The impact of novel scoring balloon and cutting balloon after orbital atherectomy on severely calcified coronary lesion as assessed by optical coherence tomography.

BACKGROUND: Debulking devices are often followed by a scoring or cutting balloon in percutaneous coronary intervention (PCI) for severely calcified lesions. However, there are limited data on balloon preparation after orbital atherectomy (OA) assessed using optical coherence tomography (OCT). AIM: We aimed to compare the effects of a novel scoring and cutting balloon on calcified coronary lesions with OCT. METHODS: We retrospectively examined 38 patients (38 lesions) who underwent PCI with a scoring or a cutting balloon after OA. All patients underwent pre-PCI, preballooning, postballooning, and post-PCI OCT imaging. We divided the patients into novel scoring-balloon (group A: n = 22) and cutting-balloon (group B: n = 16) groups and compared the OCT findings, including minimum lumen area (MLA) and expansion ratio (MLA divided by mean reference lumen area). RESULTS: The mean patient age was 76.1 ± 8.7 years; 71.5% were male. There were no significant differences in patient background between both groups. Regarding procedural characteristics, the maximum balloon pressure was significantly higher in group A (median 23 atm, interquartile range [IQR] 18-24 vs. 12 atm [IQR: 10-12], p < 0.01). Although a calcium score of 4 was more frequently observed in group A (86.4% vs. 62.5%, p = 0.12), post-PCI MLA was comparable between both groups (3.95 mm2 [IQR: 3.27-4.41] vs. 3.43 mm2 [IQR: 2.90-4.82], p = 0.63). Furthermore, the expansion ratio was significantly greater in group A (0.83 ± 0.20 vs. 0.68 ± 0.14, p < 0.01). CONCLUSION: Despite a higher calcium score, a larger expansion ratio was achieved in patients with a novel scoring balloon than in those with a cutting balloon after OA.

Drug-coated balloon strategy following orbital atherectomy for calcified coronary artery compared with drug-eluting stent: One-year outcomes and optical coherence tomography assessment.

BACKGROUND: Percutaneous coronary intervention (PCI) for calcified coronary artery remains challenging in the drug-eluting stent (DES) era. While recent studies reported the efficacy of orbital atherectomy (OA) combined with DES for calcified lesion, the effectiveness of drug-coated balloon (DCB) following OA has not been fully elucidated. METHODS: Between June 2018 and June 2021, 135 patients who received PCI for calcified de novo coronary lesions with OA were enrolled and divided into two groups; OA followed by DCB (n = 43) if the target lesion achieved acceptable preparation, or second- or third-generation DESs (n = 92) if the target lesion showed suboptimal preparation between June 2018 and June 2021. All patients underwent PCI with optical coherence tomography (OCT) imaging. The primary endpoint was 1-year major adverse cardiac event (MACE), that was a composite of cardiac death, nonfatal myocardial infarction, or target lesion revascularization. RESULTS: Mean age was 73 years and 82% was male. In OCT analysis, maximum calcium plaque was thicker (median: 1050 µm [interquartile range (IQR): 945-1175 µm] vs. 960 µm [808-1100 µm], p = 0.017), calcification arc tended to larger (median: 265° [IQR: 209-360°] vs. 222° [162-305°], p = 0.058) in patients with DCB than in DES, and the postprocedure minimum lumen area was smaller in DCB compared with minimum stent area in DES (median: 3.83 mm2 [IQR: 3.30-4.52 mm2 ] vs. 4.86 mm2 [4.05-5.82 mm2 ], p < 0.001). However, 1 year MACE free rate was not significantly different between 2 groups (90.3% in DCB vs. 96.6% in DES, log-rank p = 0.136). In the subgroup analysis of 14 patients who underwent follow-up OCT imaging, late lumen area loss was lower in patients with DCB than DES, despite lower lesion expansion rate in DCB than DES. CONCLUSIONS: In calcified coronary artery disease, DCB alone strategy (if acceptable lesion preparation was performed with OA) was feasible compared with DES following OA with respect to 1-year clinical outcomes. Our finding indicated using DCB with OA might be reduce late lumen area loss for severe calcified lesion.

Delivery-Dependent Shift in Oxytocin-Responsive Cell Population in the Central Amygdala of the Female Rat.

INTRODUCTION: Despite its recent reputation as prosocial neurohormone, the most important physiological role of oxytocin (OT) is stimulating uterine contractions. Though it is well known that plasma OT concentrations change drastically during delivery, it remains unexplored whether and how OT receptors in the maternal brain are activated. We examined whether the responses of cells in the central amygdala (CeA), an OT receptor-rich limbic site involved in pain and fear memory regulation, to exogenously applied OT analogue, Thr-Gly-OT (TGOT), vary depending on delivery. METHODS: Intracellular Ca2+ dynamics of the CeA cells were visualized in brain slices from female rats at virgin (VG), during pregnancy term (PT) days 16-21, within 24 h after delivery (G0), and within 1-3 days after delivery (G3). The Ca2+ responses to 1 µM TGOT, 20 mM KCl (high K), and 300 µM ADP were compared. RESULTS: We found that fraction of cells responding to TGOT, high K, and ADP differed significantly between the four delivery-associated terms. In particular, the fraction of cells responding to TGOT (TGOT responders) significantly increased from VG and PT at G0 and G3. Furthermore, the significant positive correlation between TGOT and high K response in TGOT and high K responders was reduced at G0, while that between TGOT and ADP responses in TGOT and ADP responders was increased at G0. CONCLUSION: These results indicate that the responses of CeA cells to an OT receptor agonist markedly change around delivery, which might play a role in controlling the labor-related pain and post-delivery emotional complications.

Effectiveness and Safety of Direct Oral Anticoagulants vs. Warfarin and Recurrence After Discontinuation in Patients With Acute Venous Thromboembolism in the Real World.

BACKGROUND: The efficacy of direct oral anticoagulants (DOACs) compared with warfarin for the treatment of venous thromboembolism (VTE), and the recurrence of VTE after discontinuation of anticoagulation therapy in research are limited.Methods and Results: This retrospective study enrolled 893 patients with acute VTE between 2011 and 2019. The cohort was divided into the transient risk, unprovoked, continued cancer treatment, and cancer remission groups. The following were compared between DOACs and warfarin: composite outcome of all-cause death, VTE recurrence, bleeding and composite outcome of VTE-related death, recurrence and bleeding. In the continued cancer treatment group, more bleeding was seen in warfarin-treated patients than in patients treated with DOACs (53.2% vs. 31.2%, [P=0.048]). In addition, composite outcome of VTE-related death and recurrence after discontinuation of anticoagulation therapy (n=369) was evaluated. The continued cancer treatment group (multivariate analysis: HR: 3.62, 95% CI: 1.84-7.12, P<0.005) and bleeding-related discontinuation of therapy (HR: 2.60, 95% CI: 1.32-5.13, P=0.006) were independent predictors of the event after discontinuation of anticoagulation therapy. VTE recurrence after discontinuation of anticoagulation therapy in the cancer remission group was 1.6% and a statistically similar occurrence was found in the transient risk group (12.4%) (P=0.754). CONCLUSIONS: DOACs may decrease bleeding incidence in patients continuing to receive cancer treatment. In patients with bleeding-related discontinuation of anticoagulation therapy, VTE recurrence may increase. Discontinuation of anticoagulant therapy might be a treatment option in patients who have completed their cancer treatment.

Geriatric nutritional risk index as a predictor of arrhythmia recurrence after catheter ablation of atrial fibrillation.

BACKGROUND AND AIMS: The nutritional risk of patients who undergo atrial fibrillation (AF) ablation varies. Its impact on the recurrence after ablation is unclear. We sought to evaluate the relationship between the nutritional risk and arrhythmia recurrence in patients who undergo AF ablation. METHODS AND RESULTS: We enrolled 538 patients (median 67 years, 69.9% male) who underwent their first AF ablation. Their nutritional risk was evaluated using the pre-procedural geriatric nutritional risk index (GNRI), and the patients were classified into two groups: No-nutritional risk (GNRI â‰§ 98) and Nutritional risk (GNRI < 98). The primary endpoint was a recurrence of an arrhythmia, and its relationship to the nutritional risk was evaluated. We used propensity-score matching to adjust for differences between patients with a GNRI-based nutritional risk and those without a nutritional risk. A nutritional risk was found in 10.6% of the patients, whereas the remaining 89.4% had no-nutritional risk. During a mean follow-up of 422 days, 91 patients experienced arrhythmia recurrences. The patients with a nutritional risk had a significantly higher arrhythmia recurrence rate both in the entire study cohort (Log-rank p = 0.001) and propensity-matched cohort (Log-rank p = 0.006). In a Cox proportional hazard analysis, the nutritional risk independently predicted arrhythmia recurrences in the entire study cohort (hazard ratio [HR]: 3.91, 95% confidence interval [CI]: 1.84-8.35, p < 0.001) and propensity-matched cohort (HR: 6.49, 95% CI: 1.42-29.8, p = 0.016). CONCLUSION: A pre-procedural malnutrition risk was significantly associated with increased arrhythmia recurrences in patients who underwent AF ablation.

Multiple mycotic aneurysms with infective endocarditis: A case report.

Mycotic aneurysms are sometimes seen in patients with infective endocarditis. We report a case of infective endocarditis with multiple mycotic aneurysms. Although antibiotics were effective, mycotic aneurysms appeared in the cerebral, hepatic, and gastroepiploic arteries. A 55-year-old man presented with mitral valve endocarditis due to Streptococcus oralis. Surgical treatment was deferred because of cerebral hemorrhage. After antibiotic initiation, his fever and C-reactive protein levels declined, and blood culture was negative. However, he experienced repeated cerebral hemorrhage and the number of cerebral mycotic aneurysms increased. Additionally, his spleen ruptured and the number of mycotic aneurysms in the hepatic and gastroepiploic arteries increased. After embolization for mycotic aneurysm and mitral valve replacement, no mycotic aneurysms appeared. Regardless of whether laboratory data improve or not, multiple mycotic aneurysms sometimes appear, and cardiac surgery for infection control should be considered in the early phase.

Potentiation of NMDA receptor-mediated synaptic transmission at the parabrachial-central amygdala synapses by CGRP in mice.

The capsular part of the central amygdala (CeC) is called the "nociceptive amygdala," as it receives nociceptive information from various pathways, including monosynaptic input from the lateral part of the parabrachial nucleus (LPB), a major target of ascending neurons in the spinal and medullary dorsal horn. LPB-CeC synaptic transmission is mediated by glutamate but the fibers from the LPB also contain calcitonin gene-related peptide (CGRP) and the CeC is rich in CGRP-binding sites. CGRP might be released in response to strong nociception and activate these CGRP receptors. Though it has been shown that CGRP affects the excitatory postsynaptic current (EPSC) amplitude at this synapse in a manner sensitive to NMDA receptor (NMDA-R) blockers, the effect of CGRP on postsynaptic NMDA-R-mediated current recorded in isolation has never been directly examined. Thus, we evaluated the effects of CGRP on NMDA-R-mediated EPSCs that were pharmacologically isolated in brain slices from naïve mice. CGRP significantly increased the amplitude of EPSCs mediated by NMDA-Rs in a manner dependent on protein kinase A activation, but not that mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, in concentration-dependent and antagonist-sensitive manners. This CGRP-induced potentiation of synaptic NMDA-R function would have a potent impact on the strengthening of the nociception-emotion link in persistent pain.

Essential role of endogenous calcitonin gene-related peptide in pain-associated plasticity in the central amygdala.

The role of the neuropeptide calcitonin gene-related peptide (CGRP) is well established in nociceptive behaviors. CGRP is highly expressed in the projection pathway from the parabrachial nucleus to the laterocapsular region of the central amygdala (CeC), which plays a critical role in relaying nociceptive information. The CeC is a key structure in pain behavior because it integrates and modulates nociceptive information along with other sensory signals. Previous studies have demonstrated that blockade of the amygdalar CGRP-signaling cascade attenuates nociceptive behaviors in pain models, while CGRP application facilitates amygdalar synaptic transmission and induces pain behaviors. Despite these lines of evidence, it remains unclear whether endogenous CGRP is involved in the development of nociceptive behaviors accompanied with amygdalar plasticity in a peripheral inflammation model in vivo. To directly address this, we utilized a previously generated CGRP knockout (KO) mouse to longitudinally study formalin-induced plasticity and nociceptive behavior. We found that synaptic potentiation in the right PB-CeC pathway that was observed in wild-type mice was drastically attenuated in the CGRP KO mice 6 h post-inflammation, when acute nociceptive behavior was no longer observed. Furthermore, the bilateral tactile allodynia 6 h post-inflammation was significantly decreased in the CGRP KO mice. In contrast, the acute nociceptive behavior immediately after the formalin injection was reduced only at 20-25 min post-injection in the CGRP KO mice. These results suggest that endogenous CGRP contributes to peripheral inflammation-induced synaptic plasticity in the amygdala, and this plasticity may underlie the exaggerated nociception-emotion linkage in pain chronification.

SAD-B kinase regulates pre-synaptic vesicular dynamics at hippocampal Schaffer collateral synapses and affects contextual fear memory.

Synapses of amphids defective (SAD)-A/B kinases control various steps in neuronal development and differentiation, such as axon specifications and maturation in central and peripheral nervous systems. At mature pre-synaptic terminals, SAD-B is associated with synaptic vesicles and the active zone cytomatrix; however, how SAD-B regulates neurotransmission and synaptic plasticity in vivo remains unclear. Thus, we used SAD-B knockout (KO) mice to study the function of this pre-synaptic kinase in the brain. We found that the paired-pulse ratio was significantly enhanced at Shaffer collateral synapses in the hippocampal CA1 region in SAD-B KO mice compared with wild-type littermates. We also found that the frequency of the miniature excitatory post-synaptic current was decreased in SAD-B KO mice. Moreover, synaptic depression following prolonged low-frequency synaptic stimulation was significantly enhanced in SAD-B KO mice. These results suggest that SAD-B kinase regulates vesicular release probability at pre-synaptic terminals and is involved in vesicular trafficking and/or regulation of the readily releasable pool size. Finally, we found that hippocampus-dependent contextual fear learning was significantly impaired in SAD-B KO mice. These observations suggest that SAD-B kinase plays pivotal roles in controlling vesicular release properties and regulating hippocampal function in the mature brain. Synapses of amphids defective (SAD)-A/B kinases control various steps in neuronal development and differentiation, but their roles in mature brains were only partially known. Here, we demonstrated, at mature pre-synaptic terminals, that SAD-B regulates vesicular release probability and synaptic plasticity. Moreover, hippocampus-dependent contextual fear learning was significantly impaired in SAD-B KO mice, suggesting that SAD-B kinase plays pivotal roles in controlling vesicular release properties and regulating hippocampal function in the mature brain.

On-site energy supply at synapses through monocarboxylate transporters maintains excitatory synaptic transmission.

ATP production through oxidative phosphorylation in the mitochondria is the most efficient way to provide energy to various energy-consuming activities of the neurons. These processes require a large amount of ATP molecules to be maintained. Of these, synaptic transmission is most energy consuming. Here we report that lactate transported through monocarboxylate transporters (MCTs) at excitatory synapses constitutively supports synaptic transmission, even under conditions in which a sufficient supply of glucose and intracellular ATP are present. We analyzed the effects of MCT inhibition on neuronal activities using whole-cell recordings in brain slices of rats in the nucleus of the solitary tract. MCT inhibitors (α-cyano-4-hydroxycinnamic acid (4-CIN), phloretin, and d-lactate) significantly decreased the amplitude of EPSCs without reducing release probability. Although 4-CIN significantly reduced currents mediated by heterologously expressed AMPA-Rs in oocytes (a novel finding in this study), the IC50 of the inhibitory effect on EPSC in brain slices was ∼3.8 times smaller than that on AMPA-R currents in oocytes. Removal of intracellular ATP significantly potentiated the inhibition of EPSC with 4-CIN in a manner that was counteracted by intracellular lactate addition. In addition, extracellular lactate rescued aglycemic suppression of EPSC, in a manner that was prevented by 4-CIN. Inhibition of MCTs also reduced NMDA-R-mediated EPSCs and, to a lesser extent, the IPSC. The reduction in EPSC amplitude by γ-d-glutamylglycine was enhanced by 4-CIN, suggesting also a decreased quantal content. We conclude that "on-site" astrocyte-neuron lactate transport to presynaptic and postsynaptic elements is necessary for the integrity of excitatory synaptic transmission.

A light-controlled phospholipase C for imaging of lipid dynamics and controlling neural plasticity.

Phospholipase C (PLC) is a key enzyme that regulates physiological processes via lipid and calcium signaling. Despite advances in protein engineering, no tools are available for direct PLC control. Here, we developed a novel optogenetic tool, light-controlled PLCß (opto-PLCß). Opto-PLCß uses a light-induced dimer module, which directs an engineered PLC to the plasma membrane in a light-dependent manner. Our design includes an autoinhibitory capacity, ensuring stringent control over PLC activity. Opto-PLCß triggers reversible calcium responses and lipid dynamics in a restricted region, allowing precise spatiotemporal control of PLC signaling. Using our system, we discovered that phospholipase D-mediated phosphatidic acid contributes to diacylglycerol clearance on the plasma membrane. Moreover, we extended its applicability in vivo, demonstrating that opto-PLCß can enhance amygdala synaptic plasticity and associative fear learning in mice. Thus, opto-PLCß offers precise spatiotemporal control, enabling comprehensive investigation of PLC-mediated signaling pathways, lipid dynamics, and their physiological consequences in vivo.

All-optical presynaptic plasticity induction by photoactivated adenylyl cyclase targeted to axon terminals.

Intracellular signaling plays essential roles in various cell types. In the central nervous system, signaling cascades are strictly regulated in a spatiotemporally specific manner to govern brain function; for example, presynaptic cyclic adenosine monophosphate (cAMP) can enhance the probability of neurotransmitter release. In the last decade, channelrhodopsin-2 has been engineered for subcellular targeting using localization tags, but optogenetic tools for intracellular signaling are not well developed. Therefore, we engineered a selective presynaptic fusion tag for photoactivated adenylyl cyclase (bPAC-Syn1a) and found its high localization at presynaptic terminals. Furthermore, an all-optical electrophysiological method revealed rapid and robust short-term potentiation by bPAC-Syn1a at brain stem-amygdala synapses in acute brain slices. Additionally, bPAC-Syn1a modulated mouse immobility behavior. These results indicate that bPAC-Syn1a can manipulate presynaptic cAMP signaling in vitro and in vivo. The all-optical manipulation technique developed in this study can help further elucidate the dynamic regulation of various cellular functions.

Predictors of target lesion failure after percutaneous coronary intervention with a drug-coated balloon for de novo lesions.

BACKGROUND: There are limited data about determinant factors of target lesion failure (TLF) in lesions after percutaneous coronary intervention (PCI) using a drug-coated balloon (DCB) for de novo coronary artery lesions, including optical coherence tomography (OCT) findings. AIMS: The present study aims to investigate the associated factors of TLF in de novo coronary artery lesions with DCB treatment. METHODS: We retrospectively enrolled 328 de novo coronary artery lesions in 328 patients who had undergone PCI with a DCB. All lesions had been treated without a stent, and both pre- and post-PCI OCT had been carried out. Patients were divided into two groups, with or without TLF, which was defined as a composite of culprit lesion-related cardiac death, myocardial infarction, and target lesion revascularisation, and the associated factors of TLF were assessed. RESULTS: At the median follow-up period of 460 days, TLF events occurred in 31 patients (9.5%) and were associated with patients requiring haemodialysis (HD; 29.0% vs 10.8%), with a severely calcified lesion (median maximum calcium arc 215° vs 104°), and with the absence of OCT medial dissection (16.1% vs 60.9%) as opposed to those without TLF events. In Cox multivariable logistic regression analysis, HD (hazard ratio [HR]: 2.26, 95% confidence interval [CI]: 1.00-5.11; p=0.049), maximum calcium arc (per 90°, HR: 1.34, 95% CI: 1.05-1.72; p=0.02), and the absence of post-PCI medial dissection on OCT (HR: 8.24, 95% CI: 3.15-21.6; p<0.001) were independently associated with TLF. CONCLUSIONS: In de novo coronary artery lesions that received DCB treatment, factors associated with TLF were being on HD, the presence of a severely calcified lesion, and the absence of post-PCI medial dissection.

Experience-dependent changes in affective valence of taste in male mice.

Taste plays an essential role in the evaluation of food quality by detecting potential harm and benefit in what animals are about to eat and drink. While the affective valence of taste signals is supposed to be innately determined, taste preference can also be drastically modified by previous taste experiences of the animals. However, how the experience-dependent taste preference is developed and the neuronal mechanisms involved in this process are poorly understood. Here, we investigate the effects of prolonged exposure to umami and bitter tastants on taste preference using two-bottle tests in male mice. Prolonged umami exposure significantly enhanced umami preference with no changes in bitter preference, while prolonged bitter exposure significantly decreased bitter avoidance with no changes in umami preference. Because the central amygdala (CeA) is postulated as a critical node for the valence processing of sensory information including taste, we examined the responses of cells in the CeA to sweet, umami, and bitter tastants using in vivo calcium imaging. Interestingly, both protein kinase C delta (Prkcd)-positive and Somatostatin (Sst)-positive neurons in the CeA showed an umami response comparable to the bitter response, and no difference in cell type-specific activity patterns to different tastants was observed. Meanwhile, fluorescence in situ hybridization with c-Fos antisense probe revealed that a single umami experience significantly activates the CeA and several other gustatory-related nuclei, and especially CeA Sst-positive neurons were strongly activated. Intriguingly, after prolonged umami experience, umami tastant also significantly activates the CeA neurons, but the Prkcd-positive neurons instead of Sst-positive neurons were highly activated. These results suggest a relationship between amygdala activity and experience-dependent plasticity developed in taste preference and the involvement of the genetically defined neural populations in this process.

Predictors of coronary artery injury after orbital atherectomy as assessed by optical coherence tomography.

PURPOSE: The association between the extent of the wire and device bias as assessed by optical coherence tomography (OCT) in the healthy portion of the vessel and the risk of coronary artery injury after orbital atherectomy (OA) has not been fully elucidated. Thus, purpose of this study is to investigate the association between pre-OA OCT findings and post-OA coronary artery injury by OCT. METHODS: We enrolled 148 de novo lesions having calcified lesion required OA (max Ca angle > 90°) in 135 patients who underwent both pre- and post-OA OCT. In pre-OA OCT, OCT catheter contact angle and the presence or absences of guide-wire (GW) contact with the normal vessel intima were assessed. Also, in post-OA OCT, we assessed there was post-OA coronary artery injury (OA injury), defined as disappearance of both of intima and medial wall of normal vessel, or not. RESULTS: OA injury was found in 19 lesions (13%). Pre-PCI OCT catheter contact angle with the normal coronary artery was significantly larger (median 137°; inter quartile range [IQR] 113-169 vs. median 0°; IQR 0-0, P < 0.001) and more GW contact with the normal vessel was found (63% vs. 8%, P < 0.001). Pre-PCI OCT catheter contact angle > 92° and GW contact with the normal vessel intima were associated with post-OA vascular injury (Both: 92% (11/12), Either: 32% (8/25), Neither: 0% (0/111), P < 0.001). CONCLUSION: Pre-PCI OCT findings, such as catheter contact angle > 92° and guide-wire contact to the normal coronary artery, were associated with post-OA coronary artery injury.

Role of capsaicin-sensitive C-fiber afferents in neuropathic pain-induced synaptic potentiation in the nociceptive amygdala.

BACKGROUND: Neurons in the capsular part of the central nucleus of the amygdala (CeC), a region also called "nociceptive amygdala," receive nociceptive information from the dorsal horn via afferent pathways relayed from the lateral parabrachial nucleus (LPB). As the central amygdala is known to be involved in the acquisition and expression of emotion, this pathway is thought to play central roles in the generation of affective responses to nociceptive inputs. Excitatory synaptic transmission between afferents arising from the LPB and these CeC neurons is potentiated in arthritic, visceral, neuropathic, inflammatory and muscle pain models. In neuropathic pain models following spinal nerve ligation (SNL), in which we previously showed a robust LPB-CeC potentiation, the principal behavioral symptom is tactile allodynia triggered by non-C-fiber low-threshold mechanoreceptor afferents. Conversely, recent anatomical studies have revealed that most of the spinal neurons projecting to the LPB receive C-fiber afferent inputs. Here, we examined the hypothesis that these C-fiber-mediated inputs are necessary for the full establishment of robust synaptic potentiation of LPB-CeC transmission in the rats with neuropathic pain. RESULTS: Postnatal capsaicin treatment, which has been shown to denervate the C-fibers expressing transient receptor potential vanilloid type-1 (TRPV1) channels, completely abolished eye-wiping responses to capsaicin eye instillation in rats, but this treatment did not affect mechanical allodynia in the nerve-ligated animals. However, the postnatal capsaicin treatment prevented LPB-CeC synaptic potentiation after SNL, unlike in the vehicle-treated rats, primarily due to the decreased incidence of potentiated transmission by elimination of TRPV1-expressing C-fiber afferents. CONCLUSIONS: C-fiber-mediated afferents in the nerve-ligated animals may be a required facilitator of the establishment of nerve injury-evoked synaptic potentiation in the CeC. These inputs might play essential roles in the chronic pain-induced plastic changes in the central network linking nociception and negative emotion.

Otic Organoids Containing Spiral Ganglion Neuron-like Cells Derived from Human-induced Pluripotent Stem Cells as a Model of Drug-induced Neuropathy.

The spiral ganglion of the cochlea is essential for hearing and contains primary bipolar neurons that relay action potentials generated by mechanosensory hair cells. Injury to spiral ganglion neurons (SGNs) causes permanent hearing loss because these cells have limited regenerative capacity. Establishment of human cell-derived inner ear tissue in vitro could facilitate the development of treatments for hearing loss. Here, we report a stepwise protocol for differentiating human-induced pluripotent stem cells (hiPSCs) into otic organoids that contain SGN-like cells and demonstrate that otic organoids have potential for use as an experimental model of drug-induced neuropathy. Otic progenitor cells (OPCs) were created by 2D culture of hiPSCs for 9 days. Otic spheroids were formed after 2D culture of OPCs for 2 days in a hypoxic environment. Otic organoids were generated by 3D culture of otic spheroids under hypoxic conditions for 5 days and normoxic conditions for a further 30 days or more. The protein expression profile, morphological characteristics, and electrophysiological properties of SGN-like cells in otic organoids were similar to those of primary SGNs. Live-cell imaging of AAV-syn-EGFP-labeled neurons demonstrated temporal changes in cell morphology and revealed the toxic effects of ouabain (which causes SGN-specific damage in animal experiments) and cisplatin (a chemotherapeutic drug with ototoxic adverse effects). Furthermore, a cyclin-dependent kinase-2 inhibitor suppressed the toxic actions of cisplatin on SGN-like cells in otic organoids. The otic organoid described here is a candidate novel drug screening system and could be used to identify drugs for the prevention of cisplatin-induced neuropathy.

Parabrachial-to-parasubthalamic nucleus pathway mediates fear-induced suppression of feeding in male mice.

Feeding behavior is adaptively regulated by external and internal environment, such that feeding is suppressed when animals experience pain, sickness, or fear. While the lateral parabrachial nucleus (lPB) plays key roles in nociception and stress, neuronal pathways involved in feeding suppression induced by fear are not fully explored. Here, we investigate the parasubthalamic nucleus (PSTN), located in the lateral hypothalamus and critically involved in feeding behaviors, as a target of lPB projection neurons. Optogenetic activation of lPB-PSTN terminals in male mice promote avoidance behaviors, aversive learning, and suppressed feeding. Inactivation of the PSTN and lPB-PSTN pathway reduces fear-induced feeding suppression. Activation of PSTN neurons expressing pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide enriched in the PSTN, is sufficient for inducing avoidance behaviors and feeding suppression. Blockade of PACAP receptors impaires aversive learning induced by lPB-PSTN photomanipulation. These findings indicate that lPB-PSTN pathway plays a pivotal role in fear-induced feeding suppression.

Case Report: Importance of MRI Examination in the Diagnosis and Evaluation of COVID-19 mRNA Vaccination Induced Myocarditis: Our Experience and Literature Review.

Acute myocarditis is a rare but serious complication associated with mRNA-based coronavirus disease 2019 (COVID-19) vaccination. In this article, four COVID-19 mRNA vaccination induced myocarditis cases managed at our tertiary Medical Center have been discussed. Three patients had typical myocarditis. One patient suffered from atrioventricular block and heart failure, which required more intensive treatment, but eventually improved. Additionally, a review of cardiac magnetic resonance imaging (MRI) features related to the diagnosis of myocarditis showed that COVID-19 mRNA vaccine-associated myocarditis tend to have more late-gadolinium enhancement (LGE) accumulation in the inferior lateral wall direction. According to a report by the U.S. Centers for Disease Control and Prevention (CDC), the diagnosis of COVID-19 mRNA vaccine-associated myocarditis is based on clinical symptoms, altered myocardial enzymes, cardiac MRI finding, or histopathology. Cardiac MRI is relatively less invasive than myocardial biopsy and plays an important role in the diagnosis of myocarditis. This review may aid in the diagnosis of COVID-19 mRNA vaccine-associated myocarditis.