Endoribonucleolytic Cleavage of m6A-Containing RNAs by RNase P/MRP Complex.

N6-methyladenosine (m6A) is the most abundant internal modification in RNAs and plays regulatory roles in a variety of biological and physiological processes. Despite its important roles, the molecular mechanism underlying m6A-mediated gene regulation is poorly understood. Here, we show that m6A-containing RNAs are subject to endoribonucleolytic cleavage via YTHDF2 (m6A reader protein), HRSP12 (adaptor protein), and RNase P/MRP (endoribonucleases). We demonstrate that HRSP12 functions as an adaptor to bridge YTHDF2 and RNase P/MRP, eliciting rapid degradation of YTHDF2-bound RNAs. Transcriptome-wide analyses show that m6A RNAs that are preferentially targeted for endoribonucleolytic cleavage have an HRSP12-binding site and a RNase P/MRP-directed cleavage site upstream and downstream of the YTHDF2-binding site, respectively. We also find that a subset of m6A-containing circular RNAs associates with YTHDF2 in an HRSP12-dependent manner and is selectively downregulated by RNase P/MRP. Thus, our data expand the known functions of RNase P/MRP to endoribonucleolytic cleavage of m6A RNAs.

Structural insights into ClpP protease side exit pore-opening by a pH drop coupled with substrate hydrolysis.

The ClpP serine peptidase is a tetradecameric degradation molecular machine involved in many physiological processes. It becomes a competent ATP-dependent protease when coupled with Clp-ATPases. Small chemical compounds, acyldepsipeptides (ADEPs), are known to cause the dysregulation and activation of ClpP without ATPases and have potential as novel antibiotics. Previously, structural studies of ClpP from various species revealed its structural details, conformational changes, and activation mechanism. Although product release through side exit pores has been proposed, the detailed driving force for product release remains elusive. Herein, we report crystal structures of ClpP from Bacillus subtilis (BsClpP) in unforeseen ADEP-bound states. Cryo-electron microscopy structures of BsClpP revealed various conformational states under different pH conditions. To understand the conformational change required for product release, we investigated the relationship between substrate hydrolysis and the pH-lowering process. The production of hydrolyzed peptides from acidic and basic substrates by proteinase K and BsClpP lowered the pH values. Our data, together with those of previous findings, provide insight into the molecular mechanism of product release by the ClpP self-compartmentalizing protease.

A cross-species approach using an in vivo evaluation platform in mice demonstrates that sequence variation in human RABEP2 modulates ischemic stroke outcomes.

Ischemic stroke, caused by vessel blockage, results in cerebral infarction, the death of brain tissue. Previously, quantitative trait locus (QTL) mapping of cerebral infarct volume and collateral vessel number identified a single, strong genetic locus regulating both phenotypes. Additional studies identified RAB GTPase-binding effector protein 2 (Rabep2) as the casual gene. However, there is yet no evidence that variation in the human ortholog of this gene plays any role in ischemic stroke outcomes. We established an in vivo evaluation platform in mice by using adeno-associated virus (AAV) gene replacement and verified that both mouse and human RABEP2 rescue the mouse Rabep2 knockout ischemic stroke volume and collateral vessel phenotypes. Importantly, this cross-species complementation enabled us to experimentally investigate the functional effects of coding sequence variation in human RABEP2. We chose four coding variants from the human population that are predicted by multiple in silico algorithms to be damaging to RABEP2 function. In vitro and in vivo analyses verify that all four led to decreased collateral vessel connections and increased infarct volume. Thus, there are naturally occurring loss-of-function alleles. This cross-species approach will expand the number of targets for therapeutics development for ischemic stroke.

Combined clinical, structural, and cellular studies discriminate pathogenic and benign TRPV4 variants.

Dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) cause diverse and largely distinct channelopathies, including inherited forms of neuromuscular disease, skeletal dysplasias, and arthropathy. Pathogenic TRPV4 mutations cause gain of ion channel function and toxicity that can be rescued by small molecule TRPV4 antagonists in cellular and animal models, suggesting that TRPV4 antagonism could be therapeutic for patients. Numerous variants in TRPV4 have been detected with targeted and whole exome/genome sequencing, but for the vast majority, their pathogenicity remains unclear. Here, we used a combination of clinical information and experimental structure-function analyses to evaluate 30 TRPV4 variants across various functional protein domains. We report clinical features of seven patients with TRPV4 variants of unknown significance and provide extensive functional characterization of these and an additional 17 variants, including structural position, ion channel function, subcellular localization, expression level, cytotoxicity, and protein-protein interactions. We find that gain-of-function mutations within the TRPV4 intracellular ankyrin repeat domain target charged amino acid residues important for RhoA interaction, whereas ankyrin repeat domain residues outside of the RhoA interface have normal or reduced ion channel activity. We further identify a cluster of gain-of-function variants within the intracellular intrinsically disordered region that may cause toxicity via altered interactions with membrane lipids. In contrast, assessed variants in the transmembrane domain and other regions of the intrinsically disordered region do not cause gain of function and are likely benign. Clinical features associated with gain of function and cytotoxicity include congenital onset of disease, vocal cord weakness, and motor predominant disease, whereas patients with likely benign variants often demonstrated late-onset and sensory-predominant disease. These results provide a framework for assessing additional TRPV4 variants with respect to likely pathogenicity, which will yield critical information to inform patient selection for future clinical trials for TRPV4 channelopathies.

Stabilization of activated mast cells by ORAI1 inhibitor suppresses peanut-induced anaphylaxis and acute diarrhea.

Mast cell (MC) activation triggered by immunoglobulin E (IgE)-antigen crosslinking involves intracellular Ca2+ influx through the ORAI1 channel, which precedes granule exteriorization and de novo synthesis of mediators. Pharmacologically suppressing MCs via the inhibition of the ORAI1 Ca2+ channel may represent a potential strategy for preventing anaphylaxis. This study demonstrated that peanut-induced anaphylaxis in sensitized mice resulted in significant hypothermia and acute diarrhea. Utilizing the Mcpt5cre-DTA mouse model, we demonstrated that this anaphylactic response was mediated by IgE-antigen-induced MC activation. Prophylactic administration of MC suppressors was an effective means of preventing peanut-induced anaphylaxis. In addition, we observed the potent efficacy of an ORAI1 inhibitor in suppressing the FcεRI-mediated response of murine or human MCs, even when administered concurrently or post-allergen exposure. Mechanistically, the ORAI1 inhibitor was found to prevent the association of Synaptotagmin-2 with the SNARE complex. In an in vivo mouse model of peanut-induced anaphylaxis, the administration of the ORAI1 inhibitor after allergen challenge effectively suppressed allergic acute diarrhea and ameliorated anaphylaxis. Therefore, pharmacological intervention of ORAI1 channel inhibition in MCs represents a promising therapeutic avenue for the treatment of peanut-induced anaphylaxis and acute diarrhea in vivo.

Use of the LC3B-fusion technique for biochemical and structural studies of proteins involved in the N-degron pathway.

The N-degron pathway, formerly the N-end rule pathway, is a protein degradation process that determines the half-life of proteins based on their N-terminal residues. In contrast to the well-established in vivo studies over decades, in vitro studies of this pathway, including biochemical characterization and high-resolution structures, are relatively limited. In this study, we have developed a unique fusion technique using microtubule-associated protein 1A/1B light chain 3B, a key marker protein of autophagy, to tag the N terminus of the proteins involved in the N-degron pathway, which enables high yield of homogeneous target proteins with variable N-terminal residues for diverse biochemical studies including enzymatic and binding assays and substrate identification. Intriguingly, crystallization showed a markedly enhanced probability, even for the N-degron complexes. To validate our results, we determined the structures of select proteins in the N-degron pathway and compared them with the Protein Data Bank-deposited proteins. Furthermore, several biochemical applications of this technique were introduced. Therefore, this technique can be used as a general tool for the in vitro study of the N-degron pathway.

Hypofractionated stereotactic radiosurgery for large-sized skull base meningiomas.

PURPOSE: Although stereotactic radiosurgery (SRS) has been proven to be effective and safe for treating intracranial meningiomas, concerns have been raised about the use of SRS for large-sized tumors involving the skull base that frequently encroach onto adjacent critical neural structures. The purpose of this study was to investigate the role of hypofractionated SRS as a therapeutic option for large-sized skull base meningiomas. METHODS: Thirty-one consecutive patients (median age: 55 years, 9 men and 22 women) who had been treated with hypofractionated SRS using CyberKnife for large-sized skull base meningiomas (> 10 cm3 in volume, median of 18.9 cm3, range 11.6-58.2 cm3) were enrolled. All patients harbored middle or posterior skull base tumors, most frequently of cavernous sinus (n = 7, 22.6%), petroclival (n = 6, 19.4%), or tentorial edge (n = 6, 19.4%) locations. SRS was delivered in five daily fractions (range 3-5 fractions) with a median cumulative dose of 27.8 Gy (range 22.6-27.8 Gy). RESULTS: With a median follow-up of 57 months (range 9-98 months), tumor control was achieved for 28 (90.3%) of 31 patients. Treatment response on MRI included partial response (volume decrease > 20%) in 17 (54.8%) patients, stable in 11 (35.5%), and progression (volume increase > 20%) in 3 (9.7%). Of 21 patients with cranial neuropathy, 20 (95.2%) showed improved neurological status. CONCLUSIONS: Our current results suggest a promising role of hypofractionated SRS for large-sized skull base megningiomas in terms of tumor control and neurological outcomes. It is a reasonable therapeutic option for select patients.

Unveiling the pathway to Z-DNA in the protein-induced B-Z transition.

Left-handed Z-DNA is an extraordinary conformation of DNA, which can form by special sequences under specific biological, chemical or physical conditions. Human ADAR1, prototypic Z-DNA binding protein (ZBP), binds to Z-DNA with high affinity. Utilizing single-molecule FRET assays for Z-DNA forming sequences embedded in a long inactive DNA, we measure thermodynamic populations of ADAR1-bound DNA conformations in both GC and TG repeat sequences. Based on a statistical physics model, we determined quantitatively the affinities of ADAR1 to both Z-form and B-form of these sequences. We also reported what pathways it takes to induce the B-Z transition in those sequences. Due to the high junction energy, an intermediate B* state has to accumulate prior to the B-Z transition. Our study showing the stable B* state supports the active picture for the protein-induced B-Z transition that occurs under a physiological setting.

Role of gamma knife radiosurgery for recurrent or residual World Health Organization grade II and III intracranial meningiomas.

Background: To analysis the role of gamma knife radiosurgery (GKRS) in treatment of the recurrent or residual World Health Organization (WHO) grade II and III meningiomas.Methods: Between 1995 and 2015, a total of 1163 meningioma patients were treated with GKRS at our single institute; 26 atypical and 6 anaplastic meningiomas were enrolled. The group consisted of 16 men and 16 women with a median age of 59.5 years (range 30-78 years). The median follow-up was 106.5 months (range 40-216 months). All were cases of tumour recurrence except 7 cases of residual lesions. Six patients were given fractionated radiotherapy before the initial course of GKRS (median dose, 56 Gy).Results: The median tumour volume was 3035 mm3 (range 247-11400 mm3). The median prescribed dose to high grade meningioma margin was 14 Gy (range 12-20 Gy,). The median prescribed dose to WHO II and III meningioma were 14 Gy (range 12-18 Gy) and 15 Gy (range 14-20 Gy), respectively. After radiosurgery, local tumour control rate was 50%. Tumour progression was observed in 28 patients; 16 recurrences were local (12 atypical and 4 anaplastic), 8 were marginal (7 atypical and 1 anaplastic), and 4 were distal (3 atypical and 1 anaplastic). Seven patients (21.88%) developed adverse radiation effects after GKRS. WHO grade was strongly associated with survival, with grade II showing a much longer survival (p = 0.01), and a prior history of radiation was associated with decreased survival (p = 0.003). Multivariate analysis showed that WHO grade (hazard ratio, HR: 5.051, p = 0.01) and prior radiation (HR: 5.763, p = 0.004) were independently associated with survival.Conclusions: WHO grade and a prior history of radiation therapy are reliable long-term predictors of overall outcome when treated with GKRS.

Targeted Degradation of Transcription Coactivator SRC-1 through the N-Degron Pathway.

Aberrantly elevated steroid receptor coactivator-1 (SRC-1) expression and activity are strongly correlated with cancer progression and metastasis. Here we report, for the first time, the development of a proteolysis targeting chimera (PROTAC) that is composed of a selective SRC-1 binder linked to a specific ligand for UBR box, a unique class of E3 ligases recognizing N-degrons. We showed that the bifunctional molecule efficiently and selectively induced the degradation of SRC-1 in cells through the N-degron pathway. Importantly, given the ubiquitous expression of the UBR protein in most cells, PROTACs targeting the UBR box could degrade a protein of interest regardless of cell types. We also showed that the SRC-1 degrader significantly suppressed cancer cell invasion and migration in vitro and in vivo. Together, these results demonstrate that the SRC-1 degrader can be an invaluable chemical tool in the studies of SRC-1 functions. Moreover, our findings suggest PROTACs based on the N-degron pathway as a widely useful strategy to degrade disease-relevant proteins.

Single-fraction versus hypofractionated stereotactic radiosurgery for medium-sized brain metastases of 2.5 to 3 cm.

PURPOSE: Given recently suggested utility of hypofractionated stereotactic radiosurgery (SRS) in treating large brain metastases (BMs) > 3 cm, we sought to prospectively control tumor size variable to investigate the efficacy and safety of hypofractionated SRS for medium-sized BMs (2.5 to 3 cm) compared with single-fraction SRS. METHODS: Between 2011 and 2015, a total of 100 patients with newly diagnosed BMs (n = 105) of 2.5 to 3 cm had been treated with either single-fraction (n = 67; median dose 20 Gy) or hypofractionated SRS (n = 38; median cumulative dose 35 Gy in 5 daily fractions). No patients received any prior or upfront whole brain radiotherapy. In each patient, treatment outcome was measured by local tumor control (LTC), overall and progression-free survival (OS and PFS), and the occurrence of radiation necrosis (RN). RESULTS: With a median follow-up of 14 months, significant differences were observed between the single-fraction versus hypofractionated SRS groups in the incidence of RN (29.9% vs. 5.3%, P < 0.001) and LTC (1-year LTC rates 66.6% vs. 92.4%, P = 0.028). There were no differences in PFS (median 6 months vs. 6 months, P = 0.381) and OS (median 13 months vs. 18 months, P = 0.239). Treatment-related adverse events ( ≥ grade 2 toxicity by CTCAE ver. 4.0) occurred more frequently in single-fraction group, although the difference did not reach statistical significance (56.3% vs. 36.1%, P = 0.084). CONCLUSIONS: Our results suggest a better safety and efficacy profile of hypofractionated SRS for medium-sized BMs compared with single-fraction SRS. Further prospective studies are needed to confirm these results.

The structure of the pleiotropic transcription regulator CodY provides insight into its GTP-sensing mechanism.

GTP and branched-chain amino acids (BCAAs) are metabolic sensors that are indispensable for the determination of the metabolic status of cells. However, their molecular sensing mechanism remains unclear. CodY is a unique global transcription regulator that recognizes GTP and BCAAs as specific signals and affects expression of more than 100 genes associated with metabolism. Herein, we report the first crystal structures of the full-length CodY complex with sensing molecules and describe their functional states. We observed two different oligomeric states of CodY: a dimeric complex of CodY from Staphylococcus aureus with the two metabolites GTP and isoleucine, and a tetrameric form (apo) of CodY from Bacillus cereus Notably, the tetrameric state shows in an auto-inhibitory manner by blocking the GTP-binding site, whereas the binding sites of GTP and isoleucine are clearly visible in the dimeric state. The GTP is located at a hinge site between the long helical region and the metabolite-binding site. Together, data from structural and electrophoretic mobility shift assay analyses improve understanding of how CodY senses GTP and operates as a DNA-binding protein and a pleiotropic transcription regulator.

A novel conformation of the LC3-interacting region motif revealed by the structure of a complex between LC3B and RavZ.

LC3-family member proteins play a critical role in autophagy, a cellular process responsible for the degradation of massive cellular components including intracellular pathogens. A variety of molecules involved in the autophagic pathway engage in specific interactions with a unique sequence motif referred to as the LIR (LC3-interacting region) motif. Although identification of conserved structural features of LIR motifs in complex with LC3-family members has established a canonical LIR motif, atypical conformations of LIR motifs have recently been revealed. Here, we determined the three-dimensional crystal structures of LC3B in complex with three different LIR motifs of RavZ from Legionella pneumophila, an intracellular pathogen that can manipulate the host autophagy system. The tandem LIR motifs located in the N-terminal region of RavZ adopt a novel ß-sheet conformation and thus provide specific ionic interactions with LC3B in addition to canonical hydrophobic plugged-in interactions. Consequently, these motifs possess higher binding affinity to LC3-family members than canonical LIR motifs, although the tandem repeats can only bind to one LC3 molecule. These findings broaden our understanding of the functional repertoire of LIR motifs in autophagy.

Hypofractionated stereotactic radiosurgery for pituitary metastases.

Pituitary metastases (PMs) are uncommon, representing only 1% of pituitary lesions. The diagnosis of PMs can be challenging and an optimal management remains to be determined. Here, we present a pilot clinical study on the efficacy and safety of hypofractionated stereotactic radiosurgery (SRS) with an optimized dosimetric plan in treating PMs. Between June 2013 and December 2014, seven consecutive patients (4 men and 3 women; median age 62 years) had been diagnosed with PMs based on their characteristic clinical and radiological features and subsequently treated using hypofractionated SRS. Primary cancers originated from the lung (n = 5) or the breast (n = 2). All patients presented with diabetes insipidus (DI). Anterior pituitary and visual dysfunction were combined in 4 and 3 patients, respectively. On magnetic resonance imaging (MRI), PMs involved the pituitary stalk and/or the posterior lobe in all patients. SRS of a cumulative marginal dose 31 Gy with dose-volume constraints for the optic apparatus was delivered in 5 daily fractions. As results, tumor was locally controlled in all patients with substantial responses on MRI (including complete remission in 4 patients). The median survival time was 14 months (range, 6-24 months) after SRS. DI and visual dysfunction improved in all patients, although anterior pituitary dysfunction did not recover. No patients experienced any deterioration in visual, pituitary, or other cranial nerve functions. These results suggest a promising role of hypofractionated SRS in treating PMs in terms of both tumor control and functional outcomes.

Self-reverse-biased solar panel optical receiver for simultaneous visible light communication and energy harvesting.

We propose a self-reverse-biased solar panel optical receiver for energy harvesting and visible light communication. Since the solar panel converts an optical component into an electrical component, it provides both energy harvesting and communication. The signal component can be separated from the direct current component, and these components are used for communication and energy harvesting. We employed a self-reverse-biased receiver circuit to improve the communication and energy harvesting performance. The reverse bias on the solar panel improves the responsivity and response time. The proposed system achieved 17.05 mbps discrete multitone transmission with a bit error rate of 1.1 x 10-3 and enhanced solar energy conversion efficiency.

Inter-cell interference mitigation in multi-cellular visible light communications.

Inter-cell interference hinders multi-cellular optical wireless communication to support various applications. We proposed and experimentally demonstrated a multicarrier-based cell partitioning scheme, combined with frequency reuse, which could be effective in optical communications although it is inefficient in RF wireless communications. For multicarrier-based cell partitioning, Orthogonal frequency division multiplexing-based multiple access (OFDMA) was employed to accommodate multi-cellular optical wireless communications without a large guard band between adjacent cells and without additional RF components. Moreover, we employed filter bank-based multicarrier (FBMC) to mitigate inter-cell interference generated in OFDMA-based cell partitioning due to asynchronous signals originated from RF path difference. By using FBMC-based cell partitioning, inter-cell interference could be effectively mitigated as well as capacity and spectral efficiency were improved about 1.5 times compared to those of OFDMA. Because no cyclic prefix (CP) is required in FBMC, the improvement factor could be increased if there is a large RF path difference between lighting cells. Moreover, it could be a stronger solution when many neighboring cells exist causing large interference. The proposed multicarrier-based cell partitioning combined with FBMC will effectively support visible light communication (VLC)-based localization-based services (LBS) and indoor positioning system by transparently providing trilateration-based positioning method.

Treatment strategies for dissecting aneurysms of the posterior cerebral artery.

BACKGROUND: Dissecting aneurysms of the posterior cerebral artery (PCA) are rare and difficult to treat because of their deep and unfamiliar locations and unusual shapes. Although several treatment modalities have been proposed, none have generated satisfying results. Our experiences with PCA-dissecting aneurysms are reviewed and the treatment strategies discussed. METHODS: All consecutive patients with PCA-dissecting aneurysm who were treated in a tertiary referral hospital between January 1998 and March 2014 were identified by retrospective review. Their clinical characteristics, radiological findings, treatment modalities and outcomes were documented. RESULTS: Of the 21 patients with 21 PCA-dissecting aneurysms, 9 had subarachnoid hemorrhage and 3 had acute infarction of the thalamus at presentation. The aneurysms involved P1 (n = 4), the P1-2 junction (n = 3), mid-P2 (n = 6), P2A (n = 3), P2P (n = 1) and the P2-3 junction (n = 4). The aneurysm shapes were as follows: fusiform (n = 12), partially thrombosed (n = 8) and blood blister-like aneurysms (n = 1). The mean size was 16.6 ± 9.7 mm. Parent artery occlusion (PAO) without bypass (n = 15), PAO with bypass (n = 2), stent-assisted endosaccular coiling (n = 3) and stent placement only (n = 1) were performed. All three patients who underwent stent-assisted endosaccular coiling and the single patient who underwent PAO without bypass developed aneurysm recurrence. Six of the ten patients who received a PAO without a balloon test occlusion (BTO) experienced PCA territory infarction, whereas only one of the five patients who received a PAO after passing the BTO experienced an infarction. CONCLUSIONS: PAO for PCA-dissecting aneurysm was effective in preventing recurrence. In addition, BTO before PAO was helpful in identifying candidates who truly needed surgical revascularization.

Experiences on two different stereotactic radiosurgery modalities of Gamma Knife and Cyberknife in treating brain metastases.

BACKGROUND: In this study, we compared the dosimetric properties between Gamma Knife (GK) and Cyberknife (CK), and investigated the clinical implications in treating brain metastases (BMs). METHODS: Between 2011 and 2013, 77 patients treated with either single-fraction GK for small BMs (n = 40) or fractionated CK for large BMs >3 cm (n = 37) were analyzed. Among a total of 160 lesions, 81 were treated with GK (median, 22 Gy) and 38 (large lesions) with three- or five-fraction CK (median, 35 Gy). The median tumor volume was 1.0 cc (IQR, 0.12-4.4 cc) for GK and 17.6 cc (IQR, 12.8-23.7 cc) for fractionated CK. A lesion-to-lesion dosimetric comparison was performed using the identical contour set in both systems. RESULTS: The mean dose to tumor was significantly higher in GK by 1.25-fold (P < 0.001), whereas normal tissue volume receiving 90-10 % of prescription dose was significantly larger in CK by 1.26-fold (P < 0.001). Nevertheless, no differences were observed in local tumor control (rates at 1 year, 89.7 % vs 87.0 %; P = 0.594) and overall survival (median, 14 vs 16 months; P = 0.493) between GK and fractionated CK groups. The incidences of radiation necrosis were also not different (12.3 % vs 15.8 %; P = 0.443). CONCLUSIONS: Despite slightly inferior dosimetric properties of CK, fractionated CK for large BMs appears to be as effective and safe as single-fraction GK for small BMs, representing fractionation as an effective strategy for enhancing efficacy and moderating toxicity in stereotactic radiosurgery for BMs.

Characteristics and outcomes of varied treatment modalities for partially thrombosed intracranial aneurysms: a review of 35 cases.

OBJECTIVE: The purpose of this study was to analyze the characteristics of partially thrombosed intracranial aneurysms (PTIAs) in terms of location, shape, size, and symptoms, and to assess outcome according to the type of treatment. METHODS: We reviewed the radiological and clinical findings of 35 cases of PTIAs followed in our institution between 2006 and 2011. We divided all treatment modalities into two groups. Patients in group A (n = 15) were treated by blood flow blockage from the lesion of the pathogenic segment of the parent where the PTIAs originated, and patients in group B (n = 20) were only treated with obliteration of the remnant perfused aneurysmal sac. Radiological and clinical outcomes of treatment were compared between the two groups. RESULTS: Group A showed complete occlusion in 15 cases (100 %) compared to six cases (30.0 %) in group B (p < 0.001). No cases required retreatment in group A, while six cases (30.0 %) underwent retreatment in group B (p = 0.027). In terms of clinical outcome, 12 cases (80.0 %) showed symptomatic improvement in group A compared to eight cases (40.0 %) in group B (p = 0.037). Nine cases (60.0 %) showed improvement in postoperative GOS at six months compared to initial preoperative GOS in group A versus four (20.0 %) in group B (p = 0.032). CONCLUSION: PTIAs should be treated by preventing blood flow from the lesion of the pathogenic segment of the parent artery where PTIAs originate. This treatment approach is associated with better clinical and radiological outcomes.

Re-exploration of the craniotomy after surgical treatment of unruptured intracranial aneurysms.

BACKGROUND: Unplanned re-exploration of the craniotomy after surgical treatment of unruptured intracranial aneurysms (UIAs) is sometimes required, but the underlying causes and rates of these procedures are seldom reported. This study retrospectively analyzed the causes of such re-explorations to identify methods for decreasing their necessity. METHOD: From January 2000 to December 2011, 1,720 patients with a total of 1,938 UIAs underwent surgical treatment at our institution. From this cohort, 26 patients (1.5 %) with 38 UIAs required re-exploration. Clinical data, aneurysm characteristics, treatment methods, and the incidence and causes of re-exploration of the craniotomy were analyzed for these 26 patients. RESULTS: Several causes of re-exploration were identified: compromised distal blood flow (eight patients, 0.47 %), hemorrhagic venous infarction (four patients, 0.23 %), brain retraction injury (three patients, 0.17 %), newly identified aneurysms (three patients, 0.17 %), bleeding from an incompletely clipped aneurysm (two patients, 0.12 %), epidural hematoma (two patients, 0.12 %), failed aneurysm clipping (two patients, 0.12 %) and other causes (two patients, 0.12 %). Annual re-exploration incidence rates ranged from 0 to 3.1 %. Annual incidence rates gradually decreased following the introduction of several intraoperative monitoring systems. CONCLUSIONS: Precise surgical planning and careful operative techniques can reduce the incidence of unplanned re-exploration of the craniotomy. The introduction of various intraoperative monitoring systems can also contribute to a reduction in this incidence.