Publications by authors named "Jiro Shimada"

34 Publications

Current situation survey for establishing personally acceptable radiation dose limits for nuclear disaster responders.

J Radiat Res 2022 Jul;63(4):615-619

Department of Radiation Disaster Medicine, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan.

When responding to disasters, emergency preparedness is essential to ensure that disaster activities are performed smoothly, safely and efficiently. Investigations on the Fukushima accident revealed that lack of preparedness, poor communication and unsuitable emergency measures contributed to an inadequate emergency response to the nuclear disaster. In this study, we conducted a questionnaire survey on the establishment of a personal radiation exposure dose among Disaster Medical Assistance Team (DMAT) members in Japan who might be involved in the initial response to a nuclear disaster. Establishing personal exposure doses for personnel can encourage emergency preparedness and inform decisions on appropriate role assignments during nuclear response activities. Valid responses were obtained from 178 participants, and the response distribution was as follows: 'Already have own acceptable dose standard,' 16 (9%); 'Follow own institution's standard (and know its value),' 30 (17%); 'Follow own institution's standard (but do not know its value),' 59 (33%); 'Haven't decided,' 63 (35%) and 'Don't understand question meaning,' 10 (6%). We also assessed intention to engage in nuclear disaster activities among respondents via engagement intent scores (EIS) and found that participants who had established personal exposure standards had significantly higher EIS scores than those who had not decided or who did not understand the question. Thus, educating potential nuclear disaster responders on personal exposure doses may contribute to a higher intention to engage in emergency responses and improve preparedness and response efficiency.
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http://dx.doi.org/10.1093/jrr/rrac026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303598PMC
July 2022

Increasing Disaster Medical Assistance Teams' Intent to Engage with Specific Hazards.

Int J Environ Res Public Health 2021 11 5;18(21). Epub 2021 Nov 5.

Department of Radiation Disaster Medicine, Fukushima Medical University, Fukushima 960-1295, Japan.

To ensure human resource availability for a smooth response during various types of disasters, there is a need to improve the intent of those involved in responding to each hazard type. However, Disaster Medical Assistance Team personnel's intent to engage with specific hazards has yet to be clarified. This study therefore aimed to clarify the factors affecting Disaster Medical Assistance Team members' ( = 178) intent to engage with each type of hazard through an anonymous web questionnaire survey containing 20 questions. Our results show that the intent to engage in disaster response activities was significantly lower for chemical (50), biological (47), radiological/nuclear (58), and explosive (52) incidents compared with natural (82) and man-made hazards (82) ( < 0.01). Multiple regression analysis showed that incentives were the most common factor affecting responders' intent to engage with all hazard types, followed by self-confidence. Thus, creating a system that provides generous incentives could effectively improve disaster responders' intent to engage with specific hazards. Another approach could be education and training to increase disaster responders' confidence. We believe that the successful implementation of these measures would improve the intent of responders to engage with hazards and promote the recruitment of sufficient human resources.
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http://dx.doi.org/10.3390/ijerph182111630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583079PMC
November 2021

Survey about Intention to Engage in Specific Disaster Activities among Disaster Medical Assistance Team Members.

Prehosp Disaster Med 2021 Dec 18;36(6):684-690. Epub 2021 Oct 18.

Department of Radiation Disaster Medicine, Fukushima Medical University, Fukushima, Japan.

Introduction: Different disaster activities should be performed smoothly. In relation to this, human resources for disaster activities must be secured. To achieve a stable supply of human resources, it is essential to improve the intentions of individuals responding to each type of disaster. However, the current intention of Disaster Medical Assistance Team (DMAT) members has not yet been assessed.

Study Objective: To facilitate a smooth disaster response, this survey aimed to assess the intention to engage in each type of disaster activity among DMAT members.

Methods: An anonymous web questionnaire survey was conducted. Japanese DMAT members in the nuclear disaster-affected area (Group A; n = 79) and the non-affected area (Group N; n = 99) were included in the analysis. The outcome was the answer to the following question: "Will you actively engage in activities during natural, human-made, and chemical (C), biological (B), radiological/nuclear (R/N), and explosive (E) (CBRNE) disasters?" Then, questionnaire responses were compared according to disaster type.

Results: The intention to engage in C (50), B (47), R/N (58), and E (52) disasters was significantly lower than that in natural (82) and human-made (82) disasters (P <.001). The intention to engage in CBRNE disasters among younger participants (age ≤39 years) was significantly higher in Group A than in Group N. By contrast, the intention to engage in R/N disasters alone among older participants (age ≥40 years) was higher in Group A than in Group N. However, there was no difference between the two groups in terms of intention to engage in C, B, and E disasters. Moreover, the intention to engage in all disasters between younger and older participants in Group A did not differ. In Group N, older participants had a significantly higher intention to engage in B and R/N disasters.

Conclusion: Experience with a specific type of calamity at a young age may improve intention to engage in not only disasters encountered, but also other types. In addition, the intention to engage in CBRNE disasters improved with age in the non-experienced population. To respond smoothly to specific disasters in the future, measures must be taken to improve the intention to engage in CBRNE disasters among DMAT members.
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http://dx.doi.org/10.1017/S1049023X21001035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8607140PMC
December 2021

Lower maximum forces on oral structures when using gum-elastic bougie than when using endotracheal tube and stylet during both direct and indirect laryngoscopy by novices: a crossover study using a high-fidelity simulator.

BMC Emerg Med 2020 05 6;20(1):34. Epub 2020 May 6.

Department of Disaster and Emergency Medicine, Graduate School of Medicine, Kobe University, 7-5-2 Kusunoki-cho, Chuo-ward, Kobe, 650-0017, Japan.

Background: Applying excessive force during endotracheal intubation (ETI) is associated with several complications, including dental trauma and hemodynamic alterations. A gum-elastic bougie (GEB), a type of tracheal tube introducer, is a useful airway adjunct for patients with poor laryngoscopic views. However, how the use of a GEB affects the force applied during laryngoscopy is unclear. We compared the force applied on the oral structures during ETI performed by novices using the GEB versus an endotracheal tube + stylet.

Methods: This prospective crossover study was conducted from April 2017 to March 2019 in a public medical university in Japan. In total, 209 medical students (4th and 5th grade, mean age of 23.7 ± 2.0 years) without clinical ETI experience were recruited. The participants used either a Macintosh direct laryngoscope (DL) or C-MAC video laryngoscope (VL) in combination with a GEB or stylet to perform ETI on a high-fidelity airway management simulator. The order of the first ETI method was randomized to minimize the learning curve effect. The outcomes of interest were the maximum forces applied on the maxillary incisors and tongue during laryngoscopy. The implanted sensors in the simulator quantified these forces automatically.

Results: The maximum force applied on the maxillary incisors was significantly lower when using a GEB than when using an endotracheal tube + stylet both with the Macintosh DL (39.0 ± 23.3 vs. 47.4 ± 32.6 N, P < 0.001) and C-MAC VL (38.9 ± 18.6 vs. 42.0 ± 22.1 N, P < 0.001). Similarly, the force applied on the tongue was significantly lower when using a GEB than when using an endotracheal tube + stylet both with the Macintosh DL (31.9 ± 20.8 vs. 37.8 ± 22.2 N, P < 0.001) and C-MAC VL (35.2 ± 17.5 vs. 38.4 ± 17.5 N, P < 0.001).

Conclusions: Compared with the use of an endotracheal tube + stylet, the use of a GEB was associated with lower maximum forces on the oral structures during both direct and indirect laryngoscopy performed by novices. Our results suggest the expanded role of a GEB beyond an airway adjunct for difficult airways.
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http://dx.doi.org/10.1186/s12873-020-00328-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201614PMC
May 2020

Human and equipment resources for difficult airway management, airway education programs, and capnometry use in Japanese emergency departments: a nationwide cross-sectional study.

Int J Emerg Med 2017 Sep 13;10(1):28. Epub 2017 Sep 13.

Emergency and Critical Care Medical Center, Fukushima Medical University Hospital, Fukushima, 960-1295, Japan.

Background: Although human and equipment resources, proper training, and the verification of endotracheal intubation are vital elements of difficult airway management (DAM), their availability in Japanese emergency departments (EDs) has not been determined. How ED type and patient volume affect DAM preparation is also unclear. We conducted the present survey to address this knowledge gaps.

Methods: This nationwide cross-sectional study was conducted from April to September 2016. All EDs received a mailed questionnaire regarding their DAM resources, airway training methods, and capnometry use for tube placement. Outcome measures were the availability of: (1) 24-h in-house back-up; (2) key DAM resources, including a supraglottic airway device (SGA), a dedicated DAM cart, surgical airway devices, and neuromuscular blocking agents; (3) anesthesiology rotation as part of an airway training program; and (4) the routine use of capnometry to verify tube placement. EDs were classified as academic, tertiary, high-volume (upper quartile of annual ambulance visits), and urban.

Results: Of the 530 EDs, 324 (61.1%) returned completed questionnaires. The availability of in-house back-up coverage, surgical airway devices, and neuromuscular blocking agents was 69.4, 95.7, and 68.5%, respectively. SGAs and dedicated DAM carts were present in 51.5 and 49.7% of the EDs. The rates of routine capnometry use (47.8%) and the availability of an anesthesiology rotation (38.6%) were low. The availability of 24-h back-up coverage was significantly higher in academic EDs and tertiary EDs in both the crude and adjusted analysis. Similarly, neuromuscular blocking agents were more likely to be present in academic EDs, high-volume EDs, and tertiary EDs; and the rate of routine use of capnometry was significantly higher in tertiary EDs in both the crude and adjusted analysis.

Conclusions: In Japanese EDs, the rates of both the availability of SGAs and DAM carts and the use of routine capnometry to confirm tube placement were approximately 50%. These data demonstrate the lack of standard operating procedures for rescue ventilation and post-intubation care. Academic, tertiary, and high-volume EDs were likely to be well prepared for DAM.
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http://dx.doi.org/10.1186/s12245-017-0155-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597568PMC
September 2017

Possible additional role for nasal jet oxygen insufflation.

J Anesth 2017 10 15;31(5):797. Epub 2017 Mar 15.

Department of Anesthesiology, Ohta General Hospital Foundation, Ohta Nishinouchi Hospital, 2-5-20 Nishinouchi, Koriyama, Fukushima, 963-8558, Japan.

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http://dx.doi.org/10.1007/s00540-017-2335-1DOI Listing
October 2017

Structural and mechanistic insights into nuclear transport and delivery of the critical pluripotency factor Oct4 to DNA.

J Biomol Struct Dyn 2018 02 17;36(3):767-778. Epub 2017 Feb 17.

a Graduate School of Integrated Basic Sciences , Nihon University , 3-25-40 Sakurajousui, Setagaya-ku, Tokyo 156-8550 , Japan.

Oct4 is a master regulator of the induction and maintenance of cellular pluripotency, and has crucial roles in early stages of differentiation. It is the only factor that cannot be substituted by other members of the same protein family to induce pluripotency. However, although Oct4 nuclear transport and delivery to target DNA are critical events for reprogramming to pluripotency, little is known about the molecular mechanism. Oct4 is imported to the nucleus by the classical nuclear transport mechanism, which requires importin α as an adaptor to bind the nuclear localization signal (NLS). Although there are structures of complexes of the NLS of transcription factors (TFs) in complex with importin α, there are no structures available for complexes involving intact TFs. We have therefore modeled the structure of the complex of the whole Oct4 POU domain and importin α2 using protein-protein docking and molecular dynamics. The model explains how the Ebola virus VP24 protein has a negative effect on the nuclear import of STAT1 by importin α but not on Oct4, and how Nup 50 facilitates cargo release from importin α. The model demonstrates the structural differences between the Oct4 importin α bound and DNA bound crystal states. We propose that the 'expanded linker' between the two DNA-binding domains of Oct4 is an intrinsically disordered region and that its conformational changes have a key role in the recognition/binding to both DNA and importin α. Moreover, we propose that this structural change enables efficient delivery to DNA after release from importin α.
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http://dx.doi.org/10.1080/07391102.2017.1289124DOI Listing
February 2018

Difficult airway management resources and capnography use in Japanese intensive care units: a nationwide cross-sectional study.

J Anesth 2016 08 29;30(4):644-52. Epub 2016 Apr 29.

Emergency and Critical Care Medical Center, Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima, 960-1295, Japan.

Purpose: The availability of difficult airway management (DAM) resources and the extent of capnometry use in Japanese intensive care units (ICUs) remained unclear. The purpose of this study was to clarify whether: (1) DAM resources were adequate, and (2) capnometry was routinely applied in Japanese ICUs.

Methods: This nationwide cross-sectional study was conducted from September 2015 to February 2016. All ICUs received a mailed questionnaire about their DAM resources and use of capnometry. Outcome measures were availability of: (1) 24-h in-house backup coverage; (2) a supraglottic airway device (SGA); (3) a dedicated DAM cart; and (4) surgical airway devices, and (5) routine use of capnometry to verify tube placement and for continuous monitoring of ventilator-dependent patients. The association between these outcomes and ICU type (academic, high-volume, closed, surgical) was also analyzed.

Results: Of the 289 ICUs, 196 (67.8 %) returned completed questionnaires. In-house backup coverage and surgical airway devices were highly available (89.3 and 95.9 %), but SGAs and dedicated DAM carts were not (60.2 and 60.7 %). The routine use of capnometry to confirm tube placement was reported by 55.6 % of the ICUs and was highest in closed ICUs (67.2 %, p = 0.03). The rate of continuous capnography monitoring was also 55.6 % and was highest in academic ICUs (64.5 %, p = 0.04).

Conclusion: In Japanese ICUs, SGAs and dedicated DAM carts were less available, and capnometry was not universally applied either to confirm tube placement, or for continuous monitoring of ventilated patients. Our study revealed areas in need of improvement.
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http://dx.doi.org/10.1007/s00540-016-2176-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956707PMC
August 2016

Are prehospital airway management resources compatible with difficult airway algorithms? A nationwide cross-sectional study of helicopter emergency medical services in Japan.

J Anesth 2016 Apr 29;30(2):205-14. Epub 2015 Dec 29.

Emergency and Critical Care Medical Center, Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima, 960-1295, Japan.

Purpose: Immediate access to the equipment required for difficult airway management (DAM) is vital. However, in Japan, data are scarce regarding the availability of DAM resources in prehospital settings. The purpose of this study was to determine whether Japanese helicopter emergency medical services (HEMS) are adequately equipped to comply with the DAM algorithms of Japanese and American professional anesthesiology societies.

Methods: This nationwide cross-sectional study was conducted in May 2015. Base hospitals of HEMS were mailed a questionnaire about their airway management equipment and back-up personnel. Outcome measures were (1) call for help, (2) supraglottic airway device (SGA) insertion, (3) verification of tube placement using capnometry, and (4) the establishment of surgical airways, all of which have been endorsed in various airway management guidelines. The criteria defining feasibility were the availability of (1) more than one physician, (2) SGA, (3) capnometry, and (4) a surgical airway device in the prehospital setting.

Results: Of the 45 HEMS base hospitals questioned, 42 (93.3 %) returned completed questionnaires. A surgical airway was practicable by all HEMS. However, in the prehospital setting, back-up assistance was available in 14.3 %, SGA in 16.7 %, and capnometry in 66.7 %. No HEMS was capable of all four steps.

Conclusion: In Japan, compliance with standard airway management algorithms in prehospital settings remains difficult because of the limited availability of alternative ventilation equipment and back-up personnel. Prehospital health care providers need to consider the risks and benefits of performing endotracheal intubation in environments not conducive to the success of this procedure.
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http://dx.doi.org/10.1007/s00540-015-2124-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819484PMC
April 2016

Comprehensive analysis of the dynamic structure of nuclear localization signals.

Biochem Biophys Rep 2015 Dec 9;4:392-396. Epub 2015 Nov 9.

Department of Integrated Sciences in Physics and Biology, College of Humanities and Sciences, Nihon University, 3-25-40 Sakurajousui, Setagaya, Tokyo 156-8550, Japan.

Most transcription and epigenetic factors in eukaryotic cells have nuclear localization signals (NLSs) and are transported to the nucleus by nuclear transport proteins. Understanding the features of NLSs and the mechanisms of nuclear transport might help understand gene expression regulation, somatic cell reprogramming, thus leading to the treatment of diseases associated with abnormal gene expression. Although many studies analyzed the amino acid sequence of NLSs, few studies investigated their three-dimensional structure. Therefore, we conducted a statistical investigation of the dynamic structure of NLSs by extracting the conformation of these sequences from proteins examined by X-ray crystallography and using a quantity defined as conformational determination rate (a ratio between the number of amino acids determining the conformation and the number of all amino acids included in a certain region). We found that determining the conformation of NLSs is more difficult than determining the conformation of other regions and that NLSs may tend to form more heteropolymers than monomers. Therefore, these findings strongly suggest that NLSs are intrinsically disordered regions.
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http://dx.doi.org/10.1016/j.bbrep.2015.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669441PMC
December 2015

EARLY STAGE RESPONSES OF INTENSIVE CARE UNITS DURING MAJOR DISASTERS: FROM THE EXPERIENCES OF THE GREAT EAST JAPAN EARTHQUAKE.

Fukushima J Med Sci 2015 3;61(1):32-7. Epub 2015 May 3.

Department of Emergency and Critical Care Medicine, School of Medicine, Fukushima Medical University.

The present study investigated the role of intensive care units (ICU) during disasters, including the responses of our ICU following the Great East Japan Earthquake on March 11, 2011. Our ICU comprises 8 beds for postoperative inpatients and those with rapidly deteriorating conditions; 20 beds in an emergency unit for critically ill patients; and 17 beds for neonates. It is important to secure empty beds when a major disaster occurs, as was the case after the Great Hanshin Earthquake, due to the resulting large numbers of trauma patients. Therefore, each ICU section cooperated to ensure sufficient space for admissions following the Great East Japan Earthquake. However, unlike the Great Hanshin Earthquake, securing beds was ultimately unnecessary due to the nature of the recent disaster, which also consisted of a subsequent tsunami and nuclear accident. Therefore, air quality monitoring was required on this occasion due to the risk of environmental radioactive pollution from the nuclear disaster causing problems with artificial respiration management involving atmospheric air. The variability in damage arising during different disasters thus requires a flexible response from ICUs that handle seriously ill patients.
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http://dx.doi.org/10.5387/fms.2014-35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131597PMC
December 2016

Establishment and implementation of an effective rule for the interpretation of computed tomography scans by emergency physicians in blunt trauma.

World J Emerg Surg 2014 27;9:40. Epub 2014 Jun 27.

Department of Emergency and Critical Care Medicine, School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan.

Introduction: Computed tomography (CT) can detect subtle organ injury and is applicable to many body regions. However, its interpretation requires significant skill. In our hospital, emergency physicians (EPs) must interpret emergency CT scans and formulate a plan for managing most trauma cases. CT misinterpretation should be avoided, but we were initially unable to completely accomplish this. In this study, we proposed and implemented a precautionary rule for our EPs to prevent misinterpretation of CT scans in blunt trauma cases.

Methods: WE ESTABLISHED A SIMPLE PRECAUTIONARY RULE, WHICH ADVISES EPS TO INTERPRET CT SCANS WITH PARTICULAR CARE WHEN A COMPLICATED INJURY IS SUSPECTED PER THE FOLLOWING CRITERIA: 1) unstable physiological condition; 2) suspicion of injuries in multiple regions of the body (e.g., brain injury plus abdominal injury); 3) high energy injury mechanism; and 4) requirement for rapid movement to other rooms for invasive treatment. If a patient meets at least one of these criteria, the EP should exercise the precautions laid out in our newly established rule when interpreting the CT scan. Additionally, our rule specifies that the EP should request real-time interpretation by a radiologist in difficult cases. We compared the accuracy of EPs' interpretations and resulting patient outcomes in blunt trauma cases before (January 2011, June 2012) and after (July 2012, January 2013) introduction of the rule to evaluate its efficacy.

Results: Before the rule's introduction, emergency CT was performed 1606 times for 365 patients. We identified 44 cases (2.7%) of minor misinterpretation and 40 (2.5%) of major misinterpretation. After introduction, CT was performed 820 times for 177 patients. We identified 10 cases (1.2%) of minor misinterpretation and two (0.2%) of major misinterpretation. Real-time support by a radiologist was requested 104 times (12.7% of all cases) and was effective in preventing misinterpretation in every case. Our rule decreased both minor and major misinterpretations in a statistically significant manner. In particular, it conspicuously decreased major misinterpretations.

Conclusion: Our rule was easy to practice and effective in preventing EPs from missing major organ injuries. We would like to propose further large-scale multi-center trials to corroborate these results.
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http://dx.doi.org/10.1186/1749-7922-9-40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085233PMC
July 2014

Patient questionnaire following closure of tracheotomy fistula: percutaneous vs. surgical approaches.

J Intensive Care 2014 24;2(1):17. Epub 2014 Feb 24.

Department of Emergency and Critical Care Medicine, School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295 Japan.

Background: Tracheotomy is an indispensable component in intensive care management. Doctors in charge of the intensive care unit (ICU) usually decide whether tracheotomy should be performed. However, long-term follow-up of a closed fistula by these doctors is rarely continued in most cases. Doctors in charge of the ICU should be interested in the long-term prognosis of tracheotomy. The purpose of this study was to evaluate whether different tracheotomy procedures affect the long-term outcome of a closed tracheal fistula.

Methods: We mailed questionnaires to patients undergoing tracheotomy in Fukushima Medical University Hospital between January 2008 and December 2010. Questions concerned problems related to perception, laryngeal function, and the appearance of a closed fistula. Patients were classified into percutaneous tracheotomy (PT) group and surgical tracheotomy (ST) group. We evaluated the statistical significance of differences in the frequency and degree of each problem between the two groups. A door-to-door objective evaluation using the original scoring system was then performed for patients who replied to the mailed questionnaire. We evaluated the percentage of patients with high scores as well as the mean scores for problems with function and appearance.

Results: We received completed questionnaires from 28/40 patients in the PT group and 35/55 patients in the ST group. There were no significant differences in age, mean hospital stay, or APACHE II score between the groups. Regarding problems with appearance, the outcomes of PT were significantly better than those of ST with respect to self-evaluation (p = 0.04) and the frequency (p = 0.03) and degree (p = 0.02) of scar unevenness according to door-to-door evaluation. However, there were no significant differences in the frequency or degree of self-evaluation in problems with perception and function between the two groups. There were no significant differences in the frequency or degree of door-to-door evaluation of problems with function.

Conclusions: This study shows that PT might be superior to ST with respect to problems with long-term appearance. Continuous follow-up of closed tracheal fistulas can help assure that patients recovering from a critical condition experience a better return to their former lives. A systematic follow-up of post-critical-care patients is required.
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http://dx.doi.org/10.1186/2052-0492-2-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407319PMC
April 2015

Activation intervals for a helicopter emergency medical service in Japan.

Air Med J 2013 Nov-Dec;32(6):346-9

Emergency and Critical Care Medical Center, Fukushima Medical University, Fukushima, Japan; Emergency and Critical Care Medical Center, Ohta General Hospital Foundation, Ohta Nishinouch Hospital, Koriyama, Japan. Electronic address:

Introduction: Prehospital time is crucial for treating acute disease; therefore, it is important to activate helicopter emergency medical services (HEMS) promptly. We investigated the differences in the activation intervals (the time elapsed from receiving the emergency call to the time of HEMS request) under various conditions to evaluate the current status of HEMS-related prehospital triage in Japan.

Methods: We retrospectively investigated activation intervals under exogenous (trauma, n = 553; intoxication, n = 56; and burns, n = 32) and endogenous conditions (acute coronary syndrome [ACS], n = 47; and stroke, n = 173) between January 31, 2008, and January 31, 2012, by reviewing flight records.

Results: Activation intervals were trauma (14.3 ± 11.5 min), intoxication (10.3 ± 8.6 min), burns (15.0 ± 13.1 min), ACS (17.9 ± 14.6 min), and stroke (19.1 ± 13.1 min). One-way analysis of variance showed a significant difference between exogenous and endogenous groups (P < .001). Post-hoc analysis using Tukey's honestly significant difference test showed significant differences between ACS and intoxication (P < .05), stroke and intoxication (P < .001), and stroke and trauma (P < .001).

Conclusions: Endogenous conditions had longer activation intervals, which may reflect a lack of mechanisms assessing their severity. We are considering developing new triage criteria for dispatchers.
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http://dx.doi.org/10.1016/j.amj.2013.01.006DOI Listing
June 2014

Dynamical excimer formation in rigid carbazolophane via charge transfer state.

J Phys Chem A 2013 Aug 2;117(33):7776-85. Epub 2013 Aug 2.

Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.

Formation dynamics of intramolecular excimer in dioxa[3.3](3,6)carbazolophane (CzOCz) was studied by time-resolved spectroscopic methods and computational calculations. In the ground state, the most stable conformer in CzOCz is the anti-conformation where two carbazole rings are in antiparallel alignment. No other isomers were observed even after the solution was heated up to 150 °C, although three characteristic isomers were found by the molecular mechanics calculation: the first is the anti-conformer, the second is the syn-conformer where two carbazole rings are stacked in the same direction, and the third is the int-conformer where two carbazole rings are aligned in an edge-to-face geometry. Because of the anti-conformation, the interchromophoric interaction in CzOCz is negligible in the ground state. Nonetheless, the intramolecular excimer in CzOCz was dynamically formed in an acetonitrile (MeCN) solution, indicating strong interchromophoric interaction and the isomerization from the anti- to syn-conformation in the excited state. The excimer formation in CzOCz is more efficient in polar solvents than in less polar solvents, suggesting the contribution of the charge transfer (CT) state to the excimer formation. The stabilization in the excited state is discussed in terms of molecular orbital interaction between two carbazole rings. The solvent-polarity-induced excimer formation is discussed in terms of the CT character in the int-conformation.
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http://dx.doi.org/10.1021/jp402126aDOI Listing
August 2013

Development of takotsubo cardiomyopathy with severe pulmonary edema before a cesarean section.

J Anesth 2014 Feb 23;28(1):121-4. Epub 2013 Jul 23.

Department of Emergency and Critical Care Medicine, Fukushima Medical University School of Medicine, Hikarigaoka-1, Fukushima, Fukushima, 960-1295, Japan,

Takotsubo cardiomyopathy is an acute syndrome involving apical ballooning and consequent dysfunction of the left ventricle. Most cases of left ventricular dysfunction resolve within 1 month. We present the case of a 40-year-old woman who developed severe heart failure caused by takotsubo cardiomyopathy with severe left ventricular dysfunction during the perinatal period. Because of the presence of multiple myomas, she was scheduled to undergo a cesarean section under general anesthesia. However, after induction of general anesthesia, she had to be awakened because of the presence of a difficult airway. Because she exhibited insufficient oxygenation, she was transferred to the emergency center. Upon hospital admission, she expectorated large amounts of pink sputum, indicating severe pulmonary edema. Cesarean section was performed immediately. Echocardiography revealed severe left ventricular dysfunction. Full recovery of cardiac function required almost 1 month, after which she was discharged from the hospital without further complications. This is the first reported case of takotsubo cardiomyopathy induced by a failed intubation during a scheduled cesarean section. Takotsubo cardiomyopathy usually shows a good prognosis, but if this myopathy develops during the perinatal period, it can worsen because of excessive preload following the termination of fetoplacental circulation.
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http://dx.doi.org/10.1007/s00540-013-1677-6DOI Listing
February 2014

Screening of Residents Following the Tokyo Electric Fukushima Daiichi Nuclear Power Plant Accident.

Health Phys 2013 Jul;105(1):11-20

*National Hospital Organization Disaster Medical Center, 3256 Midori-cho, Tachikawa, Tokyo, Japan; †Fukushima Medical University, Fukushima, Japan; ‡National Institute of Radiological Sciences, Chiba, Japan; §Hiroshima University, Hiroshima, Japan.

Abstract: On 11 March 2011, the Great Eastern Japan Earthquake occurred, causing the accident at the Fukushima Daiichi Nuclear Power Plant of Tokyo Electric Power Co. Residents were surveyed for contamination, and hospitalized patients within a 30-km area were transferred. In this report, the authors review the results of the survey and the effects. The screening teams measured total body contamination of each person using a Geiger-Mueller survey meter. Decontamination level was set at 100 kcpm (100,000 cpm). For levels of 13 to <100 kcpm, decontamination by wiping was planned and took place. Contamination screening during 11-21 March 2011, was carried out for 72,660 people at 200 sites. From 12 March 2011 until 10 February 2012, a total of 244,281 people were screened. As a result, there were 110 cases exceeding 100 kcpm, and 901 cases with contamination levels of 13-100 kcpm. The number of contaminated individuals screened reached a peak from 16-18 March. In the accident, contamination screening of victims and residents was performed to deal with anxiety and discrimination toward the residents. Although there was some early delay, almost all of the evacuees were relatively promptly screened. There was no external contamination at levels thought to affect the health of residents. In addition, the detection of contamination levels over 13 kcpm peaked between 15-22 March. Considering factors such as the evacuation period, this suggests that even if iodine tablets had been administered during this time, they would not have been effective.
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http://dx.doi.org/10.1097/HP.0b013e318287bf0eDOI Listing
July 2013

Repeated embolization of intercostal arteries after blunt chest injury.

Gen Thorac Cardiovasc Surg 2014 Nov 1;62(11):696-9. Epub 2013 Jun 1.

Department of Emergency and Critical Care Medicine, Fukushima Medical University School of Medicine, Hikarigaoka-1, Fukushima, Fukushima, 960-1295, Japan,

To deal with an arterial bleeding from the chest wall after a blunt chest injury, embolization of the bleeding arteries can be a valuable therapeutic option, which is less invasive than a thoracotomy. However, its results are variable, being highly operator-dependent. In the present case, we performed successful emergency embolization of the 4th and 5th intercostal arteries for persistent hemorrhage following blunt trauma to the chest. Several days after the first embolization, secondary embolization was required for treating a pseudoaneurysm that was formed in the 5th intercostal artery. Although the mechanisms underlying pseudoaneurysm formation are not clearly understood, its rupture is potentially fatal. Therefore, it is essential to carefully follow-up patients who experience blunt chest injury to avoid this serious complication.
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http://dx.doi.org/10.1007/s11748-013-0269-6DOI Listing
November 2014

In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction.

Proc Natl Acad Sci U S A 2013 May 29;110(20):8182-7. Epub 2013 Apr 29.

Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.

Mutational activation of the Ras oncogene products (H-Ras, K-Ras, and N-Ras) is frequently observed in human cancers, making them promising anticancer drug targets. Nonetheless, no effective strategy has been available for the development of Ras inhibitors, partly owing to the absence of well-defined surface pockets suitable for drug binding. Only recently, such pockets have been found in the crystal structures of a unique conformation of Ras⋅GTP. Here we report the successful development of small-molecule Ras inhibitors by an in silico screen targeting a pocket found in the crystal structure of M-Ras⋅GTP carrying an H-Ras-type substitution P40D. The selected compound Kobe0065 and its analog Kobe2602 exhibit inhibitory activity toward H-Ras⋅GTP-c-Raf-1 binding both in vivo and in vitro. They effectively inhibit both anchorage-dependent and -independent growth and induce apoptosis of H-ras(G12V)-transformed NIH 3T3 cells, which is accompanied by down-regulation of downstream molecules such as MEK/ERK, Akt, and RalA as well as an upstream molecule, Son of sevenless. Moreover, they exhibit antitumor activity on a xenograft of human colon carcinoma SW480 cells carrying the K-ras(G12V) gene by oral administration. The NMR structure of a complex of the compound with H-Ras⋅GTP(T35S), exclusively adopting the unique conformation, confirms its insertion into one of the surface pockets and provides a molecular basis for binding inhibition toward multiple Ras⋅GTP-interacting molecules. This study proves the effectiveness of our strategy for structure-based drug design to target Ras⋅GTP, and the resulting Kobe0065-family compounds may serve as a scaffold for the development of Ras inhibitors with higher potency and specificity.
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http://dx.doi.org/10.1073/pnas.1217730110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657810PMC
May 2013

Role of perferryl-oxo oxidant in alkane hydroxylation catalyzed by cytochrome P450: a hybrid density functional study.

J Phys Chem B 2012 Apr 17;116(16):4713-30. Epub 2012 Apr 17.

Department of Chemistry, Graduate School of Science, Osaka University , Toyonaka, Osaka 560-0043, Japan.

We have performed hybrid density functional theory (DFT) calculations on the reactivities of low-lying doublet and quartet ferryl-oxo [Fe(IV)═O] oxidants and a doublet perferryl-oxo [Fe(V)═O] oxidant as a new key active species in cytochrome P450. Several aspects of the mechanism of hydrogen-atom abstraction from propane by the above active species of compound I models have been addressed in detail. The results, based on fully optimized structures, demonstrate that the perferryl-oxo oxidant can contribute to the reactivity of compound I owing to the presence of a highly reactive pπ atomic radical character of the oxo ligand. The perferryl-oxo species can abstract a hydrogen atom from propane with an activation barrier of only 0.6-2.5 kcal mol(-1), which is substantially smaller than that for the ferryl-oxo species (13.4-17.8 kcal mol(-1)). The role of the doublet perferryl species in the heterolytic and homolytic O-O bond cleavage in precursor (protonated) compound 0 coupled with the subsequent C-H bond activation has also been explored by grid search of ferryl and perferryl potential surfaces using two parameters. Our calculations suggest that the perferryl-oxo oxidant is catalytically competent, if the O-O bond cleaves heterolytically. The interplay between the accessible ferryl and perferryl states of compound I with quite different reactivities could be a possible reason for elusiveness of compound I in native P450 catalysis on the one hand and various degrees of detection in shunt reactions using peroxy acids on the other hand.
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http://dx.doi.org/10.1021/jp211184yDOI Listing
April 2012

Antigen-antibody interactions and structural flexibility of a femtomolar-affinity antibody.

Biochemistry 2012 Mar 13;51(12):2597-605. Epub 2012 Mar 13.

Green Innovation Research Laboratories, NEC Corporation, 34, Miyukigaoka, Tsukuba, Ibaraki 305-8501, Japan.

The femtomolar-affinity mutant antibody (4M5.3) generated by directed evolution is interesting because of the potential of antibody engineering. In this study, the mutant and its wild type (4-4-20) were compared in terms of antigen-antibody interactions and structural flexibility to elucidate the effects of directed evolution. For this purpose, multiple steered molecular dynamics (SMD) simulations were performed. The pulling forces of SMD simulations elucidated the regions that form strong attractive interactions in the binding pocket. Structural analysis in these regions showed two important mutations for improving attractive interactions. First, mutation of Tyr102(H) to Ser (sequence numbering of Protein Data Bank entry 1FLR ) played a role in resolving the steric hindrance on the pathway of the antigen in the binding pocket. Second, mutation of Asp31(H) to His played a role in resolving electrostatic repulsion. Potentials of mean force (PMFs) of both the wild type and the mutant showed landscapes that do not include obvious intermediate states and go directly to the bound state. These landscapes were regarded as funnel-like binding free energy landscapes. Furthermore, the structural flexibility based on the fluctuations of the positions of atoms was analyzed. It was shown that the fluctuations in the positions of the antigen and residues in contact with antigen tend to be smaller in the mutant than in the wild type. This result suggested that structural flexibility decreases as affinity is improved by directed evolution. This suggestion is similar to the relationship between affinity and flexibility for in vivo affinity maturation, which was suggested by Romesberg and co-workers [Jimenez, R., et al. (2003) Proc. Natl. Acad. Sci. U.S.A.100, 92-97]. Consequently, the relationship was found to be applicable up to femotomolar affinity levels.
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http://dx.doi.org/10.1021/bi3000319DOI Listing
March 2012

Role of a mutated residue at the entrance of the substrate access channel in cytochrome p450 engineered for vitamin D(3) hydroxylation activity.

Biochemistry 2011 Oct 12;50(39):8302-10. Epub 2011 Sep 12.

Green Innovation Research Laboratories, NEC Corporation, 34, Miyukigaoka, Tsukuba, Ibaraki 305-8501, Japan.

The cytochrome P450 enzyme engineered for enhancement of vitamin D(3) (VD(3)) hydroxylation activity, Vdh-K1, includes four mutations (T70R, V156L, E216M, and E384R) compared to the wild-type enzyme. Plausible roles for V156L, E216M, and E384R have been suggested by crystal structure analysis (Protein Data Bank 3A50 ), but the role of T70R, which is located at the entrance of the substrate access channel, remained unclear. In this study, the role of the T70R mutation was investigated by using computational approaches. Molecular dynamics (MD) simulations and steered molecular dynamics (SMD) simulations were performed, and differences between R70 and T70 were compared in terms of structural change, binding free energy change (PMF), and interaction force between the enzyme and substrate. MD simulations revealed that R70 forms a salt bridge with D42 and the salt bridge affects the locations and the conformations of VD(3) in the bound state. SMD simulations revealed that the salt bridge tends to be formed strongly when VD(3) passes through the binding pocket. PMFs showed that the T70R mutation leads to energetic stabilization of enzyme-VD(3) binding in the region near the heme active site. Interestingly, these results concluded that the D42-R70 salt bridge at the entrance of the substrate access channel affects the region near the heme active site where the hydroxylation of VD(3) occurs; i.e., it is thought that the T70R mutation plays an important role in enhancing VD(3) hydroxylation activity. A significant future challenge is to compare the hydroxylation activities of R70 and T70 directly by a quantum chemical calculation, and three-dimensional coordinates of the enzyme and VD(3) obtained from MD and SMD simulations will be available for the future challenge.
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http://dx.doi.org/10.1021/bi2006493DOI Listing
October 2011

Unique structural and electronic features of perferryl-oxo oxidant in Cytochrome P450.

J Phys Chem B 2011 Sep 24;115(36):10730-8. Epub 2011 Aug 24.

Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan.

We have performed hybrid density functional theory (DFT) calculations on the geometric and electronic structures of low-lying doublet and quartet ferryl-oxo [Fe(IV)═O] oxidants and a doublet perferryl-oxo [Fe(V)═O] oxidant in Cytochrome P450. Fully optimized structures of compound I models have been determined, and the proper symmetry of wave functions has been restored by the spin-projection technique. The results show that the perferryl-oxo species is relatively low lying, as compared with the excited state of the ferryl-oxo species, if the iron-oxo bond is properly described as the mixing of several appropriate excited electronic configurations to minimize electron repulsion. This means that the perferryl-oxo species is virtually in a mixed-valent resonance state, ↑Fe(V)═O ↔ ↑Fe(IV)•↑-↓•O, containing a highly reactive pπ atomic oxygen radical. The anionic thiolate ligand acts as a Lewis σ base and functions to achieve the stability of the perferryl-oxo complex and to activate the oxo ligand trans to it by asymmetric bond distortion along the O-Fe-S axis by lengthening the Fe-O bond and shortening the Fe-S bond, prior to the hydrogen-atom abstraction from the substrate.
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http://dx.doi.org/10.1021/jp206004yDOI Listing
September 2011

Survival of a refractory ventricular fibrillation by cooperative treatments.

Fukushima J Med Sci 2010 Dec;56(2):139-43

Emergency and Critical Care Medical Center, Fukushima Medical University Hospital, Japan.

In the case of acute myocardial infarction (AMI), prompt and appropriate initial treatment is essential for increasing the rate of survival and early reperfusion is a main determinant factor for long-term prognosis. The survival of a patient with refractory ventricular fibrillation was made possible by cooperative emergency medical care including air medical transport, despite long distance to the hospital. The patient was a 60-year-old man. Under a diagnosis of AMI, a helicopter emergency medical service (HEMS) with medical staff on board was requested. Although ventricular fibrillation (VF) occurred at the scene, quick and appropriate advanced cardiovascular life support (ACLS) was provided by the attending doctor, leading to the return of heartbeat. Since the patient still exhibited serious bradycardia and cardiac failure, he was airlifted while undergoing transcutaneous pacing. Upon arrival at the hospital, the patient underwent emergency percutaneous coronary intervention (PCI). During the PCI, VF recurred and chest compressions and a total of 17 defibrillations were performed. The PCI was continued with percutaneous cardiopulmonary support (PCPS). The patient survived without sequelae. Smoother cooperation between pre-hospital medical procedures and post-hospital emergency care is considered to be essential for the survival of patients such as this case.
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http://dx.doi.org/10.5387/fms.56.139DOI Listing
December 2010

Two cases of acute atraumatic compartment syndrome complicated with severe heat stroke.

Fukushima J Med Sci 2010 Dec;56(2):129-33

Department of Emergency and Critical Care Medicine, Fukushima Medical University School of Medicine, Fukushima, Japan.

Acute compartment syndrome is a life-threatening complication in trauma patients. Not only regional neuromuscular disability, but also systemic organ disorders can result from prolonged tissue ischemia. In this report, we describe 2 cases of acute atraumatic compartment syndrome complicated with severe heat stroke. In both cases, emergency fasciotomy was rapidly performed after recognition of the syndrome, but serious regional neuromuscular disabilities remained. Microvascular endothelial injury is an important mechanism of acute atraumatic compartment syndrome. Thrombi diffusely formed in the compartmental space hinder establishment of reperfusion even after fasciotomy. Furthermore, disruption of fibrinolysis due to heat stroke could enhance this damage.
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http://dx.doi.org/10.5387/fms.56.129DOI Listing
December 2010

Helicopter emergency medical services (doctor-helicopter) in Fukushima Prefecture: present state and problems.

Fukushima J Med Sci 2010 Jun;56(1):71-9

Emergency and Critical Care Medical Cente, Fukushima University Hospital, Fukushima, Japan.

The purpose of this study is to identify the problems in operating an emergency medical service helicopter with an emergency medicine doctor on board (doctor-helicopter) in Fukushima Prefecture, Japan, which covers wide regions and many rural areas. The study looked at the numbers of flights and patients during the 523 days since the start of the doctor-helicopter service at the Fukushima Medical University Hospital. The items investigated were: number of flights, number of helicopter dispatches per month, number of patients, the hospitals where patients were taken to, the fire department dispatch centers that requested the doctor-helicopter, and the number of times each doctor flew on the helicopter. There were 450 flights. When the service was started, there were a few flights, but they gradually increased. The majority of the flights were to emergency scenes (295), while 75 flights were interfacility transports of critically ill patients, 79 flights were cancelled after take-off, and one flight was for a disaster relief operation. The nature of requests differed greatly depending on the fire department dispatch center requesting the service. The majority of patients were trauma patients (62.2%). Stroke (8.5%) and acute coronary syndrome (5.2%) patients requiring emergency treatment were fewer than anticipated. The final destination hospitals were appropriate hospitals in the region. Because the number of flight doctors is small, the burden on individual doctors is large. A system for early on-site diagnosis and helicopter request by emergency rescue team is required to maintain a high quality of emergency care.
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http://dx.doi.org/10.5387/fms.56.71DOI Listing
June 2010

Investigation of final destination hospitals for patients in helicopter emergency medical services (doctor-helicopter) in Fukushima Prefecture.

J Anesth 2010 Jun 6;24(3):441-6. Epub 2010 Apr 6.

Emergency and Critical Care Medical Center, Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima 960-1295, Japan.

Purpose: In using an emergency medical service helicopter with an emergency medicine doctor on board (doctor-helicopter), transporting all patients to the University Hospital (base hospital for the helicopter) could cause a chronic bed shortage at the University Hospital. It is also disadvantageous for patients from distant areas. We investigated whether appropriate hospital selections are being carried out in Fukushima Prefecture.

Methods: The subjects of the study were patients who were transported by doctor-helicopter since the services started. We investigated the medical conditions of patients at emergency scenes, whether they were transported to a hospital inside or outside the region, the means of transportation, and the final destination hospital.

Results: There were 450 flights, of which 295 were to emergency scenes, involving 307 patients. The majority were trauma patients (191 patients, 62.2%). The final destination hospital was the University Hospital for 104 patients (33.9%); 99 patients (30.3%) were transported to three emergency and critical care medical centers (ECCMCs) in other regions. Most patients were transported to appropriate hospitals in the respective regions. The means of transportation from the emergency scene was by doctor-helicopter in the largest number of cases (223 patients, 72.6%), and the final destination hospital was ECCMCs in 81.6% of cases.

Conclusion: Patients from emergency scenes are transported by doctor-helicopter to appropriate hospitals in the region, and hospitals in each region are cooperating with the doctor-helicopter operations.
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http://dx.doi.org/10.1007/s00540-010-0902-9DOI Listing
June 2010

Bootstrap-based consensus scoring method for protein-ligand docking.

J Chem Inf Model 2008 May 22;48(5):988-96. Epub 2008 Apr 22.

Nano Electronics Research Laboratories, NEC Corporation, 34, Miyukigaoka, Tsukuba, Ibaraki 305-8501, Japan.

To improve the performance of a single scoring function used in a protein-ligand docking program, we developed a bootstrap-based consensus scoring (BBCS) method, which is based on ensemble learning. BBCS combines multiple scorings, each of which has the same function form but different energy-parameter sets. These multiple energy-parameter sets are generated in two steps: (1) generation of training sets by a bootstrap method and (2) optimization of energy-parameter set by a Z-score approach, which is based on energy landscape theory as used in protein folding, against each training set. In this study, we applied BBCS to the FlexX scoring function. Using given 50 complexes, we generated 100 training sets and obtained 100 optimized energy-parameter sets. These parameter sets were tested against 48 complexes different from the training sets. BBCS was shown to be an improvement over single scoring when using a parameter set optimized by the same Z-score approach. Comparing BBCS with the original FlexX scoring function, we found that (1) the success rate of recognizing the crystal structure at the top relative to decoys increased from 33.3% to 52.1% and that (2) the rank of the crystal structure improved for 54.2% of the complexes and worsened for none. We also found that BBCS performed better than conventional consensus scoring (CS).
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http://dx.doi.org/10.1021/ci700204vDOI Listing
May 2008

Hidden active information in a random compound library: extraction using a pseudo-structure-activity relationship model.

J Chem Inf Model 2008 Mar 16;48(3):575-82. Epub 2008 Feb 16.

Nano Electronics Research Laboratories, Central Research Laboratories, NEC Corporation, 34, Miyukigaoka, Tsukuba, Ibaraki 305-8501, Japan.

We propose a hypothesis that "a model of active compound can be provided by integrating information of compounds high-ranked by docking simulation of a random compound library". In our hypothesis, the inclusion of true active compounds in the high-ranked compound is not necessary. We regard the high-ranked compounds as being pseudo-active compounds. As a method to embody our hypothesis, we introduce a pseudo-structure-activity relationship (PSAR) model. Although the PSAR model is the same as a quantitative structure activity relationship (QSAR) model, in terms of statistical methodology, the implications of the training data are different. Known active compounds (ligands) are used as training data in the QSAR model, whereas the pseudo-active compounds are used in the PSAR model. In this study, Random Forest was used as a machine-learning algorithm. From tests for four functionally different targets, estrogen receptor antagonist (ER), thymidine kinase (TK), thrombin, and acetylcholine esterase (AChE), using five scoring functions, we obtained three conclusions: (1) the PSAR models significantly gave higher percentages of known ligands found than random sampling, and these results are sufficient to support our hypothesis; (2) the PSAR models gave higher percentages of known ligands found than normal scoring by scoring function, and these results demonstrate the practical usefulness of the PSAR model; and (3) the PSAR model can assess compounds failed in the docking simulation. Note that PSAR and QSAR models are used in different situations; the advantage of the PSAR model emerges when no ligand is available as training data or when one wants to find novel types of ligands, whereas the QSAR model is effective for finding compounds similar to known ligands when the ligands are already known.
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http://dx.doi.org/10.1021/ci7003384DOI Listing
March 2008
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