Do Young Kim

Excitatory actions of GABA in the suprachiasmatic nucleus.

Neurons in the suprachiasmatic nucleus (SCN) are responsible for the generation of circadian oscillations, and understanding how these neurons communicate to form a functional circuit is a critical issue. The neurotransmitter GABA and its receptors are widely expressed in the SCN where they mediate cell-to-cell communication. Previous studies have raised the possibility that GABA can function as an excitatory transmitter in adult SCN neurons during the day, but this work is controversial. In the present study, we first tested the hypothesis that GABA can evoke excitatory responses during certain phases of the daily cycle by broadly sampling how SCN neurons respond to GABA using extracellular single-unit recording and gramicidin-perforated-patch recording techniques. We found that, although GABA inhibits most SCN neurons, some level of GABA-mediated excitation was present in both dorsal and ventral regions of the SCN, regardless of the time of day. These GABA-evoked excitatory responses were most common during the night in the dorsal SCN region. The Na+-K+-2Cl− cotransporter (NKCC) inhibitor, bumetanide, prevented these excitatory responses. In individual neurons, the application of bumetanide was sufficient to change GABA-evoked excitation to inhibition. Calcium-imaging experiments also indicated that GABA-elicited calcium transients in SCN cells are highly dependent on the NKCC isoform 1 (NKCC1). Finally, Western blot analysis indicated that NKCC1 expression in the dorsal SCN is higher in the night. Together, this work indicates that GABA can play an excitatory role in communication between adult SCN neurons and that this excitation is critically dependent on NKCC1.

Voltage‐gated calcium channels play crucial roles in the glutamate‐induced phase shifts of the rat suprachiasmatic circadian clock

The resetting of the circadian clock based on photic cues delivered by the glutamatergic retinohypothalamic tract is an important process helping mammals to function adaptively to the daily light–dark cycle. To see if the photic resetting relies on voltage‐gated Ca2+ channels (VGCCs), we examined the effects of VGCC blockers on the glutamate‐induced phase shifts of circadian firing activity rhythms of suprachiasmatic nucleus (SCN) neurons in hypothalamic slices. First, we found that a cocktail of amiloride, nimodipine and ω‐conotoxin MVIIC (T‐, L‐ and NPQ‐type VGCC antagonists, respectively) completely blocked both phase delays and advances, which were, respectively, induced by glutamate application in early and late night. Next, we discovered that: (i) amiloride and another T‐type VGCC antagonist, mibefradil, completely obstructed the delays without affecting the advances; (ii) nimodipine completely blocked the advances while having less impact on delays; and (iii) ω‐conotoxin MVIIC blocked largely, if not entirely, both delays and advances. Subsequent whole‐cell recordings revealed that T‐type Ca2+ currents in neurons in the ventrolateral, not dorsomedial, region of the SCN were larger during early than late night, whereas L‐type Ca2+ currents did not differ from early to late night in both regions. These results indicate that VGCCs play important roles in glutamate‐induced phase shifts, T‐type being more important for phase delays and L‐type being so for phase advances. Moreover, the results point to the possibility that a nocturnal modulation of T‐type Ca2+ current in retinorecipient neurons is related to the differential involvement of T‐type VGCC in phase delays and advances.

Translation of clock rhythmicity into neural firing in suprachiasmatic nucleus requires mGluR-PLCβ4 signaling

Phospholipase C β4 (PLCβ4) is expressed in the suprachiasmatic nucleus (SCN), as well as in tissues in the circadian entrainment pathway, including the retina and the lateral geniculate nucleus in the mouse. Using PLCβ4−/− mice, we previously reported that PLCβ4 is coupled to metabotropic glutamate receptors (mGluRs), which regulate the ionotropic glutamate responsiveness of SCN neurons, and thus were proposed to be involved in photic entrainment. We show here that the group-I mGluR–PLCβ4 signaling pathway is involved in translating circadian oscillations of the molecular clock into rhythmic outputs of SCN neurons.

Electrophysiological evidence for the role of substance P in retinohypothalamic transmission in the rat

The retinohypothalamic tract (RHT) is a neural pathway through which photic time cues are delivered directly to the mammalian circadian pacemaker in the suprachiasmatic nucleus (SCN). Although the excitatory amino acid glutamate is the primary neurotransmitter in the RHT, other substances such as substance P (SPq also have been suggested to play a role. The present study tested the hypothesis that SP participates in retinohypothalamic transmission and selectively modulates either N-methyl-D-aspartate (NMDA) or non-NMDA receptor-mediated neurotransmission. The SP antagonist L-703,606 depressed the excitatory postsynaptic current (EPSC) evoked by optic nerve stimulation in SCN neurons in rat hypothalamic slices. The SP antagonist also had a similar depressive effect on the NMDA and non-NMDA receptor-mediated components of the EPSC. These results suggest that SP is an excitatory neuromodulator contributing to the expression of both the NMDA and non-NMDA receptor-mediated components of retinohypothalamic transmission.

Decrease in spinal CGRP and substance p is not related to neuropathic pain in a rat model

We tested the hypothesis that the decrease in spinal levels of SP and CGRP after peripheral nerve injury is related to neuropathic pain. We compared two groups of rats, both of which were subjected to unilateral transection of the inferior and superior caudal trunks between the S1 and S2 spinal nerves. One group exhibited well-developed neuropathic signs after the nerve injury, whereas the other group showed poorly developed signs despite the same nerve injury. The decrease in immunoreactivity of CGRP and SP in the S1 dorsal horn (injured segment) was not significantly different between the two groups. These results suggest that the decrease in spinal levels of CGRP and SP after peripheral nerve injury is not related to neuropathic pain.

Oral Anticoagulants for Atrial Fibrillation Patients with Active Cancer

https://e-kcj.org Cancer patients are at elevated risk of both thrombotic and bleeding complications.1) Furthermore, they are likely to have atrial fibrillation (AF) and the risk of AF is already increased in cancer patients before diagnosis of malignancy.1)2) The association between cancer and AF could be explained by common risk factors such as old age, obesity, inflammation, and metabolic disorders.1) In this regard, proper management for prevention of thromboembolic event is clinically important in AF patients with active cancer. Despite a hypercoagulable state associated with AF as well as cancer, optimal oral anticoagulants (OACs) therapy remains challenging because of drug interaction between OAC and chemotherapy agents and changes in nutritional and metabolic status related to nausea, vomiting, anorexia, and weight loss.3)4) As a result, only limited AF patients with cancer could achieve adequate time in therapeutic range (TTR) of warfarin therapy.4) Non-vitamin K oral anticoagulants (NOACs) emerge as an attractive OAC treatment option for those patients because of no or minimal drug-drug interaction and fixed dose without requiring frequent international normalized ratio (INR) monitoring,3)5) but evidence regarding NOACs for AF patients with active cancer is limited because major randomized clinical trials (RCTs) of NOACs for AF patients excluded patients with active cancer. As a large RCT regarding NOACs versus warfarin in AF patients with active cancer is absent, retrospective comparative study using observational data offers the opportunity to address this undetermined issue in a timely manner.

Feasibility of intracardiac echocardiography imaging from the left superior pulmonary vein for left atrial appendage occlusion

Intracardiac echocardiography (ICE) is considered an alternative imaging modality for left atrium appendage occlusion (LAAO) to avoid general anesthesia. However, the quality of ICE images obtained from right atrium can be suboptimal compared with transesophageal echocardiography (TEE) imaging. Although placing an ICE probe into left atrium can improve imaging quality, there are limited data regarding procedure outcomes of ICE-guided LAAO versus TEE-guided LAAO. One hundred forty four patients who underwent LAAO with Amplatzer Cardiac Plug, Amulet, or Watchman device were enrolled from two referral institutes. TEE-guided LAAO was performed under general anesthesia or deep sedation (n = 103), and ICE-guided LAAO was conducted under local anesthesia (n = 41). An ICE probe was placed into left superior pulmonary vein (LSPV) via transseptal approach. The procedure success and complication rates of the ICE-guided LAAO were comparable with the TEE-guided LAAO (100 vs. 97.1%, p = 1.0; 2.4 vs. 6.8%, p = 0.734, respectively). The procedure time and total radiation dose were significantly lower in ICE-guided group compared with TEE-guided group (58.0 [55.0, 61.0] min vs. 80.0 [58.0, 95.0] min, p < 0.001; 456.0 [359.0, 604.0] mGy vs. 625.0 [439.0, 1502.5] mGy, p < 0.001, respectively). In multivariate analysis, younger age, the last time period of procedure, and local anesthesia were independent factors affecting shorter procedure time. ICE imaging from the LSPV provided optimal views for LAAO procedure with a significant reduction of total procedure time through performing under local anesthesia. This approach can be very useful for LAAO procedure especially in patients who are ineligible for general anesthesia.

Effect of Pitavastatin Compared with Atorvastatin andRosuvastatin on New-Onset Diabetes Mellitus in PatientsWith Acute Myocardial Infarction

Although statin use in patients with acute myocardial infarction (AMI) is mandatory, it has been suggested to be associated with new-onset diabetes mellitus (NODM). In real world practice, moderate-intensity statin therapy is more commonly used than high-intensity statin therapy. In this study, we investigated the impact of moderate-intensity pitavastatin (2 to 4 mg) compared with moderate-intensity atorvastatin (10 to 20 mg) and rosuvastatin (5 to 10 mg) on the development of NODM during a follow-up period of up to 3years. Between November 2011 and May 2015, 2001 patients with AMI who did not have diabetes mellitus were investigated. The cumulative incidence of NODM was evaluated in all groups. To adjust for potential confounders, multinomial propensity scores were used. Cox proportional hazard models were used to assess the hazard ratio of NODM in the atorvastatin and rosuvastatin groups compared with pitavastatin group. The cumulative incidence of NODM was significantly lower in pitavastatin group compared with the atorvastatin and rosuvastatin groups (3.0% vs 8.4% vs 10.4%, respectively; Log-rank p value = 0.001). After weighting the baseline characteristics of the 3 statin groups by multinomial propensity scores, atorvastatin (hazard ratio: 2.615, 95% confidence interval: 1.163 to 5.879) and rosuvastatin (hazard ratio: 3.906, 95% confidence interval: 1.756 to 8.688) were found to be associated with a higher incidence of NODM compared with pitavastatin therapy on multivariable analysis. Moderate-intensity pitavastatin therapy is associated with a lower incidence of NODM in patients with AMI andhas similar clinical outcomes to moderate-intensity atorvastatin and rosuvastatin therapy.

Growth and Characteristics of IrO 2 Thin Films for Application as Bottom Electrodes of Ferroelectric Capacitors

In this work, thin films as bottom electrode of ferroelectric capacitors were deposited and characterized. The films deposited in the conditions of 25, 40 and 50% oxygen ambient by sputtering method were annealed at 600, 700 and , respectively. It was found that the crystallinity and the surface morphology of films affected the surface properties and electrical properties of SBT thin films prepared by the MOD method. With increasing temperature, the crystallinity and the roughness of films were also increasing. This increasing of roughness degraded the surface properties and electrical properties of SBT films. We found an optimum condition of films as bottom electrode for ferroelectric capacitor at 50% oxygen ambient and annealing temperature. Electrical characterizations were performed by usingbottom electrodes grown at an optimum conditions. The remanent polarization () of the Pt/SBT///Si structure was 2.75 C/ at an applied voltage of 3 V. The leakage current density was

Substance P Plays a Critical Role in Photic Resetting of the Circadian Pacemaker in the Rat Hypothalamus

1.0610^{-3}