Publications by authors named "Koji Tsutsumi"

52 Publications

Total aortic arch replacement using the J-graft open stent graft for distal aortic arch aneurysm: report from two centres in Japan.

Interact Cardiovasc Thorac Surg 2021 Jul 30. Epub 2021 Jul 30.

Department of Cardiovascular Surgery, Saiseikai Utsunomiya Hospital, Tochigi, Japan.

Objectives: The open-style stent graft technique has been changing the strategy for true distal arch aneurysms extending to the descending aorta. Our mid-term results of surgical repair using a J-graft open stent graft are presented.

Methods: Between May 2015 and June 2020, 69 patients with a distal arch aneurysm (53 males, median age 74 years) underwent total arch replacement combined with J-graft open stent deployment. All 59 surviving patients were followed for a median follow-up period of 1.8 (0.6-3.6) years.

Results: Antegrade deployment was successfully performed in all patients without any difficulties. The deployed device was securely fixed at the target area, and it initiated thrombus formation. The diameter of the excluded aneurysm was decreased in 54 patients (91.5%) during the follow-up period. There were no type I endoleaks, but there were 3 type II endoleaks; 2 of the 3 type II endoleaks disappeared during the follow-up period. Additional endovascular operations were performed in 3 patients. There were 10 in-hospital deaths (14.5%), and the incidences of stroke, spinal cord injury and distal embolism were 11.6%, 5.8% and 2.9%, respectively. The 1- and 3-year survival rates were 84.8% and 79.4%, respectively, and the 1- and 3-year freedom from reintervention rates were 97.2% and 81.3%, respectively.

Conclusions: The J-graft open stent graft was easy to deploy, and it could shift the distal anastomosis to a more proximal side. The mid-term performance of this device was good. It has the potential to provide one-stage repair.
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http://dx.doi.org/10.1093/icvts/ivab114DOI Listing
July 2021

The effect of rotator cuff physical exercise combined with electrically stimulated antagonist on shoulder rotator cuff strength.

J Orthop Sci 2020 Dec 29. Epub 2020 Dec 29.

Division of Rehabilitation, Kurume University Hospital, Kurume, Fukuoka, Japan; Department of Orthopaedics, Kurume University, Kurume, Fukuoka, Japan.

Background: An elastic band (EB) is generally used with a low load for rotator cuff physical exercise, but the resulting increase in muscle strength is insufficient. We assessed the efficacy on external rotator muscle strength of the shoulder joint; of a hybrid training system (HTS) that resists the motion of a volitionally contracting agonist muscle using the force generated by its electrically stimulated antagonist vs. general rotator cuff exercise with EB.

Methods: Twenty healthy men with no shoulder joint disorders were randomized to 6 weeks of triweekly 10-min rotator cuff exercise with HTS or EB in a clinical research laboratory. Isokinetic concentric external rotator muscle strength at angular velocities of 60°/s and 180°/s (CON60, CON180, respectively) and isokinetic eccentric external rotator muscle strength at an angular velocity of 60°/s (ECC60) were measured as rotator cuff function before and after 6 weeks of intervention.

Results: There were no significant intergroup differences in baseline characteristics. There were statistically significant differences (p = 0.0358, p = 0.0213, respectively) in the increase in CON180 (mean ± SD) and ECC60 between the HTS group (Δ6.0 ± 6.0Nm, p = 0.015; Δ7.5 ± 4.7Nm p = 0.0007, respectively) and the EB group (Δ0.3 ± 5.2Nm, p = 0.8589; Δ1.8 ± 5.3 Nm p = 0.3133, respectively). There was a trend toward CON60 increasing in the HTS group (Δ4.7 ± 6.5Nm, p = 0.0494) which was greater than in the control group (Δ-0.9 ± 6.3Nm, p = 0.6637) (inter-group, p = 0.0677).

Conclusions: The results of this study support the conclusion that HTS is more effective for increasing external rotator muscle strength more effectively than EB. HTS would be useful for rotator cuff physical exercise.
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http://dx.doi.org/10.1016/j.jos.2020.11.015DOI Listing
December 2020

Hyperactive and impulsive behaviors of LMTK1 knockout mice.

Sci Rep 2020 09 22;10(1):15461. Epub 2020 Sep 22.

Laboratory of Molecular Neuroscience, Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University, Minami-osawa, Hachioji, Tokyo, 192-0397, Japan.

Lemur tail kinase 1 (LMTK1), previously called Apoptosis-Associated Tyrosine Kinase (AATYK), remains an uncharacterized Ser/Thr protein kinase that is predominantly expressed in the brain. It is recently reported that LMTK1A, an isoform of LMTK1, binds to recycling endosomes through its palmitoylation and regulates endosomal trafficking by suppressing the activity of Rab11 small GTPase. In neurons, knockdown or knockout of LMTK1 results in longer axons, greater branching of dendrites and increased number of spines, suggesting that LMTK1 plays a role in neuronal circuit formation. However, its in vivo function remained to be investigated. Here, we examined the brain structures and behaviors of LMTK1 knockout (KO) mice. LMTK1 was expressed in most neurons throughout the brain. The overall brain structure appeared to be normal in LMTK1 KO mice, but the numbers of synapses were increased. LMTK1 KO mice had a slight impairment in memory formation and exhibited distinct psychiatric behaviors such as hyperactivity, impulsiveness and high motor coordination without social interaction deficits. Some of these abnormal behaviors represent core features of attention deficit hyperactive disorder (ADHD), suggesting the possible involvement of LMTK1 in the pathogenesis of ADHD.
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http://dx.doi.org/10.1038/s41598-020-72304-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508861PMC
September 2020

Therapeutic potential of fibrinogen γ-chain peptide-coated, ADP-encapsulated liposomes as a haemostatic adjuvant for post-cardiopulmonary bypass coagulopathy.

Sci Rep 2020 07 9;10(1):11308. Epub 2020 Jul 9.

Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan.

Fibrinogen γ-chain peptide-coated, adenosine 5'-diphosphate (ADP)-encapsulated liposomes (H12-ADP-liposomes) are a potent haemostatic adjuvant to promote platelet thrombi. These liposomes are lipid particles coated with specific binding sites for platelet GPIIb/IIIa and encapsulating ADP. They work at bleeding sites, facilitating haemostasis by promoting aggregation of activated platelets and releasing ADP to strongly activate platelets. In this study, we investigated the therapeutic potential of H12-ADP-liposomes on post-cardiopulmonary bypass (CPB) coagulopathy in a preclinical setting. We created a post-CPB coagulopathy model using male New Zealand White rabbits (body weight, 3 kg). One hour after CPB, subject rabbits were intravenously administered H12-ADP-liposomes with platelet-rich plasma (PRP) collected from donor rabbits (H12-ADP-liposome/PRP group, n = 8) or PRP alone (PRP group, n = 8). Ear bleeding time was greatly reduced for the H12-ADP-liposome/PRP group (263 ± 111 s) compared with the PRP group (441 ± 108 s, p < 0.001). Electron microscopy showed platelet thrombus containing liposomes at the bleeding site in the H12-ADP-liposome/PRP group. However, such liposome-involved platelet thrombi were not observed in the end organs after H12-ADP-liposome administration. These findings suggest that H12-ADP-liposomes could help effectively and safely consolidate platelet haemostasis in post-CPB coagulopathy and may have potential for reducing bleeding complications after cardiovascular surgery with CPB.
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http://dx.doi.org/10.1038/s41598-020-68307-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347858PMC
July 2020

A case of a highly tortuous descending thoracic aortic aneurysm treated by surgical exclusion.

SAGE Open Med Case Rep 2020 2;8:2050313X20926440. Epub 2020 Jun 2.

Department of Cardiovascular Surgery, Keio University, Tokyo, Japan.

The patient was a 76-year-old woman with an atypical descending thoracic aortic aneurysm due to a highly tortuous descending aorta. The surgical approach in this case required special consideration because of the aneurysm's location. The main body of the aneurysm was in the right thoracic cavity. Descending thoracic aorta replacement with a prosthetic graft and aneurysmal total exclusion were performed through a left curvilinear thoracoabdominal incision. The patient's postoperative course was uneventful. Surgical exclusion of a thoracic aortic aneurysm may be a useful technique in this special situation. Postoperative follow-up is needed to prevent early and late complications.
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http://dx.doi.org/10.1177/2050313X20926440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268160PMC
June 2020

AGAP1 regulates subcellular localization of FilGAP and control cancer cell invasion.

Biochem Biophys Res Commun 2020 02 28;522(3):676-683. Epub 2019 Nov 28.

Division of Cell Biology, Department of Biosciences, School of Science, Kitasato University, 1-15-1 Kitasato, Sagamihara, Minami-ku, Kanagawa, 252-0373, Japan. Electronic address:

The Arf (ADP-ribosylation factor) GAPs (GTPase-activating proteins) regulate membrane trafficking and actin cytoskeleton. The molecular mechanism of how Arf GAPs regulate actin cytoskeleton remains to be elucidated. We identified AGAP1, a subtype of Arf GAP, as a binding protein of FilGAP, a Rac-specific GAP, in mammalian cells. AGAP1 binds to C-terminus of FilGAP whereas FilGAP binds to N-terminus of AGAP1 containing GLD domain. FilGAP co-localized with AGAP1 at intracellular vesicles and targeting of FilGAP at the vesicles requires its interaction with AGAP1. Consistently, depletion of endogenous AGAP1 induced the accumulation of endogenous FilGAP into paxillin-positive focal adhesions and actin cytoskeletal structures. Knockdown of endogenous AGAP1 suppressed cell spreading on collagen and the suppression was released by depletion of endogenous FilGAP. Moreover, depletion of AGAP1 in MDA-MB-231 cells promoted cell invasion in extracellular matrices and depletion of FilGAP blocked the invasion. Taken together, the present study suggests that AGAP1 may regulate subcellular localization of FilGAP and control cell migration and invasion through interaction with FilGAP.
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http://dx.doi.org/10.1016/j.bbrc.2019.11.147DOI Listing
February 2020

Adult untreated coarctation of the aorta developing acute type B dissection.

Asian Cardiovasc Thorac Ann 2020 Feb 19;28(2):120-122. Epub 2019 Nov 19.

Department of Cardiovascular Surgery, National Defense Medical College, Saitama, Japan.

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http://dx.doi.org/10.1177/0218492319891028DOI Listing
February 2020

The LMTK1-TBC1D9B-Rab11A Cascade Regulates Dendritic Spine Formation via Endosome Trafficking.

J Neurosci 2019 11 18;39(48):9491-9502. Epub 2019 Oct 18.

Department of Biological Sciences, Tokyo Metropolitan University, Minami-osawa, Hachioji, Tokyo 192-0397, Japan,

Dendritic spines are postsynaptic protrusions at excitatory synapses that are critical for proper neuronal synaptic transmission. While lipid and protein membrane components are necessary for spine formation, it is largely unknown how they are recruited to developing spines. Endosomal trafficking is one mechanism that may influence this development. We recently reported that Lemur kinase 1A (LMTK1A), a membrane-bound Ser/Thr kinase, regulates trafficking of endosomes in neurons. LMTK1 has been shown to be a p35 Cdk5 activator-binding protein and a substrate for Cdk5-p35; however, its neuronal function has not been sufficiently studied. Here, we investigate the role of LMTK1 in spine formation. Depletion of LMTK1 increases spine formation, maturation, and density in primary cultured neurons and in mouse brain of either sex. Additionally, expression of kinase-negative LMTK1 stimulates spine formation in primary neurons and LMTK1 controls spine formation through Rab11, a regulator of recycling endosome trafficking. We identify TBC1D9B, a Rab11A GTPase-activating protein (Rab11A GAP), as a LMTK1 binding protein, and find that TBC1D9B mediates LMTK1 activity on Rab11A. TBC1D9B inactivates Rab11A under the control of LMTK1A. Further, by analyzing the effect of decreased TBC1D9B expression in primary neurons, we demonstrate that TBC1D9B indeed regulates spine formation. This is the first demonstration of the biological function of TBC1D9B. Together, with the regulation of LMTK1 by Cdk5-p35, we propose the Cdk5-LMTK1-TBC1D9B-Rab11A cascade as a novel signaling mechanism regulating endosomal transport for synapse formation and function. Dendritic spines are postsynaptic specializations essential for synaptic transmission. However, it is not known how critical membrane components are recruited to spines for their formation. Endosomal trafficking is one such mechanism that may mediate this process. Here we investigate regulators of endosomal trafficking and their contribution to spine formation. We identify two novel factors, LMTK1 and TBC1D9B, which regulate spine formation upstream of Rab11A, a small GTPase. LMTK1 is a membrane bound Ser/Thr kinase regulated by Cdk5-p35, and TBC1D9B is a recently identified Rab11 GAP. LMTK1 controls the GAP activity of TBC1D9B on Rab11A, and TBC1D9B mediates the LMTK1 activity on Rab11A. We propose the Cdk5-LMTK1-TBC1D9B-Rab11A cascade as a novel mechanism controlling spine formation and function.
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http://dx.doi.org/10.1523/JNEUROSCI.3209-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880470PMC
November 2019

FilGAP regulates distinct stages of epithelial tubulogenesis.

Biochem Biophys Res Commun 2019 06 9;514(3):742-749. Epub 2019 May 9.

Division of Cell Biology, Department of Biosciences, School of Science, Kitasato University, Kanagawa, 252-0373, Japan. Electronic address:

Epithelial cells form a globular organ-like multi-cellular structure called cyst when cultured in extracellular matrix. The cyst generates extension followed by cell chains and tubules in response to hepatocyte growth factor (HGF). The Rho family small GTPases play essential roles for tubulogenesis. FilGAP, a Rac specific Rho GTPase-activating protein, is highly expressed in kidney. In this study, we examined the role of FilGAP in the tubulogenesis of Madin-Darby Canine Kidney (MDCK) epithelial cells. HGF induces basolateral extensions from cysts. Depletion of FilGAP by siRNA increased the number of extensions in response to HGF, whereas forced expression of FilGAP decreased the number of the extensions. FilGAP is phosphorylated and activated downstream of Rho-ROCK-signaling. Overexpression of phospho-mimic FilGAP (ST/D) mutant blocked formation of the membrane extensions induced by HGF in the presence of ROCK inhibitor, Y-27632. On the other hand, treatment of the tubules with Y27632 induced scattering of the cells, but FilGAP (ST/D) blocked cell scattering and promoted lumen formation. Taken together, our study suggests that FilGAP may suppress formation of extensions whereas stabilize tubule formation downstream of Rho-ROCK-signaling.
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http://dx.doi.org/10.1016/j.bbrc.2019.04.187DOI Listing
June 2019

Emergency surgery for left main disease: with and without cardioplegic arrest.

Asian Cardiovasc Thorac Ann 2019 Mar 19;27(3):157-162. Epub 2019 Jan 19.

1 Division of Cardiovascular Surgery, Saiseikai Utsunomiya Hospital, Tochigi, Japan.

Background: The aims of this study were to evaluate the on-pump beating-heart technique of coronary artery bypass in patients with acute myocardial infarction and left main disease, and to retrospectively compare the early postoperative results with those of conventional on-pump arrested-heart coronary surgery.

Methods: Eighty-five patients with acute myocardial infarction caused by left main disease, who underwent emergency surgery between January 1998 and April 2017 at Saiseikai Utsunomiya Hospital, were enrolled in this study. Of these patients, 56 were evaluated using propensity-matched analysis. The patients were divided into two groups according to the surgical procedure: group A ( n = 28) had on-pump surgery on the arrested heart, and group B ( n = 28) had on-pump surgery on the beating heart. Early postoperative results were compared between the two groups.

Results: Preoperative and intraoperative characteristics showed no significant differences between the two groups. The peak creatine kinase myocardial band level was significantly lower in group B (group A 151 vs. group B 91 IU·L, p = 0.01). The early mortality rate was higher in group A than group B, but the difference was not significant (group A 28.6% vs. group B 17.9%, p = 0.53).

Conclusions: There was no significant advantage based on surgical procedure between on-pump beating-heart surgery and on-pump surgery on the arrested heart. On-pump beating-heart coronary artery bypass grafting significantly reduced the peak creatine kinase myocardial band level, but there were no significant differences in the early postoperative data, including the mortality rate and left ventricular function.
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http://dx.doi.org/10.1177/0218492319826434DOI Listing
March 2019

Environmental responsiveness of tubulin glutamylation in sensory cilia is regulated by the p38 MAPK pathway.

Sci Rep 2018 05 30;8(1):8392. Epub 2018 May 30.

Department of Cellular & Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan.

Glutamylation is a post-translational modification found on tubulin that can alter the interaction between microtubules (MTs) and associated proteins. The molecular mechanisms regulating tubulin glutamylation in response to the environment are not well understood. Here, we show that in the sensory cilia of Caenorhabditis elegans, tubulin glutamylation is upregulated in response to various signals such as temperature, osmolality, and dietary conditions. Similarly, tubulin glutamylation is modified in mammalian photoreceptor cells following light adaptation. A tubulin glutamate ligase gene ttll-4, which is essential for tubulin glutamylation of axonemal MTs in sensory cilia, is activated by p38 MAPK. Amino acid substitution of TTLL-4 has revealed that a Thr residue (a putative MAPK-phosphorylation site) is required for enhancement of tubulin glutamylation. Intraflagellar transport (IFT), a bidirectional trafficking system specifically observed along axonemal MTs, is required for the formation, maintenance, and function of sensory cilia. Measurement of the velocity of IFT particles revealed that starvation accelerates IFT, which was also dependent on the Thr residue of TTLL-4. Similarly, starvation-induced attenuation of avoidance behaviour from high osmolality conditions was also dependent on ttll-4. Our data suggest that a novel evolutionarily conserved regulatory system exists for tubulin glutamylation in sensory cilia in response to the environment.
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http://dx.doi.org/10.1038/s41598-018-26694-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976657PMC
May 2018

An adult case of Kommerell's diverticulum with a right-sided aortic arch.

Asian Cardiovasc Thorac Ann 2017 May 29;25(4):307-309. Epub 2017 Apr 29.

Division of Cardiovascular Surgery, National Defense Medical College, Saitama, Japan.

The patient was a 56-year-old woman with Kommerell's diverticulum associated with a right-sided aortic arch with mirror-image branching. No other congenital heart anomalies or vascular rings were observed. Descending aortic replacement through a right posterolateral thoracotomy was performed to eliminate the risk of diverticular rupture. The patient's postoperative course was uneventful. This was a rare adult case of right-sided aortic arch with Kommerell's diverticulum associated with no other congenital heart disease.
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http://dx.doi.org/10.1177/0218492317707146DOI Listing
May 2017

Proper cytoskeletal architecture beneath the plasma membrane of red blood cells requires .

Mol Biol Cell 2017 Feb 14;28(4):535-544. Epub 2016 Dec 14.

Department of Cellular and Molecular Anatomy and International Mass Imaging Center

Mammalian red blood cells (RBCs) circulate through blood vessels, including capillaries, for tens of days under high mechanical stress. RBCs tolerate this mechanical stress while maintaining their shape because of their elastic membrane skeleton. This membrane skeleton consists of spectrin-actin lattices arranged as quasi-hexagonal units beneath the plasma membrane. In this study, we found that the organization of the RBC cytoskeleton requires tubulin tyrosine ligase-like 4 (). RBCs from -knockout mice showed larger average diameters in smear test. Based on the rate of hemolysis, -knockout RBCs showed greater vulnerability to phenylhydrazine-induced oxidative stress than did wild-type RBCs. Ultrastructural analyses revealed the macromolecular aggregation of cytoskeletal components in RBCs of -knockout mice. Immunoprecipitation using the anti-glutamylation antibody GT335 revealed nucleosome assembly protein 1 (NAP1) to be the sole target of TTLL4 in the RBCs, and NAP1 glutamylation was completely lost in -knockout RBCs. In wild-type RBCs, the amount of glutamylated NAP1 in the membrane was nearly double that in the cytosol. Furthermore, the absence of TTLL4-dependent glutamylation of NAP1 weakened the binding of NAP1 to the RBC membrane. Taken together, these data demonstrate that is required for proper cytoskeletal organization in RBCs.
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http://dx.doi.org/10.1091/mbc.E16-02-0089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5305260PMC
February 2017

The role of FilGAP, a Rac-specific Rho-GTPase-activating protein, in tumor progression and behavior of astrocytomas.

Cancer Med 2016 12 27;5(12):3412-3425. Epub 2016 Oct 27.

Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.

FilGAP, a Rac-specific Rho-GTPase-activating protein (GAP), acts as a mediator of Rho/ROCK-dependent amoeboid movement, and its knockdown results in Rac-driven mesenchymal morphology. Herein, we focused on the possible roles of FilGAP expression in astrocytomas. In clinical samples, FilGAP expression was significantly increased in grade (G) II astrocytomas as compared to normal astrocytes, but its expression strongly decreased in a grade-dependent manner, and was positively associated with isocitrate dehydrogenase 1 (IDH1) mutations and inversely to cytoplasmic Rac1. Patients with astrocytoma showing a high FilGAP score had favorable overall survival as compared to the low score patients. Multivariate Cox regression analysis also showed that a high FilGAP score was a significant and independent favorable prognostic factor. Moreover, patients with high FilGAP score and IDH1 mutant-type astrocytomas had significantly the best Overall survival (OS) and Progression-free survival (PFS), in contrast to the patients with low FilGAP score and wild-type IDH1 tumors who had the worst prognosis. In GIV tumors (GBM: glioblastomas), elongated tumor cells with low FilGAP expression were frequently observed in tumor core lesions, whereas the rounded cells with abundant expression were found in the peripheral areas adjacent to non-neoplastic brain tissues. In an astrocytoma cell line, suppression of endogenous FilGAP expression by siRNAs caused an increased proportion of mesenchymal elongated cells, probably through increased Rac1 activity. These findings suggest that FilGAP, as well as IDH1 status, may be useful for predicting the behavior of astrocytomas. In addition, the FilGAP/Rac1 axis may serve as an important regulator of tumor progression in GBMs, probably through alteration of cell morphology.
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http://dx.doi.org/10.1002/cam4.937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224849PMC
December 2016

Quantitative and combinatory determination of in situ phosphorylation of tau and its FTDP-17 mutants.

Sci Rep 2016 09 19;6:33479. Epub 2016 Sep 19.

Laboratory of Molecular Neuroscience, Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.

Tau is hyperphosphorylated in the brains of patients with tauopathies, such as Alzheimer's disease and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). However, neither the mechanism of hyperphosphorylation nor its contribution to pathogenesis is known. We applied Phos-tag SDS-PAGE, a phosphoaffinity electrophoresis, to the analysis of tau phosphorylation in vitro by Cdk5, in cultured cells and in mouse brain. Here, we found that Cdk5-p25 phosphorylated tau in vitro at Ser404, Ser235, Thr205 and Ser202 in this order. In contrast in cultured cells, Ser404 was preferentially phosphorylated by Cdk5-p35, whereas Thr205 was not phosphorylated. Ser202 and Ser235 were phosphorylated by endogenous kinases. Tau exhibited ~12 phosphorylation isotypes in COS-7 cells with different combinations of phosphorylation at Thr181, Ser202, Thr231, Ser235 and Ser404. These phosphorylation sites were similar to tau phosphorylated in mouse brains. FTDP-17 tau with a mutation in the C-terminal region had different banding patterns, indicating a different phosphorylation pattern. In particular, it was clear that the R406W mutation causes loss of Ser404 phosphorylation. These results demonstrate the usefulness of the Phos-tag technique in the quantitative analysis of site-specific in vivo phosphorylation of tau and provide detailed information on in situ combinatory phosphorylation of tau.
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http://dx.doi.org/10.1038/srep33479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027580PMC
September 2016

Kinase activity of endosomal kinase LMTK1A regulates its cellular localization and interactions with cytoskeletons.

Genes Cells 2016 Oct 7;21(10):1080-1094. Epub 2016 Sep 7.

Laboratory of Molecular Neuroscience, Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo, 192-0397, Japan.

Neurite formation, a fundamental process in neuronal maturation, requires the coordinated regulation of cytoskeletal reorganization and membrane transport. Compared to the understanding of cytoskeletal functions, less is known about the supply of membranes to growing neurites. Lemur kinase 1A (LMTK1A) is an endosomal protein kinase that is highly expressed in neurons. We recently reported that LMTK1A regulates the trafficking of Rab11-positive recycling endosomes in growing axons and dendrites. Here, we used the kinase-negative (kn) mutant to investigate the role of the kinase activity of LMTK1A in its cellular localization and interactions with the cytoskeleton in Neuro2A and PC-12 cells. Kinase activity was required for the localization of LMTK1A in the perinuclear endocytic recycling compartment. Perinuclear accumulation was microtubule dependent, and LMTK1A wild type (wt) localized mainly on microtubules, whereas kn LMTK1A was found in the actin-rich cell periphery. In the neurites of PC-12 cells, LMTK1A showed contrasting distributions depending on the kinase activity, with wt being located in the microtubule-rich shaft and the kn form in the actin-rich tip. Taken together, these results suggest that the kinase activity of LMTK1A regulates the pathway for endosomal vesicles to transfer from microtubules to actin filaments at the tip of growing neurites.
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http://dx.doi.org/10.1111/gtc.12404DOI Listing
October 2016

Src Family Tyrosine Kinase Signaling Regulates FilGAP through Association with RBM10.

PLoS One 2016 11;11(1):e0146593. Epub 2016 Jan 11.

Division of Cell Biology, Department of Biosciences, School of Science, Kitasato University, Kanagawa, 252-0373, Japan.

FilGAP is a Rac-specific GTPase-activating protein (GAP) that suppresses lamellae formation. In this study, we have identified RBM10 (RNA Binding Motif domain protein 10) as a FilGAP-interacting protein. Although RBM10 is mostly localized in the nuclei in human melanoma A7 cells, forced expression of Src family tyrosine kinase Fyn induced translocation of RBM10 from nucleus into cell peripheries where RBM10 and FilGAP are co-localized. The translocation of RBM10 from nucleus appears to require catalytic activity of Fyn since kinase-negative Fyn mutant failed to induce translocation of RBM10 in A7 cells. When human breast carcinoma MDA-MB-231 cells are spreading on collagen-coated coverslips, endogenous FilGAP and RBM10 were localized at the cell periphery with tyrosine-phosphorylated proteins. RBM10 appears to be responsible for targeting FilGAP at the cell periphery because depletion of RBM10 by siRNA abrogated peripheral localization of FilGAP during cell spreading. Association of RBM10 with FilGAP may stimulate RacGAP activity of FilGAP. First, forced expression of RBM10 suppressed FilGAP-mediated cell spreading on collagen. Conversely, depletion of endogenous RBM10 by siRNA abolished FilGAP-mediated suppression of cell spreading on collagen. Second, FilGAP suppressed formation of membrane ruffles induced by Fyn and instead produced spiky cell protrusions at the cell periphery. This protrusive structure was also induced by depletion of Rac, suggesting that the formation of protrusions may be due to suppression of Rac by FilGAP. We found that depletion of RBM10 markedly reduced the formation of protrusions in cells transfected with Fyn and FilGAP. Finally, depletion of RBM10 blocked FilGAP-mediated suppression of ruffle formation induced by EGF. Taken together, these results suggest that Src family tyrosine kinase signaling may regulate FilGAP through association with RBM10.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146593PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709192PMC
July 2016

Natural history of the ascending aorta after aortic valve replacement: risk factor analysis for late aortic complications after aortic valve replacement.

Gen Thorac Cardiovasc Surg 2016 May 24;64(5):243-50. Epub 2015 Dec 24.

Division of Cardiovascular Surgery, Hiratsuka Municipal Hospital, Hiratsuka, Kanagawa, Japan.

Background: The purpose of this study was to clarify the natural history of the ascending aorta and to identify risk factors for late ascending aortic events after first isolated aortic valve replacement (AVR).

Methods: A total of 287 patients undergoing AVR were enrolled. The patients were categorized into two groups based on the diameter of the ascending aorta at the time of AVR, as determined by computed tomography: Group A (n = 233) was defined as an ascending aortic diameter <40 mm, and Group B (n = 54) was defined as an ascending aortic diameter ≥40 mm.

Results: The mean follow-up period was 7.6 years. The baseline diameter of the ascending aorta was 31.4 ± 4.8 mm in Group A and 44.7 ± 4.2 mm in Group B. These values increased to 35.9 ± 7.4 mm in Group A and 50.1 ± 7.3 mm in Group B during the follow-up period (P < 0.001). Ten patients had acute type A aortic dissection (Group A: 1 patient vs. Group B: 9 patients; P < 0.001), and three patients had enlargement of the ascending aorta to ≥55 mm in diameter (Group A: 1 patient vs. Group B: 2 patients). Multivariate analysis revealed that the baseline ascending aortic diameter was the only significant risk factor for developing late ascending aortic events (P < 0.001).

Conclusions: AVR alone may not prevent further enlargement of the ascending aorta. An ascending aorta ≥40 mm in diameter at the time of AVR increased the risk of late ascending aortic events.
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http://dx.doi.org/10.1007/s11748-015-0617-9DOI Listing
May 2016

Phosphorylation of Serine 402 Regulates RacGAP Protein Activity of FilGAP Protein.

J Biol Chem 2015 Oct 10;290(43):26328-38. Epub 2015 Sep 10.

From the Division of Cell Biology, Department of Biosciences, School of Science, Kitasato University, 1-15-1 Kitasato, Sagamihara, Minami-ku, Kanagawa 252-0373, Japan

FilGAP is a Rho GTPase-activating protein (GAP) that specifically regulates Rac. FilGAP is phosphorylated by ROCK, and this phosphorylation stimulates its RacGAP activity. However, it is unclear how phosphorylation regulates cellular functions and localization of FilGAP. We found that non-phosphorylatable FilGAP (ST/A) mutant is predominantly localized to the cytoskeleton along actin filaments and partially co-localized with vinculin around cell periphery, whereas phosphomimetic FilGAP (ST/D) mutant is diffusely cytoplasmic. Moreover, phosphorylated FilGAP detected by Phos-tag is also mainly localized in the cytoplasm. Of the six potential phosphorylation sites in FilGAP tested, only mutation of serine 402 to alanine (S402A) resulted in decreased cell spreading on fibronectin. FilGAP phosphorylated at Ser-402 is localized to the cytoplasm but not at the cytoskeleton. Although Ser-402 is highly phosphorylated in serum-starved quiescent cells, dephosphorylation of Ser-402 is accompanied with the cell spreading on fibronectin. Treatment of the cells expressing wild-type FilGAP with calyculin A, a Ser/Thr phosphatase inhibitor, suppressed cell spreading on fibronectin, whereas cells transfected with FilGAP S402A mutant were not affected by calyculin A. Expression of constitutively activate Arf6 Q67L mutant stimulated membrane blebbing activity of both non-phosphorylatable (ST/A) and phosphomimetic (ST/D) FilGAP mutants. Conversely, depletion of endogenous Arf6 suppressed membrane blebbing induced by FilGAP (ST/A) and (ST/D) mutants. Our study suggests that Arf6 and phosphorylation of FilGAP may regulate FilGAP, and phosphorylation of Ser-402 may play a role in the regulation of cell spreading on fibronectin.
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http://dx.doi.org/10.1074/jbc.M115.666875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646280PMC
October 2015

FilGAP, a Rho-ROCK-regulated GAP for Rac, controls adherens junctions in MDCK cells.

J Cell Sci 2015 Jun 23;128(11):2047-56. Epub 2015 Apr 23.

Division of Cell Biology, Department of Biosciences, School of Science, Kitasato University, Kanagawa 252-0373, Japan

Rho family small GTPases are essential for the formation of adherens junctions in epithelial cells. Here, we found that FilGAP (also known as ARHGAP24), a Rac-specific Rho GTPase-activating protein, promoted the formation of adherens junctions in Madin-Darby canine kidney (MDCK) cells. Knockdown of FilGAP by siRNA stimulated the disassembly and migration of MDCK cells induced by hepatocyte growth factor (HGF). By contrast, forced expression of FilGAP induced accumulation of E-cadherin at adherens junctions. Endogenous FilGAP colocalized with E-cadherin at adherens junctions, and depletion of FilGAP reduced the amount of E-cadherin expressed at the surface. The Rac GAP domain of FilGAP was necessary for the suppression of cell scattering induced by HGF. In agreement with this, siRNA-mediated knockdown of both Rac1 and FilGAP suppressed cell scattering induced by HGF. Forced expression of Rho kinase (ROCK, of which there are two isoforms ROCK1 and ROCK2) induced the accumulation of E-cadherin at the adherens junction, and depletion of FilGAP prevented the accumulation of E-cadherin. Moreover, wild-type FilGAP but not a non-phosphorylatable FilGAP mutant rescued the accumulation of E-cadherin at adherens junctions. These results suggest that FilGAP might regulate cell-cell adhesion through inactivation of Rac downstream of Rho-ROCK-signaling in MDCK cells.
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http://dx.doi.org/10.1242/jcs.160192DOI Listing
June 2015

Successful stent graft insertion for endovascular aneurysm repair and closure of patent ductus arteriosus in an adult patient.

Case Rep Cardiol 2015 1;2015:317061. Epub 2015 Feb 1.

Department of Cardiology, Ashikaga Red Cross Hospital, Yobechou 284-1, Ashikaga, Tochigi 326-0843, Japan.

Patent ductus arteriosus (PDA) is sometimes undetected until adulthood, and surgical closure of a PDA is dangerous because of the calcification of the ductus. Percutaneous approaches such as coil embolization and use of a PDA occluder are less invasive; however, these devices are not suitable for PDA with thoracic aortic aneurysm (TAA). We present the case of a 72-year-old female patient who underwent successful stent graft insertions for PDA with TAA.
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http://dx.doi.org/10.1155/2015/317061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336929PMC
March 2015

Evaluation of the effect of tranilast on rats with spinal cord injury.

J Neurol Sci 2014 Nov 28;346(1-2):209-15. Epub 2014 Aug 28.

Department of Orthopaedic Surgery, Hamamatsu University School of Medicine, Handayama 1-20-1, Hamamatsu, Shizuoka 431-3192, Japan. Electronic address:

Background: Glial and fibrotic scars inhibit neural regeneration after spinal cord injury (SCI). N-[3,4-dimethoxycinnamoyl]-anthranilic acid (tranilast) inhibits transforming growth factor β, alleviates allergic reactions, and decreases hypertrophic skin scars. We evaluated its ability to improve motor function and inhibit the spread of tissue damage in rats with SCI.

Methods: Rats with SCI were divided into groups that received tranilast (30 mg/[kg · day]) by intravenous administration (group IV), tranilast (200mg/[kg · day]) by oral administration (group OR), and saline injections (control). Motor functions were assessed by determining Basso, Beattie, and Bresnahan (BBB) scores and %grip tests for 8 weeks after SCI. Histological evaluation of ionized calcium binding adaptor molecule 1 (Iba1) at 1 week after SCI and glial fibrillary acidic protein (GFAP), fibronectin, and chondroitin sulfate (CS) at week 8 was performed.

Results: Motor function recovery, BBB score, and the %grip test were significantly higher in the tranilast-treated groups than in the control group. At week 1 after SCI, inflammatory-cell invasion was more severe and Iba1 expression was significantly higher in the control group. At week 8, although the number of GFAP-positive cells increased greatly from the impaction site to the proximal and distal sites in the control group, these cells were confined around a cavity in the tranilast-treated groups. GFAP distribution coincided with that of fibronectin. Anti-CS antibody level in the tranilast-treated groups was significantly lower than that in the control group.

Conclusions: Tranilast inhibits inflammation in the acute phase of SCI and reduces glial and fibrotic scars and could present a new method for treating SCI.
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http://dx.doi.org/10.1016/j.jns.2014.08.028DOI Listing
November 2014

Phosphorylation of cyclin-dependent kinase 5 (Cdk5) at Tyr-15 is inhibited by Cdk5 activators and does not contribute to the activation of Cdk5.

J Biol Chem 2014 Jul 28;289(28):19627-36. Epub 2014 May 28.

From the Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan,

Cdk5 is a member of the cyclin-dependent kinase (Cdk) family. In contrast to other Cdks that promote cell proliferation, Cdk5 plays a role in regulating various neuronal functions, including neuronal migration, synaptic activity, and neuron death. Cdks responsible for cell proliferation need phosphorylation in the activation loop for activation in addition to binding a regulatory subunit cyclin. Cdk5, however, is activated only by binding to its activator, p35 or p39. Furthermore, in contrast to Cdk1 and Cdk2, which are inhibited by phosphorylation at Tyr-15, the kinase activity of Cdk5 is reported to be stimulated when phosphorylated at Tyr-15 by Src family kinases or receptor-type tyrosine kinases. We investigated the activation mechanism of Cdk5 by phosphorylation at Tyr-15. Unexpectedly, however, it was found that Tyr-15 phosphorylation occurred only on monomeric Cdk5, and the coexpression of activators, p35/p25, p39, or Cyclin I, inhibited the phosphorylation. In neuron cultures, too, the activation of Fyn tyrosine kinase did not increase Tyr-15 phosphorylation of Cdk5. Further, phospho-Cdk5 at Tyr-15 was not detected in the p35-bound Cdk5. In contrast, expression of active Fyn increased p35 in neurons. These results indicate that phosphorylation at Tyr-15 is not an activation mechanism of Cdk5 but, rather, indicate that tyrosine kinases could activate Cdk5 by increasing the protein amount of p35. These results call for reinvestigation of how Cdk5 is regulated downstream of Src family kinases or receptor tyrosine kinases in neurons, which is an important signaling cascade in a variety of neuronal activities.
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http://dx.doi.org/10.1074/jbc.M113.501148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094073PMC
July 2014

Salvage of severe ischemic lower limb having peak creatine phosphokinase level exceeding 200,000 IU/L treated by continuous hemodiafiltration.

Ann Vasc Surg 2014 Oct 21;28(7):1795.e15-8. Epub 2014 May 21.

Department of Cardiovascular Surgery, Ashikaga Red Cross Hospital, Ashikaga, Tochigi, Japan.

We performed revascularization by an anti-anatomical bypass in a 40-year-old man with extended ischemia of both legs beyond 12 hr after onset because of traumatic aortic dissection. This patient developed myonephropathic metabolic syndrome, including renal and circulatory failure accompanied by a creatine phosphokinase level above 200,000 IU/L. Nevertheless, his bilateral affected limbs were salvaged by intensive care based on aggressive hemocatharsis with continuous hemodiafiltration with treatment for poor hemodynamics and respiratory distress.
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http://dx.doi.org/10.1016/j.avsg.2014.04.013DOI Listing
October 2014

Surgical repair of anomalous connection of the left coronary artery.

Authors:
Koji Tsutsumi

SAGE Open Med Case Rep 2014 10;2:2050313X14550118. Epub 2014 Sep 10.

Department of Cardiovascular Surgery, Ashikaga Red Cross Hospital, Tochigi, Japan.

An asymptomatic 10-year-old girl with anomalous connection of the left coronary artery to the pulmonary artery underwent successful surgical repair to create a two-artery coronary system with a coronary elongation technique using an autologous pulmonary arterial wall flap. This technique facilitates direct and tension-free coronary artery re-implantation.
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http://dx.doi.org/10.1177/2050313X14550118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4857338PMC
August 2016

Arundic acid (ONO-2506) inhibits secondary injury and improves motor function in rats with spinal cord injury.

J Neurol Sci 2014 Feb 13;337(1-2):186-92. Epub 2013 Dec 13.

Department of Orthopaedic Surgery, Hamamatsu University School of Medicine, Handayama 1-20-1, Hamamatsu, Shizuoka 431-3192, Japan. Electronic address:

Background: Arundic acid (ONO-2506) inhibits the production and release of S100 protein from astrocytes. While numerous studies have assessed the effect of ONO-2506 in the diseased brain, to the best of our knowledge, no study has examined the effect of ONO-2506 in spinal cord injury (SCI). In this study, we administered ONO-2506 to rats with SCI in order to evaluate its effectiveness in improving motor function and protecting against histological injury.

Methods: All rats underwent laminectomy with SCI at the 10th thoracic vertebra. Rats were divided into 3 groups that received different concentrations of ONO-2506 as follows: 10 mg/kg (Group I) and 20 mg/kg (Group II). The third group (control group) was administered only saline. ONO-2506 or saline was administered by intravenous injection for a week after SCI. Recovery of motor function was assessed by determining the Basso, Beattie, and Bresnahan (BBB) scores and using the %grip test. Using immunohistochemistry, S100 protein and glial fibrillary acidic protein expression was assessed at week 12 post SCI.

Results: The BBB score of Group II was significantly better than that of the control group. At week 12 post SCI, the %grip was 43.0% in Group II and 20.3% in Group I. The score for the %grip test was greater for Group II than for the control group (7.0%); thus, motor function improvement appeared to be dose dependent. Regarding immunostaining evaluation, S100 protein staining was lower in Group II compared to the control group, and the astrocytic morphology resembled that of normal spinal cord sections. The SCI lesion expanded from the injured site to both proximal and distal sites in the control group and in Group I. However, despite the presence of cavitation, secondary expansion of the SCI lesion was prevented in Group II as a result of inhibition of S100 protein.

Conclusions: Administration of ONO-2506 (20 mg/kg) improves motor function and inhibits expansion of secondary injury in SCI rats.
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http://dx.doi.org/10.1016/j.jns.2013.12.008DOI Listing
February 2014

Isomerase Pin1 stimulates dephosphorylation of tau protein at cyclin-dependent kinase (Cdk5)-dependent Alzheimer phosphorylation sites.

J Biol Chem 2013 Mar 28;288(11):7968-7977. Epub 2013 Jan 28.

Laboratory of Molecular Neuroscience, Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan. Electronic address:

Neurodegenerative diseases associated with the pathological aggregation of microtubule-associated protein Tau are classified as tauopathies. Alzheimer disease, the most common tauopathy, is characterized by neurofibrillary tangles that are mainly composed of abnormally phosphorylated Tau. Similar hyperphosphorylated Tau lesions are found in patients with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) that is induced by mutations within the tau gene. To further understand the etiology of tauopathies, it will be important to elucidate the mechanism underlying Tau hyperphosphorylation. Tau phosphorylation occurs mainly at proline-directed Ser/Thr sites, which are targeted by protein kinases such as GSK3β and Cdk5. We reported previously that dephosphorylation of Tau at Cdk5-mediated sites was enhanced by Pin1, a peptidyl-prolyl isomerase that stimulates dephosphorylation at proline-directed sites by protein phosphatase 2A. Pin1 deficiency is suggested to cause Tau hyperphosphorylation in Alzheimer disease. Up to the present, Pin1 binding was only shown for two Tau phosphorylation sites (Thr-212 and Thr-231) despite the presence of many more hyperphosphorylated sites. Here, we analyzed the interaction of Pin1 with Tau phosphorylated by Cdk5-p25 using a GST pulldown assay and Biacore approach. We found that Pin1 binds and stimulates dephosphorylation of Tau at all Cdk5-mediated sites (Ser-202, Thr-205, Ser-235, and Ser-404). Furthermore, FTDP-17 mutant Tau (P301L or R406W) showed slightly weaker Pin1 binding than non-mutated Tau, suggesting that FTDP-17 mutations induce hyperphosphorylation by reducing the interaction between Pin1 and Tau. Together, these results indicate that Pin1 is generally involved in the regulation of Tau hyperphosphorylation and hence the etiology of tauopathies.
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http://dx.doi.org/10.1074/jbc.M112.433326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597833PMC
March 2013

Prophylactic use of intra-aortic balloon pumps in open heart surgery.

Artif Organs 2012 Dec 30;36(12):1056-9. Epub 2012 Jul 30.

Department of Cardiovascular Surgery, Kawasaki Municipal Hospital, Kawasaki-city, Kanagawa-ken, Japan.

During a 1-year period, intra-aortic balloon pumps (IABPs) were used in open heart surgery on 57 patients. Indications were prophylactic usage for coronary artery bypass grafting (CABG) in 52 patients, prophylactic usage for valve replacement in three patients, and cardiopulmonary bypass (CPB) weaning during valve replacement in two patients. The 52 CABG patients comprised 94.5% of all CABG procedures during the period. Sheathless 8 Fr IABPs were used in all cases. The 57 patients using IABPs were analyzed. The mean duration of IABP use was 41.7 h. Morbidity was not associated with using IABPs. There was one case of balloon rupture. Hemostasis was performed easily after removing IABP catheters by compressing the groin for approximately 15 min. The lowest blood pressure during anastomosis or cardiac arrest was also assessed. The lowest peak pressure was 55.9 ± 17.3 mm Hg for patients with IABP still turned on, and the lowest mean pressure was 34.7 ± 6.5 mm Hg for patients with IABP temporarily turned off. Peak blood pressure after CPB was 73.8 ± 17.8 mm Hg. During open heart surgery under anesthesia with the low blood pressure presented by this series, use of IABPs enabled patients to tolerate the procedure. In conclusion, aggressive use of IABPs is easy, safe, and effective with no related morbidity.
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http://dx.doi.org/10.1111/j.1525-1594.2012.01505.xDOI Listing
December 2012

LMTK1/AATYK1 is a novel regulator of axonal outgrowth that acts via Rab11 in a Cdk5-dependent manner.

J Neurosci 2012 May;32(19):6587-99

Department of Biological Sciences, Tokyo Metropolitan University, Tokyo 192-0397, Japan.

Axonal outgrowth is a coordinated process of cytoskeletal dynamics and membrane trafficking; however, little is known about proteins responsible for regulating the membrane supply. LMTK1 (lemur kinase 1)/AATYK1 (apoptosis-associated tyrosine kinase 1) is a serine/threonine kinase that is highly expressed in neurons. We recently reported that LMTK1 plays a role in recycling endosomal trafficking in CHO-K1 cells. Here we explore the role of LMTK1 in axonal outgrowth and its regulation by Cdk5 using mouse brain cortical neurons. LMTK1 was expressed and was phosphorylated at Ser34, the Cdk5 phosphorylation site, at the time of axonal outgrowth in culture and colocalized with Rab11A, the small GTPase that regulates recycling endosome traffic, at the perinuclear region and in the axon. Overexpression of the unphosphorylated mutant LMTK1-S34A dramatically promoted axonal outgrowth in cultured neurons. Enhanced axonal outgrowth was diminished by the inactivation of Rab11A, placing LMTK1 upstream of Rab11A. Unexpectedly, the downregulation of LMTK1 by knockdown or gene targeting also significantly enhanced axonal elongation. Rab11A-positive vesicles were transported anterogradely more quickly in the axons of LMTK1-deficient neurons than in those of wild-type neurons. The enhanced axonal outgrowth was reversed by LMTK1-WT or the LMTK1-S34D mutant, which mimics the phosphorylated state, but not by LMTK1-S34A. Thus, LMTK1 can negatively control axonal outgrowth by regulating Rab11A activity in a Cdk5-dependent manner, and Cdk5-LMTK1-Rab11 is a novel signaling pathway involved in axonal outgrowth.
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http://dx.doi.org/10.1523/JNEUROSCI.5317-11.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6621118PMC
May 2012

Risk factor analysis for acute type A aortic dissection after aortic valve replacement.

Gen Thorac Cardiovasc Surg 2010 Dec 18;58(12):601-5. Epub 2010 Dec 18.

Department of Cardiovascular Surgery, Saiseikai Utsunomiya Hospital, 911-1 Takebayashi-machi, Utsunomiya, Tochigi, 321-0974, Japan.

Purpose: Previous aortic valve replacement (AVR) is considered to be an independent risk factor for late acute type A aortic dissection (AAAD). However, the predictors of late AAAD at the time of AVR have not been characterized.

Methods: A total of 285 patients who underwent isolated AVR were followed for 7.6 ± 8.1 years (mean ± SD). These 285 patients were divided into two groups. Group A consisted of 275 patients who did not develop late aortic complications after AVR, and group B consisted of 10 patients (3.5%) who developed late AAAD after AVR.

Results: The mean time interval between initial AVR and developing late AAAD was 6.1 ± 5.2 years. The diameter of the ascending aorta at the time of AVR was significantly greater in group B than those of group A (47.7 ± 4.6 vs. 35.6 ± 6.3 mm; P < 0.001). Univariate analysis identified other predictors as well: aortic regurgitation (P = 0.029), systemic hypertension (P < 0.001), thinning or fragility of the aortic wall (P < 0.001), and male sex (P = 0.039).

Conclusion: Aortic regurgitation combined with systemic hypertension, male sex, and thinned or fragile aortic walls in patients with ascending aortic dilatation (≥45 mm diameter) at the time of AVR may be predisposing factors for postsurgical aortic complications. These patients should be considered for concomitant replacement of the ascending aorta unless the patient has a high operative risk or older age.
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http://dx.doi.org/10.1007/s11748-010-0658-zDOI Listing
December 2010
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