Tenascin-C in Tissue Repair after Myocardial Infarction in Humans.

Adverse ventricular remodeling after myocardial infarction (MI) is progressive ventricular dilatation associated with heart failure for weeks or months and is currently regarded as the most critical sequela of MI. It is explained by inadequate tissue repair due to dysregulated inflammation during the acute stage; however, its pathophysiology remains unclear. Tenascin-C (TNC), an original member of the matricellular protein family, is highly up-regulated in the acute stage after MI, and a high peak in its serum level predicts an increased risk of adverse ventricular remodeling in the chronic stage. Experimental TNC-deficient or -overexpressing mouse models have suggested the diverse functions of TNC, particularly its pro-inflammatory effects on macrophages. The present study investigated the roles of TNC during human myocardial repair. We initially categorized the healing process into four phases: inflammatory, granulation, fibrogenic, and scar phases. We then immunohistochemically examined human autopsy samples at the different stages after MI and performed detailed mapping of TNC in human myocardial repair with a focus on lymphangiogenesis, the role of which has recently been attracting increasing attention as a mechanism to resolve inflammation. The direct effects of TNC on human lymphatic endothelial cells were also assessed by RNA sequencing. The results obtained support the potential roles of TNC in the regulation of macrophages, sprouting angiogenesis, the recruitment of myofibroblasts, and the early formation of collagen fibrils during the inflammatory phase to the early granulation phase of human MI. Lymphangiogenesis was observed after the expression of TNC was down-regulated. In vitro results revealed that TNC modestly down-regulated genes related to nuclear division, cell division, and cell migration in lymphatic endothelial cells, suggesting its inhibitory effects on lymphatic endothelial cells. The present results indicate that TNC induces prolonged over-inflammation by suppressing lymphangiogenesis, which may be one of the mechanisms underlying adverse post-infarct remodeling.

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.

Successful Treatment of Full Thickness Frontal Skull Bone Defect With Dermal Fat Grafting and Artificial Bone Grafts.

Rigid reconstruction for frontal bone defects not only improves function, but also approximates more normal appearance. However, in cases involving dural scar contractures, a concave deformation remains when rigid reconstruction is performed without compensating for dead space created by swelling of the brain. This study involved 4 cases in which a 2-stage reconstruction procedure was used to first eliminate dead space by grafting dermal fat, and subsequently carry out rigid reconstruction to achieve a natural forehead configuration. This method is advantageous and considered to be effective in allowing dead space to be easily filled with minimal invasiveness for concave deformations of the dura mater with bone defects. Furthermore, the risk of artificial bone exposure is reduced by adding the dermal component of dermal fat, which is grafted to thinned frontal skin.

Simultaneous aortic valve replacement and pectus excavatum correction in a 76-year-old man.

A 76-year-old man was admitted to our department to undergo surgical treatment for aortic valve regurgitation. On physical examination, a bowl-shaped concavity was noted. Chest computed tomography revealed left-sided heart displacement by severe pectus excavatum with a Haller index of 6.40. Considering the postoperative cardiopulmonary complications that may result from mechanical compression due to uncorrected sternal deformities, we decided to perform a simultaneous aortic valve replacement and pectus excavatum correction. The operation time was long (570 min) and involved a high-volume transfusion due to excessive bleeding caused by resection of the deformed costal cartilages and sternal osteotomy under the use of heparin. The endotracheal tube was removed on the fifth postoperative day, but reintubation was required because of hypercapnea and difficulty in sputum discharge. With the aid of tube feeding for nutritional management, his cardiopulmonary function gradually ameliorated and his general condition improved. Consequently, he was weaned from mechanical ventilation on the 14th postoperative day. The patient is doing well 1 year after surgery. We report on the surgical management for pectus excavatum in adult patients.

Ceramide triggers caspase activation during gamma-radiation-induced apoptosis of human glioma cells lacking functional p53.

We have previously shown that treatment of human glioma U87-MG cells expressing wild-type p53 with a DNA topoisomerase II inhibitor, etoposide resulted in ceramide-dependent apoptotic cell death. However, U87-W E6 cells lacking functional p53 due to the expression of human papilloma virus type 16 (HPV-16) E6 oncoprotein were resistant to etoposide. In order to gain insight into the roles of p53 and ceramide in gamma-radiation-induced glioma cell death, we used U87-W E6 and vector-infected U87-LXSN cells. U87-LXSN glioma cells expressing wild-type p53 were relatively resistant to gamma-radiation. U87-W E6 cells, which lost functional p53, became susceptible to radiation-induced apoptosis. Activation of caspase-3, and formation of ceramide by acid sphingomyelinase, but not by neutral sphingomyelinase, were associated with p53-independent apoptosis. Radiation-induced caspase activation and apoptotic death in U87-W E6 cells were modified by the agents which affected ceramide metabolism. SR33557, an inhibitor of acid sphingomyelinase, suppressed radiation-induced caspase activation and then apoptotic cell death. In contrast, N-oleoylethanolamine (OE) and D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), which inhibit ceramidase and UDP-glucose:ceramide glucosyltransferase-1, respectively, and then augment ceramide formation, enhanced radiation-induced caspase activation. These results indicate that glioma cells with functional p53 were relatively resistant to gamma-radiation, and that ceramide may play an important role in caspase activation during gamma-radiation-induced apoptosis of glioma cells lacking functional p53.

[A case of a bacterial brain abscess presenting as symptoms of 'sudden stroke-like' onset].

We report a case of a bacterial brain abscess presenting symptoms of 'sudden stroke-like' onset, associated with infective endocarditis. A 59-year-old woman experienced a sudden stroke-like onset of left hemiplegia. Computed tomography (CT) and magnetic resonance imaging (MRI) were performed on the day of ictus. No lesion responsible for the symptom was seen on either CT or a T2 weighted image (T2WI), but a diffusion-weighted image (DWI) revealed focal increased signal intensity in the right frontal lobe. An initial diagnosis of acute embolic infarction associated with infective endocarditis was made. Although the patient's neurological state had been stable, motor paresis of her left extremities became worse starting one month after her admission. MRI with gadolinium-diethylenetriaminepenta-acid (Gd-DTPA) at 37 days after admission showed an irregular-shaped ring-enhancement lesion located at the same place as the initial infarction, and in the left frontal lobe. Surgical drainage of the lesion in the right frontal lobe was performed, and diagnosed as a bacterial abscess. The exact mechanism of a bacterial brain abscess presenting with 'sudden stroke-like' onset is unknown, but various hypotheses have been proposed. One is that paroxysmal septic emboli lead to abscess formation within or near the area of embolic infarction. Our case showed that the creation of a brain abscess followed embolic strokes, and that this hypothesis was demonstrated by MRI carried out on the day of ictus.

Cell permeable ROS scavengers, Tiron and Tempol, rescue PC12 cell death caused by pyrogallol or hypoxia/reoxygenation.

The role of superoxide anion (O(2)*-) in neuronal cell injury induced by reactive oxygen species (ROS) was examined in PC12 cells using pyrogallol (1,2,3-benzenetrior), a donor to release O(2)*-. Pyrogallol induced PC12 cell death at concentrations, which evidently increased intracellular O(2)*-, as assessed by O(2)(*-)-sensitive fluorescent precursor hydroethidine (HEt). Caspase inhibitors, Z-VAD-FMK and Z-Asp-CH(2)-DCB, failed to protect cells from injury caused by elevation of intracellular O(2)*-, although these inhibitors had effects on hypoxia- or hydrogen peroxide (H(2)O(2))-induced PC12 cell death. Two known O(2)*- scavengers, Tiron (4,5-dihydroxy-1,3-benzenedisulfonic acid) and Tempol (4-hydroxy-2,2,6,6-tetramethylpiperydine-1-oxyl) rescued PC12 cells from pyrogallol-induced cell death. Hypoxia/reoxygenation injury of PC12 cells was also blocked by Tiron and Tempol. Further understanding of the underlying mechanism of the protective effects of these radical scavengers reducing intracellular O(2)*- on neuronal cell death may lead to development of new therapeutic treatments for hypoxic/ischemic brain injury.

Acid sphingomyelinase activation requires caspase-8 but not p53 nor reactive oxygen species during Fas-induced apoptosis in human glioma cells.

During apoptosis of human glioma cells induced by anti-Fas antibody, ceramide formation with activation of acid, but not neutral sphingomyelinase (SMase), was observed. A potent inhibitor of acid SMase, SR33557, effectively inhibited ceramide formation and apoptosis. Fas-induced apoptosis and ceramide formation proceeded regardless of p53 status. The agents, which modify intracellular levels of reactive oxygen species (ROS) and reduced glutathione (GSH), failed to modulate Fas-induced acid SMase activation and apoptosis. Moreover, expression of functional p53 protein using a temperature-sensitive human p53val(138) induced ceramide generation by activation of neutral SMase but not acid SMase through ROS formation. Peptide inhibitors for caspases-8 (z-IETD-fmk) and -3 (z-DEVD-fmk) suppressed Fas-induced apoptosis. However, activation of acid SMase was inhibited only by z-IETD-fmk. Thus, ceramide generated by acid SMase may take a part in Fas-induced apoptosis of human glioma cells and acid SMase activation may be dependent on caspase-8 activation, but not on p53 nor ROS.