidepressant action of ECT.

Role of the 5-HT4 receptor in chronic fluoxetine treatment-induced neurogenic activity and granule cell dematuration in the dentate gyrus.

BACKGROUND: Chronic treatment with selective serotonin (5-HT) reuptake inhibitors (SSRIs) facilitates adult neurogenesis and reverses the state of maturation in mature granule cells (GCs) in the dentate gyrus (DG) of the hippocampus. Recent studies have suggested that the 5-HT4 receptor is involved in both effects. However, it is largely unknown how the 5-HT4 receptor mediates neurogenic effects in the DG and, how the neurogenic and dematuration effects of SSRIs interact with each other. RESULTS: We addressed these issues using 5-HT4 receptor knockout (5-HT4R KO) mice. Expression of the 5-HT4 receptor was detected in mature GCs but not in neuronal progenitors of the DG. We found that chronic treatment with the SSRI fluoxetine significantly increased cell proliferation and the number of doublecortin-positive cells in the DG of wild-type mice, but not in 5-HT4R KO mice. We then examined the correlation between the increased neurogenesis and the dematuration of GCs. As reported previously, reduced expression of calbindin in the DG, as an index of dematuration, by chronic fluoxetine treatment was observed in wild-type mice but not in 5-HT4R KO mice. The proliferative effect of fluoxetine was inversely correlated with the expression level of calbindin in the DG. The expression of neurogenic factors in the DG, such as brain derived neurotrophic factor (Bdnf), was also associated with the progression of dematuration. These results indicate that the neurogenic effects of fluoxetine in the DG are closely associated with the progression of dematuration of GCs. In contrast, the DG in which neurogenesis was impaired by irradiation still showed significant reduction of calbindin expression by chronic fluoxetine treatment, suggesting that dematuration of GCs by fluoxetine does not require adult neurogenesis in the DG. CONCLUSIONS: We demonstrated that the 5-HT4 receptor plays an important role in fluoxetine-induced adult neurogenesis in the DG in addition to GC dematuration, and that these phenomena are closely associated. Our results suggest that 5-HT4 receptor-mediated phenotypic changes, including dematuration in mature GCs, underlie the neurogenic effect of SSRIs in the DG, providing new insight into the cellular mechanisms of the neurogenic actions of SSRIs in the hippocampus.

Eosinophils control the resolution of inflammation and draining lymph node hypertrophy through the proresolving mediators and CXCL13 pathway in mice.

Resolution of inflammation is critical to restoration of tissue function after an inflammatory response. We previously demonstrated that 12/15-lipoxygenase (12/15-LOX)-expressing eosinophils contribute to this process in murine zymosan-induced peritonitis. In this study, eosinophils promoted resolution by regulating expression of macrophage CXCL13. Microarray analysis revealed that eosinophils significantly increased (∼3-fold) the expression of macrophage CXCL13 by a 12/15-LOX-dependent mechanism. CXCL13 depletion caused a resolution defect, with the reduced appearance of phagocytes carrying engulfed zymosan in the draining lymph nodes. Inflamed lymph node hypertrophy, a critical feature of the resolution process, was reduced by ∼60% in eosinophil-deficient mice, and adoptive transfer of eosinophils or administration of CXCL13 corrected this defect. Administration of the 12/15-LOX-derived mediator lipoxin A4 (LXA4) increased the expression of CXCL13 and restored the defect of lymph node hypertrophy in eosinophil-deficient mice. These results demonstrate that eosinophils control the resolution of inflammation and draining lymph node hypertrophy through proresolving lipid mediators and the CXCL13 pathway in mice.

Electroconvulsive seizures activate anorexigenic signals in the ventromedial nuclei of the hypothalamus.

The ventromedial nucleus of the hypothalamus (VMH) plays an important role in feeding and energy homeostasis. Electroconvulsive seizure (ECS) therapy is highly effective in the treatment of several psychiatric diseases, including depression, but may also have beneficial effects in other neurological diseases. Although it has been reported that the neurons of the VMH are strongly activated by ECS stimulation, the specific effects of ECS in this hypothalamic subnucleus remain unknown. To address this issue, we investigated the changes in gene expression in microdissected-VMH samples in response to ECS in mice, and examined the behavioral effects of ECS on feeding behavior. ECS significantly induced the expression of immediate-early genes such as Fos, Fosb, and Jun, as well as Bdnf, Adcyap1, Hrh1, and Crhr2 in the VMH. Given that signals of these gene products are suggested to have anorexigenic roles in the VMH, we also examined the effect of ECS on food intake and body weight. Repeated ECS had a suppressive effect on food intake and body weight gain under both regular and high-fat diet conditions. Furthermore, gold-thioglucose-induced hypothalamic lesions, including the VMH and the arcuate nucleus, abolished the anorexigenic effects of ECS, indicating the requirement for the activation of the hypothalamus. Our data show an effect of ECS on increased expression of anorexigenic factors in the VMH, and suggest a role in the regulation of energy homeostasis by ECS.

Prostaglandin E2-mediated attenuation of mesocortical dopaminergic pathway is critical for susceptibility to repeated social defeat stress in mice.

Various kinds of stress are thought to precipitate psychiatric disorders, such as major depression. Whereas studies in rodents have suggested a critical role of medial prefrontal cortex (mPFC) in stress susceptibility, the mechanism of how stress susceptibility is determined through mPFC remains unknown. Here we show a critical role of prostaglandin E(2) (PGE(2)), a bioactive lipid derived from arachidonic acid, in repeated social defeat stress in mice. Repeated social defeat increased the PGE(2) level in the subcortical region of the brain, and mice lacking either COX-1, a prostaglandin synthase, or EP1, a PGE receptor, were impaired in induction of social avoidance by repeated social defeat. Given the reported action of EP1 that augments GABAergic inputs to midbrain dopamine neurons, we analyzed dopaminergic response upon social defeat. Analyses of c-Fos expression of VTA dopamine neurons and dopamine turnover in mPFC showed that mesocortical dopaminergic pathway is activated upon social defeat and attenuated with repetition of social defeat in wild-type mice. EP1 deficiency abolished such repeated stress-induced attenuation of mesocortical dopaminergic pathway. Blockade of dopamine D1-like receptor during social defeat restored social avoidance in EP1-deficient mice, suggesting that disinhibited dopaminergic response during social defeat blocks induction of social avoidance. Furthermore, mPFC dopaminergic lesion by local injection of 6-hydroxydopamine, which mimicked the action of EP1 during repeated stress, facilitated induction of social avoidance upon social defeat. Taken together, our data suggest that PGE(2)-EP1 signaling is critical for susceptibility to repeated social defeat stress in mice through attenuation of mesocortical dopaminergic pathway.