Methods. NETs were induced by treating human neutrophils with phorbol myristate acetate (PMA) in vitro. We examined whether the addition of PTU influenced the NET formation induced by PMA and the degradation of NETs by DNase I, which is regarded as a regulator of NETs. Furthermore, we examined whether NETs generated by the combination of PMA and PTU induced MPO ANCA and MPO AAV in vivo in rats.Results. When NETs were induced by PMA with PTU using human neutrophils in vitro, abnormal conformation of NETs was observed. Interestingly, the abnormal NETs were hardly digested by DNase I. Moreover, rats immunized with the abnormal NETs, which had been induced by PMA with PTU using rat neutrophils, produced MPO ANCA and developed pulmonary capillaritis. When rats were given oral PTU with intraperitoneal injection of PMA, pauci-immune glomerulonephritis and pulmonary capillaritis occurred with MPO ANCA production in the serum.Conclusion. Our findings indicate that abnormal conformation and impaired degradation of NETs induced by PTU are involved in the pathogenesis of PTU-induced MPO ANCA production and MPO AAV. These findings suggest that disordered NETs can be critically implicated in the pathogenesis of MPO AAV.
Polycystic kidney disease (PKD) is a genetic disorder that is characterized by cyst formation in kidney tubules. PKD arises from abnormalities of the primary cilium, a sensory organelle located on the cell surface. Here, we show that the primary cilium of renal epithelial cells contains a protein complex comprising adenylyl cyclase 5/6 (AC5/6), A-kinase anchoring protein 150 (AKAP150), and protein kinase A. Loss of primary cilia caused by deletion of
Kif3a
results in activation of AC5 and increased cAMP levels. Polycystin-2 (PC2), a ciliary calcium channel that is mutated in human PKD, interacts with AC5/6 through its C terminus. Deletion of PC2 increases cAMP levels, which can be corrected by reexpression of wild-type PC2 but not by a mutant lacking calcium channel activity. Phosphodiesterase 4C (PDE4C), which catabolizes cAMP, is also located in renal primary cilia and interacts with the AKAP150 complex. Expression of PDE4C is regulated by the transcription factor hepatocyte nuclear factor-1β (HNF-1β), mutations of which produce kidney cysts. PDE4C is down-regulated and cAMP levels are increased in HNF-1β mutant kidney cells and mice. Collectively, these findings identify PC2 and PDE4C as unique components of an AKAP complex in primary cilia and reveal a common mechanism for dysregulation of cAMP signaling in cystic kidney diseases arising from different gene mutations.
Functional analyses of neural RNA-binding proteins have focused mainly on their roles as modulators of posttranscriptional gene regulation, e.g., alternative splicing, dendritic mRNA localization, and local translation. Here we identified a mouse homologue of human IMP3, which is known to bind to and repress the translation of igf2 leader 3 mRNA. The mouse igf2 mRNA-binding protein 3 (mIMP3) is a member of the zipcode binding protein-1 (ZBP-1) family previously reported in chick fibroblast cells. mIMP3 was expressed in undifferentiated neuroepithelial cells and some postmitotic neurons at early embryonic stages (E10.5--E12.5), and its expression level decreased after the midembryonic stage (E12.5) until birth. The expression profile of mIMP3 is very similar to that of mouse igf2 leader 3 mRNA. In vitro UV cross-linking experiments showed that mIMP3 preferentially bound to igf2 leader 3 mRNA rather than igf2 leader 4 mRNA and did not bind the zipcode region of beta-actin or c-myc mRNA. Furthermore, persistent expression of mIMP3 protein in an undifferentiated P19 cell line revealed that mIMP3 inhibited neuronal differentiation morphologically and immunohistochemically. Taken together, these observations raise the possibility that mIMP3 represses neuronal differentiation through the regulation of igf2 mRNA expression.
Surfactants reduced bubble adhesion force and preserved basic endothelial structure and vasodilatory function despite attempts to damage the endothelium. Surfactants seem to protect the endothelium from mechanically induced injury in addition to decreasing bubble adhesion forces.
Vascular closure staple clips made of titanium were originally developed for microvascular anastomosis. Clinical applications for these clips include arteriotomy closure for carotid endarterectomy, extracranial-intracranial bypass, and dural closure. This is the first report in which vascular closure staple clips have been used successfully for direct repair of a tear on the internal carotid artery (ICA). This report involves a 65-year-old man who presented with sudden onset of headache. Admission computerized tomography scans demonstrated a diffuse and thick subarachnoid hemorrhage in the basal cisterns. Cerebral angiograms demonstrated a broad-based, small bulge on the superomedial wall of the left ICA. Intraoperatively, an extremely thin-walled aneurysm was seen on the segment of the ICA at the C-2 vertebral level. The aneurysm ruptured abruptly, although no surgical manipulation was being performed on the aneurysm itself. After temporary clips were applied on the vessel, a large tear of the ICA was repaired with vascular closure staple clips. Reconstruction with the vascular closure staple clips required only a short period of temporary occlusion of the ICA. Postoperative angiograms revealed reduction of the aneurysm bulge and good patency of the ICA. The postoperative course was uneventful, and the patient has been free of symptoms. The vascular closure staple clipping procedure is useful for urgent repair of an aneurysm tear. This method is a new treatment option for these fragile aneurysms in cases in which other options, such as encircling clips or bypass procedures, may have drawbacks or be impossible.
This special group of aneurysms is very rare, is located exclusively in the intradural space, and carries the risk of SAH. The results of surgical treatment for this aneurysm are quite satisfactory.
Simultaneous monitoring with the microscope and endoscope is extremely useful in applying clips to ICA aneurysms. This combined method allows for direct dissection of the aneurysm, perforating vessels, and the main trunk in an area not visible through the microscope's eyepiece and promises better surgical results.
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