Involvement of ghrelin in the regulation of swallowing motor activity in an arterially perfused rat preparation.

Ghrelin, a peripheral peptide produced in the stomach, is involved in the neural networks that control food intake. Alterations in motor components, such as swallowing, are believed to be significant in the regulation food intake by orexigenic signals. However, there has been no detailed investigation of the relationship between ghrelin and swallowing activities induced in motor nerves innervating the pharyngeal and laryngeal muscles. In this study, we examined the effects of ghrelin administration on swallowing motor activity in arterially perfused rats. Injection of distilled water (0.5 ml) into the oral cavity or electrical stimulation of the superior laryngeal nerve evoked swallowing motor activity in the cervical vagus nerve. Administration of ghrelin (6 nM), but not des-acylated ghrelin (6 nM), into the perfusate increased the peak burst amplitude and burst duration, and shortened the first burst interval of water injection-induced swallowing. These ghrelin-induced changes in swallowing motor activity were blocked by the administration of JMV2959 (6 µM), a growth hormone secretagogue receptor antagonist. In preparations in which the hypothalamus was removed, ghrelin had no effect on swallowing motor activity. Furthermore, ghrelin-induced changes were counteracted by the administration of BIBO3304 (1 µM) or L-152,804 (1 µM), antagonists of neuropeptide Y Y1 and Y5 receptors, respectively, which are essential for ghrelin-induced enhancement of food intake. Ghrelin also increased the peak burst amplitude and burst duration of the swallowing motor activity evoked by electrical stimulation of the superior laryngeal nerve, although the effects of ghrelin on the number of swallowing bursts and burst intervals varied with stimulus intensity. These results suggest that ghrelin enhances the magnitude and frequency of bursts of swallowing motor activity by acting via the hypothalamic neural network, and that neuropeptide Y Y1 and Y5 receptors are involved in this enhancement.

The Device of Ethylene Vinyl Acetate Sheet for Trismus Caused by Bilateral Mandible Fractures.

Trismus is commonly caused by temporomandibular joint disorders and maxillofacial fractures. We report the case of a 62-year-old woman with trismus and difficulty in mastication caused by bilateral mandibular fractures. She had a maximal interincisal opening distance (MID) of 22 mm. Mouth-opening training was administered using a novel dental mouth-training device custom-made using ethylene vinyl acetate sheets and according to the dentition and extent of mouth-opening of the patient. After 2 months of training, the MID increased to 42 mm. With adequate training, this device is effective in treating trismus due to scarring.

The Diagnosis and Management of Acute Stroke with Emergent Large Vessel Occlusion Screen.

Objective: Endovascular therapy (EVT) is a well-documented treatment for acute occlusion of major cerebral arteries. We carried out in-hospital triage using the emergency large vessel occlusion (ELVO) screen, a pre-hospital scale for acute stroke, to diagnose EVT cases and considered its efficacy. Methods: We investigated stroke cases examined within 24 hours of onset in a 6-month period beginning on March 15, 2019. The results of ELVO screen were retrospectively considered with the presence of atrial fibrillation and treatment of EVT. Results: A total of 146 cases were included. Of the 65 positive ELVO screen cases, 33 (51%) had large vessel occlusion (LVO). Of the 81 negative ELVO screen cases, 11 (14%) had LVO (sensitivity, 75%; specificity, 69%; positive predictive value, 51%; negative predictive value, 86%; accuracy, 71%; P <0.001). Among LVO cases, 16 of the 33 (48%) positive ELVO screen cases and 2 of the 11 (18%) negative ELVO screen cases were treated by EVT. Complications of atrial fibrillation were significantly more common in positive ELVO screen cases (P = 0.001). EVT was carried out in nearly half of the positive ELVO screen cases of atrial fibrillation, being a significantly higher rate (10 of 24 cases, 42%; P = 0.02). Conclusion: The accuracy of EVT use increased in positive ELVO screen cases, particularly in those with atrial fibrillation. In-hospital triage using ELVO screen, a pre-hospital scale, significantly aided in selecting patients requiring EVT.

Responses evoked by electrical stimulation of the brainstem reticular formation in the jaw-opening and hypoglossal motor nerves of an arterially perfused rat preparation.

The interneuronal system in the brainstem reticular formation plays an important role in elaborate muscle coordination during various orofacial motor behaviors. In this study, we examined the distribution in the brainstem reticular formation of the sites that induce monosynaptic motor activity in the mylohyoid (jaw-opening) and hypoglossal nerves using an arterially perfused rat preparation. Electrical stimulation applied to 286 and 247 of the 309 sites in the brainstem evoked neural activity in the mylohyoid and hypoglossal nerves, respectively. The mean latency of the first component in the mylohyoid nerve response was significantly shorter than that in the hypoglossal nerve response. Moreover, the latency histogram of the first component in the hypoglossal nerve responses was bimodal, which was separated by 4.0 ms. The sites that induced short-latency (<4.0 ms) motor activity in the mylohyoid nerve and the hypoglossal nerve were frequently distributed in the rostral portion and the caudal portion of the brainstem reticular formation, respectively. Such difference in distributions of short-latency sites for mylohyoid and hypoglossal nerve responses likely corresponds to the distribution of excitatory premotor neurons targeting mylohyoid and hypoglossal motoneurons.

Efficacy and limitations of multimodal endovascular revascularization other than clot retrieval for acute stroke caused by large-vessel occlusion.

BACKGROUND: The purpose of this study was to evaluate the efficacy of multimodal endovascular treatment (EVT) other than clot retrieval for acute large-vessel occlusion (LVO). METHODS: Fifty-six consecutive patients with a median National Institutes of Health Stroke Scale (NIHSS) score of 15 were included this study. In all cases, intravenous administration of recombinant tissue plasminogen activator had failed (n = 23) or was contraindicated (n = 33). The modes of EVT performed included intra-arterial thrombolysis, mechanical clot disruption including balloon angioplasty, and stent placement. We retrospectively analyzed the treatment efficacy of these techniques and patient outcome. RESULTS: Successful reperfusion (Thrombolysis in Cerebral Infarction grade 2B or 3) was achieved in 40 of 56 patients (71.4%), and 26 of 56 patients (46.4%) had a favorable clinical outcome (modified Rankin Scale [mRS] score 0 to 2 at 90 days). Successful reperfusion (odds ratio [OR] 163; P = .003), age (OR 0.83; P = .007), and baseline NIHSS score (OR 0.71; P = .009) were independently associated with favorable clinical outcome by multivariate analysis. Successful reperfusion rates of internal carotid terminus or M1 proximal occlusions were significantly lower than those of other vessel occlusion (47.6% v 85.7%; P = .005). Clinically significant procedure-related complications occurred in 1.8% (1/56), and symptomatic intracerebral hemorrhage (sICH) within 48 hours after EVT was observed in 5.4% (3/56) of patients. CONCLUSIONS: Multimodal EVT for acute LVO yields a high reperfusion rate with a minimal risk of sICH and contributes to favorable patient outcomes. These techniques should be considered when clot retrieval is unsuitable or ineffective.

Tissue plasminogen activator prevents restoration of tight junction proteins through upregulation of angiopoietin-2.

We examined the temporal profiles of changes in the expressions of tight junction proteins (TJPs; namely, claudin-5, occludin, and ZO-1) after focal cerebral ischemia/reperfusion in mice. We also examined the effects of delayed treatment with tissue plasminogen activator (tPA) on the expressions of TJPs and angiopoietin (Ang) -1/2/Tie2. Mice subjected to a 6-h filamental middle cerebral artery (MCA) occlusion were treated with tPA (10 mg/kg, intravenously, just after the start of reperfusion) or vehicle. The expressions of TJPs were significantly decreased in the early phase of ischemia/reperfusion, and then gradually recovered. A delayed treatment with tPA decreased the expressions of TJPs when examined at 42 h after reperfusion. In contrast, delayed tPA treatment markedly increased Ang-2, but not Ang-1 expression, when examined at 30 h after reperfusion. Treatment with tPA at 300 µg/ml also significantly decreased Ang- 2, but not Tie2 expression, in an in vitro monolayer model generated using human brain microvascular endothelial cells subjected to serum-deprivation. These findings suggest that delayed tPA treatment prevents recovery of TJPs following focal cerebral ischemia/reperfusion, partially via upregulation of Ang-2.

Ultra-early endovascular embolization of ruptured cerebral aneurysm and the increased risk of hematoma growth unrelated to aneurysmal rebleeding.

OBJECT: Hematoma growth unrelated to aneurysmal rebleeding is recognized as a somewhat common complication following endovascular embolization of ruptured aneurysms, but it is scarcely studied. The aim of this study is to elucidate the possible risk factors for this phenomenon. METHODS: Included in this study were 101 consecutive patients with subarachnoid hemorrhage (SAH) who underwent endovascular embolization for saccular aneurysms at the authors' institution within 72 hours of symptom onset. All endovascular procedures were conducted under intraprocedural systemic anticoagulation. Age, sex, hypertension, type 2 diabetes, preoperative antiplatelet or anticoagulation use, neurological grade, Fisher grade, location and size of the aneurysm, grade of aneurysm occlusion, and timing of the endovascular procedure were retrospectively analyzed to determine the risk factors for hematoma growth unrelated to aneurysmal rebleeding. To determine the clinical significance of this complication, the authors also investigated the risk factors for poor clinical outcome (modified Rankin Scale Scores 3-6 at 30 days after onset). RESULTS: This series included 32 men (31.7%) and 69 women (68.3%) with a mean age ± SD of 65.5 ± 14.0 years. The mean time from onset to endovascular procedure was 12.1 ± 14.0 hours. After the procedure, hematoma growth unrelated to aneurysmal rebleeding occurred in 14 patients (13.9%), 10 of whom required surgical removal of the hematoma and/or ventriculostomy to control intracranial pressure. All 14 patients had an anterior circulation aneurysm and had Fisher Grade 3 or 4 SAH. Ultra-early embolization (conducted within 6 hours after onset), female sex, history of hypertension, and poor neurological grade (World Federation of Neurosurgical Societies Grades IV and V) were significant risk factors for hematoma growth (p < 0.05 for all, univariate logistic analysis). In multivariate analysis, ultra-early embolization (OR 18.0 [95% CI 3.26-338], p < 0.001) and female sex (OR 9.83 [95% CI 1.73-187], p = 0.007) were independent risk factors for this phenomenon. Anterior circulation aneurysms and Fisher Grade 3 or 4 SAH were also revealed to be significant risk factors (p = 0.02 for each, chi-square test). Furthermore, hematoma growth without aneurysmal rebleeding was determined as an independent risk factor for poor clinical outcome by multivariate logistic analysis (OR 11.8 [95% CI 2.31-87.1], p = 0.002). CONCLUSIONS: Ultra-early endovascular embolization for ruptured cerebral aneurysms under systemic anticoagulation increases the risk of growth of hematomas unrelated to aneurysmal rebleeding. It is important to recognize the risk of this complication and to either reduce the amount of heparin or to refer the patient for direct clipping if appropriate.

Pharmacological inhibition of TLR4-NOX4 signal protects against neuronal death in transient focal ischemia.

Recent data have shown that TLR4 performs a key role in cerebral ischemia-reperfusion injury which serves as the origin of the immunological inflammatory reactions. However, the therapeutic effects of pharmacological inhibitions of TLR4 and its immediate down-stream pathway remain to be uncovered. In the present study, on mice, intracerebroventricular injection of resatorvid (TLR4 signal inhibitor; 0.01 µg) significantly reduced infarct volume and improved neurological score after middle cerebral artery occlusion and reperfusion. The levels of phospho-p38, nuclear factor-kappa B, and matrix metalloproteinase 9 expressions were significantly suppressed in the resatorvid-treated group. In addition, NOX4 associates with TLR4 after cerebral ischemia-reperfusion seen in mice and human. Genetic and pharmacological inhibitions of TLR4 each reduced NOX4 expression, leading to suppression of oxidative/nitrative stress and of neuronal apoptosis. These data suggest that resatorvid has potential as a therapeutic agent for stroke since it inhibits TLR4-NOX4 signaling which may be the predominant causal pathway.

[Protective effects of cilostazol against transient focal cerebral ischemia and hemorrhagic transformation].

Cilostazol, a selective inhibitor of phosphodiesterase III, is an antiplatelet drug and a vasodilator via increased cAMP levels. It has been approved for the treatment of ischemic symptoms in chronic peripheral arterial obstruction or intermittent claudication and for secondary prevention of cerebral infarction (CSPS I). Recently, cilostazol has been reported to be more effective than aspirin in the secondary prevention of all types of stroke in patients and, in particular, prevent the secondary attack of hemorrhagic stroke in patients (CSPS II). Laboratory investigations revealed that cilostazol has a neuroprotective effect against ischemic brain injury. The neuroprotective potential is dependent on its antiinflammatory and antiapoptotic effects mediated by scavenging hydroxyl radicals, decreasing formation of tumor necrosis factor-α, and inhibition of poly (ADP-ribose) polymerase activity. In addition, increasing evidence indicates that cilostazol may offer endothelial protection via both the inhibition of lipopolysaccharide-induced apoptosis and induced nitric oxide (NO) production by endothelial NO synthase activation. The breakdown of the barrier permeability of the blood brain barrier (BBB) often accelerates the progression of diseases such as cerebral ischemia. However, the molecular mechanisms involved in BBB disruption have not been fully determined. Identification of the molecules responsible for the disruption of the endothelial barrier may yield new therapeutic targets in intractable diseases. This article reviews the protective effects of cilostazol against transient focal cerebral ischemia and hemorrhagic transformation and its mechanism of action.

Blockade of phosphodiesterase-III protects against oxygen-glucose deprivation in endothelial cells by upregulation of VE-cadherin.

We recently reported that a phosphodiesterase-III inhibitor, cilostazol, prevented the hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tissue plasminogen activator (tPA) and that it reversed tPA-induced cell damage by protecting the neurovascular unit, particularly endothelial cells. However, the mechanisms of cilostazol action are still not clearly defined. The adheren junction (AJ) protein, VE-cadherin, is a known mediator of endothelial barrier sealing and maintenance. Therefore, we tested whether cilostazol might promote expression of adhesion molecules in endothelial cells, thereby preventing deterioration of endothelial barrier functions. Human brain microvascular endothelial cells were exposed to 6-h oxygen-glucose deprivation (OGD). We compared cilostazol with aspirin treatments and examined 2 representative AJ proteins: VE-cadherin and platelet endothelial cell adhesion molecule-1 (PECAM-1). A protein kinase A (PKA) inhibitor, LY294002 (a PI3-K inhibitor), db-cAMP, and RP-cAMPS were used to assess the roles of cAMP, PKA, and PI3-K signaling, respectively, in cilostazol-induced responses. Cilostazol and db-cAMP prevented OGD-stress injury in endothelial cells by promoting VE-cadherin expression, but not PECAM-1. Aspirin did not prevent cell damage. P13-K inhibition by LY294002 had no influence on the effects of cilostazol, but inhibition of cAMP/PKA with PKA inhibitor and Rp-cAMPS suppressed cilostazol-induced inhibition of cell damage and promotion of VE-cadherin expression. In contrast, OGD stress had no detectable effects on VEGF, VEGF receptor, or angiopoietin-1 levels. Cilostazol promotes VE-cadherin expression through cAMP/PKA-dependent pathways in brain endothelial cells; thus, cilostazol effects on adhesion molecule signaling may provide protection against OGD stress in endothelial cells.

Phosphodiesterase-III inhibitor prevents hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA.

The purpose of the present study was to investigate whether cilostazol, a phosphodiesterase-III inhibitor and antiplatelet drug, would prevent tPA-associated hemorrhagic transformation. Mice subjected to 6-h middle cerebral artery occlusion were treated with delayed tPA alone at 6 h, with combined tPA plus cilostazol at 6 h, or with vehicle at 6 h. We used multiple imaging (electron microscopy, spectroscopy), histological and neurobehavioral measures to assess the effects of the treatment at 18 h and 7 days after the reperfusion. To further investigate the mechanism of cilostazol to beneficial effect, we also performed an in vitro study with tPA and a phosphodiesterase-III inhibitor in human brain microvascular endothelial cells, pericytes, and astrocytes. Combination therapy with tPA plus cilostazol prevented development of hemorrhagic transformation, reduced brain edema, prevented endothelial injury via reduction MMP-9 activity, and prevented the blood-brain barrier opening by inhibiting decreased claudin-5 expression. These changes significantly reduced the morbidity and mortality at 18 h and 7 days after the reperfusion. Also, the administration of both drugs prevented injury to brain human endothelial cells and human brain pericytes. The present study indicates that a phosphodiesterase-III inhibitor prevents the hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA.