Publications by authors named "Masahiko Kimura"

68 Publications

Ionic strength-sensitive and pH-insensitive interactions between C-reactive protein (CRP) and an anti-CRP antibody.

Biophys Physicobiol 2022 9;19:e190003. Epub 2022 Feb 9.

SANKEN, Osaka University, Ibaraki, Osaka 567-0047, Japan.

C-reactive protein (CRP) is an important biomarker of infection and inflammation, as CRP is one of the most prominent acute-phase proteins. CRP is usually detected using anti-CRP antibodies (Abs), where the intermolecular interactions between CRP and the anti-CRP Ab are largely affected by the pH and ionic strength of environmental solutions. Therefore, it is important to understand the environmental effects of CRP-anti-CRP Ab interactions when designing highly sensitive biosensors. Here, we investigated the efficiency of fluorescently labeled CRP-anti-CRP monoclonal antibody (mAb) interactions at different pHs and ionic strengths. Our results indicate that the affinity was insensitive to pH changes in the range of 5.9 to 8.1, while it was significantly sensitive to ionic strength changes. The binding affinity decreased by 55% at an ionic strength of 1.6 mM, when compared to that under a physiological condition (~150 mM). Based on the isoelectric focusing results, both the labeled CRP and anti-CRP mAb were negatively charged in the studied pH range, which rendered the system insensitive to pH changes, but sensitive to ionic strength changes. The decreased ionic strength led to a significant enhancement of the repulsive force between CRP and the anti-CRP mAb. Although the versality of the findings is not fully studied yet, the results provide insights into designing highly sensitive CRP sensors, especially field-effect transistor-based sensors.
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http://dx.doi.org/10.2142/biophysico.bppb-v19.0003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8926308PMC
February 2022

Interhospital transmission of vancomycin-resistant Enterococcus faecium in Aomori, Japan.

Antimicrob Resist Infect Control 2022 07 23;11(1):99. Epub 2022 Jul 23.

Department of Clinical Laboratory Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifucho, Hirosaki, Aomori, 036-8562, Japan.

Background: Spread of vancomycin-resistant Enterococcus (VRE) is a global concern as a significant cause of healthcare-associated infections. A series of VRE faecium (VREf) outbreaks caused by clonal propagation due to interhospital transmission occurred in six general hospitals in Aomori prefecture, Japan.

Methods: The number of patients with VREf was obtained from thirty seven hospitals participating in the local network of Aomori prefecture. Thirteen hospitals performed active screening tests for VRE. Whole genome sequencing analysis was performed.

Results: The total number of cases with VREf amounted to 500 in fourteen hospitals in Aomori from Jan 2018 to April 2021. It took more than three years for the frequency of detection of VRE to return to pre-outbreak levels. The duration and size of outbreaks differed between hospitals according to the countermeasures available at each hospital. Whole genome sequencing analysis indicated vanA-type VREf ST1421 for most samples from six hospitals.

Conclusions: This was the first multi-jurisdictional outbreak of VREf sequence type 1421 in Japan. In addition to strict infection control measures, continuous monitoring of VRE detection in local medical regions and smooth and immediate communication among hospitals are required to prevent VREf outbreaks.
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http://dx.doi.org/10.1186/s13756-022-01136-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9308179PMC
July 2022

Drift Suppression of Solution-Gated Graphene Field-Effect Transistors by Cation Doping for Sensing Platforms.

Sensors (Basel) 2021 Nov 10;21(22). Epub 2021 Nov 10.

The Institute of Scientific and Industrial Research, Osaka University, Ibaraki 567-0047, Osaka, Japan.

Solution-gated graphene field-effect transistors (SG-GFETs) provide an ideal platform for sensing biomolecules owing to their high electron/hole mobilities and 2D nature. However, the transfer curve often drifts in an electrolyte solution during measurements, making it difficult to accurately estimate the analyte concentration. One possible reason for this drift is that p-doping of GFETs is gradually countered by cations in the solution, because the cations can permeate into the polymer residue and/or between graphene and SiO substrates. Therefore, we propose doping sufficient cations to counter p-doping of GFETs prior to the measurements. For the pre-treatment, GFETs were immersed in a 15 mM sodium chloride aqueous solution for 25 h. The pretreated GFETs showed that the charge neutrality point (CNP) drifted by less than 3 mV during 1 h of measurement in a phosphate buffer, while the non-treated GFETs showed that the CNP was severely drifted by approximately 50 mV, demonstrating a 96% reduction of the drift by the pre-treatment. X-ray photoelectron spectroscopy analysis revealed the accumulation of sodium ions in the GFETs through pre-treatment. Our method is useful for suppressing drift, thus allowing accurate estimation of the target analyte concentration.
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http://dx.doi.org/10.3390/s21227455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618120PMC
November 2021

Role of the supinator muscle in the pathophysiological mechanism of a pulled elbow.

Authors:
Masahiko Kimura

Acta Paediatr 2022 Apr 14;111(4):756-759. Epub 2022 Feb 14.

Kimura Children and Family Clinic, Izumo, Japan.

A pulled elbow is a common childhood orthopaedic injury that is usually caused by longitudinal traction on the hand. The pathophysiological mechanism of a pulled elbow involves interposition of the annular ligament into the radiohumeral joint. Recent ultrasonographic studies have shown that both the supinator muscle and annular ligament were trapped into the radiohumeral joint. This paper discusses why pulled elbows can occur during pronation and how a pulled elbow can be reduced either by hyperpronation or supination followed by elbow flexion based on the function of the supinator muscle.
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http://dx.doi.org/10.1111/apa.16194DOI Listing
April 2022

Effects on physical performance of high protein intake for critically ill adult patients admitted to the intensive care unit: A retrospective propensity-matched analysis.

Nutrition 2021 Nov-Dec;91-92:111407. Epub 2021 Jul 1.

Department of Physical Therapy, Faculty of Health Science, Kyorin University, Mitaka, Tokyo, Japan. Electronic address:

Objectives: This study aimed to examine the effects of protein intake on physical performance in critically ill adult patients admitted to the intensive care unit (ICU).

Methods: This was a retrospective cohort study of adult patients mechanically ventilated over 48 h in the ICU who were classified into two groups based on the amount of protein intake: >1.0 g/kg/d (high-protein group) or <1.0 g/kg/d (low-protein group). After adjustment for possible confounding factors with propensity score matching, we compared muscle strength at the time of ICU discharge and the rate of recovery to independent walking between the two groups.

Results: One-to-one propensity score matching created 20 pairs. The high-protein group had significantly higher muscle strength than the low-protein group at the time of discharge from the ICU. In addition, the rate of recovery to independent walking before hospital discharge was higher in the high-protein group than the low-protein group (16 of 20 patients [80%] vs. 8 of 20 patients [40%]; P = 0.032).

Conclusions: Our findings indicate that a sufficient amount of protein intake may lead to a higher rate of recovery to independent walking before discharge from the hospital in critically ill patients admitted to the ICU. This finding is likely related to preserved muscle strength at the time of ICU discharge.
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http://dx.doi.org/10.1016/j.nut.2021.111407DOI Listing
December 2021

Chest physical therapy reduces pneumonia following inhalation injury.

Burns 2021 02 12;47(1):198-205. Epub 2020 Jul 12.

Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Japan. Electronic address:

Purpose: The purpose of this study was to clarify the efficacy of chest physiotherapy (CPT) in patients with inhalation injury in the acute phase.

Patients And Methods: This was a single-institution retrospective study of patients with inhalation injury admitted to the Chukyo Hospital Burn Center from April 2004 to March 2014 who required endotracheal intubation for respiratory care. The patients were divided into two groups: the CPT group and the conventional physical therapy group. We compared the two groups according to the incidence of pneumonia, length of ICU/hospital stay, and level of activities of daily living at discharge. To match subject backgrounds, we conducted a propensity score matching analysis, and using a Cox regression analysis, we evaluated the effect of CPT on the first pneumonia event.

Results: Of 271 patients admitted to the burn center, 139 patients were included. The incidence of pneumonia in the CPT group was significantly lower and these patients required fewer days until they could sit on the edge of the bed compared with the conventional physical therapy group. In a Cox regression model, the hazard ratio for the first incidence of pneumonia in the CPT group vs. the conventional therapy group was 0.27 (95% confidence interval: 0.13-0.54, P = 0.0002) after propensity score matching.

Conclusions: CPT reduces the incidence of pneumonia and facilitates patient mobilization following inhalation injury.
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http://dx.doi.org/10.1016/j.burns.2020.06.034DOI Listing
February 2021

[Consideration of Advanced Pharmaceutical Control Functions through Pharmacy-provided Home Pharmaceutical Care].

Authors:
Masahiko Kimura

Yakugaku Zasshi 2020 ;140(7):841-850

Akebono Pharmacy.

In October 2015, the Ministry of Health, Labour and Welfare of Japan newly included "health support functions" and "advanced pharmaceutical control functions" as part of "primary-care pharmacy" in the pharmacy vision for patients. "Health support functions" were defined as recommending that patients seek medical consultations, introducing them to relevant medical institutions, and contributing to disease prevention and health support among local residents, apart from health counseling and the consolidation of a framework for the appropriate selection and supply of and advice on pharmacist-only over-the-counter medications, etc. On the other hand, the term "advanced pharmaceutical control functions" is presumed to imply meeting the needs for advanced pharmaceutical control, e.g., cooperation with specialized medical institutions in addressing adverse reactions caused by anticancer drugs and support of the selection of anti-HIV drugs. However, the details remain unknown. Since the opening of the Akebono pharmacy group 22 years ago, our staff members have visited home-care patients, controlled and guided the use of pharmaceuticals, and supported all types of home-care patients including those with end-stage cancer and amyotrophic lateral sclerosis, undergoing home parenteral nutrition, and pediatric home-care patients. We have experienced many cases requiring sophisticated pharmaceutical control, e.g., pain control with opioids, sterile preparation of transfusions, and supply of special medical devices. We would like to consider the requirements for pharmacy-provided home healthcare that depends heavily on medical treatment as one advanced pharmaceutical control function.
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http://dx.doi.org/10.1248/yakushi.19-00237-1DOI Listing
September 2020

Clinical relevance of procalcitonin values in bacteremia.

J Infect Chemother 2020 Oct 25;26(10):1048-1053. Epub 2020 Jun 25.

Clinical Laboratory, Hirosaki University Hospital, Hirosaki, Japan; Department of Clinical Laboratory Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Aomori Infection Control Netowork, Hirosaki, Japan. Electronic address:

Introduction: The aim of this study was to investigate procalcitonin levels according to the causative pathogens of bacteremia. The relationships between the clinical outcomes and procalcitonin levels were also studied.

Methods: From among 452 patients, 507 cases of positive blood culture were included in the present study. Procalcitonin levels were studied according to the pathogen types. The prevalence of septic shock and the mortality rates were also studied in four groups stratified by the procalcitonin levels (groups 1, 2, 3, and 4 had procalcitonin levels of <0.5 ng/mL, 0.5 ≤ 2.0 ng/mL, 2.0 < 10 ng/mL, and ≥10 ng/mL, respectively).

Results: The procalcitonin levels were significantly higher in bacteremia cases with Gram-negative rods (19.50 ng/mL), such as Escherichia coli (32.5 ng/mL), than those with Gram-positive rods (8.45 ng/mL) or Gram-positive cocci (9.21 ng/mL) (p < 0.01). The 28-day mortality rates in groups 1, 2, 3, and 4 were 6.0%, 12.0%, 14.9%, and 19.8%, respectively. The procalcitonin levels of samples taken before or on the same day of blood cultures were significantly lower than those taken one day after blood cultures. Multiple logistic regression analysis showed that C-reactive protein and procalcitonin ≥10 ng/mL were independently associated with a higher risk of mortality within 28 days.

Conclusions: The PCT levels were higher in cases of bacteremia caused by GNR than those caused by GPR or GPC. The 28-day mortality rate increased as the PCT levels increased. Clinical importance of early evaluations and appropriate interpretation of procalcitonin levels for bacteremia were indicated.
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http://dx.doi.org/10.1016/j.jiac.2020.05.023DOI Listing
October 2020

Impact of Geographical Variations on the Prevalence of Multidrug-Resistant Organisms in Japan.

Jpn J Infect Dis 2020 Sep 30;73(5):354-360. Epub 2020 Apr 30.

Department of Clinical Laboratory Medicine, Hirosaki University Graduate School of Medicine, Japan.

Emergence and spread of multidrug-resistant organisms (MDRO) is an urgent social and public health problem. Here, we carried out an epidemiological survey to clarify the geographical characteristics and factors influencing the prevalence of MDRO. Data on the prevalence of MDRO in 47 prefectures in Japan were extracted from the Japanese Nosocomial Infection Surveillance, a nationwide database for infection control. Potential factors for MDRO were analyzed using data selected from the pharmacological, medical service, infection control, environmental, social, and food-related categories, based on the characteristics of each organism and the correlations between them and MDRO prevalence. Statistical data for potential factors were obtained from public domains. The use of antibiotics was found to be correlated with the prevalence of penicillin-resistant Streptococcus pneumoniae, 3rd-generation cephalosporin- and fluoroquinolone-resistant Escherichia coli, and methicillin-resistant Staphylococcus aureus. Negative correlation between the consumption of food such as kelp and fermented soybeans that facilitate the growth of lactic acid bacteria and the prevalence of 3rd-generation cephalosporin- and fluoroquinolone-resistant E. coli suggested an association between the intestinal microflora and MDRO colonization. In addition to the use of antibiotics, lifestyle, food culture, and social factors such as tobacco smoking, average atmospheric temperature, prevalence of three-generation households, ratio of elderly population, average duration of tourist stay, chicken and fermented soybean consumption, and the competency of healthcare services may also affect MDRO prevalence.
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http://dx.doi.org/10.7883/yoken.JJID.2019.498DOI Listing
September 2020

Graphene Field Effect Transistor-Based Immunosensor for Ultrasensitive Noncompetitive Detection of Small Antigens.

ACS Sens 2020 01 15;5(1):24-28. Epub 2020 Jan 15.

Institute of Scientific and Industrial Research , Osaka University , Ibaraki , Osaka 567-0047 , Japan.

Due to its high carrier mobility, graphene is considered a suitable material for use in field-effect transistors. However, its application to immunosensing of small molecules is still elusive. To investigate the potential of graphene field effect transistors (G-FET) as a sensor for small molecules with small or no charge, we applied the open-sandwich immunoassay (OS-IA), which detects low-molecular-weight antigens noncompetitively, to G-FET. Using an antibody variable fragment V immobilized on graphene and a hyperacidic region of amyloid precursor protein fused to the other variable fragment V, we successfully detected a small antigen peptide consisting of 7 amino acids (BGP-C7), with a more than 100-fold increase in sensitivity compared with that measured by enzyme-linked OS-IA. Furthermore, we succeeded in detecting BGP-C7 in the presence of human serum with similar sensitivity, suggesting its potential application in clinical diagnostics.
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http://dx.doi.org/10.1021/acssensors.9b02137DOI Listing
January 2020

High incidence of status epilepticus and ongoing seizures on arrival to the hospital due to high prevalence of febrile seizures in Izumo, Japan: A questionnaire-based study.

Brain Dev 2019 Nov 12;41(10):848-853. Epub 2019 Aug 12.

Division of Health Administration and Promotion, Department of Social Medicine, Faculty of Medicine, Tottori University, Yonago, Japan.

Objectives: To determine the incidence of prolonged febrile seizures and status epilepticus in the first three years of life.

Methods: A questionnaire was sent to 1560 families between April 2016 and March 2017 before their child attended a routine health check at three years of age in Izumo, Shimane prefecture, Japan. The questionnaire included an overview of febrile seizures, including the age at which febrile seizures occurred, the duration, and how the condition was managed.

Results: We received 1089 (69.8%) responses and these showed that 134 (12.3%) children had a history of febrile seizures. Fourteen children with febrile seizures (10.4%) had prolonged seizures lasting 10-30 min and six children (4.5%) had status epilepticus. Ongoing febrile seizures that did not terminate on arrival to the hospital were observed in 11 children (8.2%) with febrile seizures. The incidence rates of status epilepticus, prolonged febrile seizures including status epilepticus and ongoing febrile seizures were 184, 612 and 337 per 100,000 children aged 36 months or less, respectively.

Conclusions: There was a greater incidence of status epilepticus than previously thought, possibly due to the high prevalence of febrile seizures in Japan. Eight percent of children with febrile seizures were seizing on arrival to the hospital. These ongoing seizures requiring emergency interventions were almost twice more than status epilepticus. Thus, it is necessary to develop an early intervention for the termination of prolonged febrile seizures.
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http://dx.doi.org/10.1016/j.braindev.2019.07.009DOI Listing
November 2019

Genioglossus muscle activity during sniff and reverse sniff in healthy men.

Exp Physiol 2018 12 17;103(12):1656-1665. Epub 2018 Oct 17.

School of Allied Health Sciences, Kitasato University, Kanagawa, Japan.

New Findings: What is the central question of this study? Maximal sniff nasal inspiratory and reverse sniff nasal expiratory pressures are measured as inspiratory and expiratory muscle strength, respectively. Is the genioglossus muscle activated during short maximal inspiratory and expiratory efforts through the nose? What is the main finding and its importance? Genioglossus muscle activity occurred with inspiratory muscle activity during a maximal sniff and with expiratory muscle activity during a maximal reverse sniff. These results indicate that genioglossus muscle activity is closely related to the generation of maximal sniff nasal inspiratory and reverse sniff nasal expiratory pressures.

Abstract: Maximal sniff nasal inspiratory pressure (SNIP ) is widely used to assess inspiratory muscle strength. The sniff nasal inspiratory pressure (SNIP) is lower in patients with neuromuscular disease with bulbar involvement compared with those without, possibly owing to impaired upper airway muscle function. However, the degree to which the genioglossus (GG) muscle, one of the upper airway muscles, is activated during inspiratory and expiratory efforts through the nose remains unclear. Therefore, we examined GG activity during short and sharp inspiratory and expiratory efforts through the nose, i.e. sniff and reverse sniff manoeuvres. In eight normal young subjects, we inserted fine wire electrodes into the GG muscle, parasternal intercostal and scalene (inspiratory) muscles and transversus abdominis (expiratory) muscle. We assessed EMG activity of each muscle and measured SNIP and reverse sniff nasal expiratory pressure (RSNEP) during sniffs and reverse sniffs from low to high intensities in the sitting position. The highest SNIP and RSNEP were analysed as SNIP and maximal RSNEP (RSNEP ), respectively. In each subject, GG EMG activity increased linearly with increasing SNIP and RSNEP. The SNIP and RSNEP were -85.1 ± 15.9 and 83.2 ± 24.2 cmH O, respectively. Genioglossus EMG activity varied with EMG activity of the parasternal intercostal and scalene muscles during generation of SNIP and with EMG activity of the transversus abdominis muscle during RSNEP . Genioglossus EMG activity during generation of SNIP was higher than during RSNEP (62.9 ± 31.1% EMG of SNIP , P = 0.012). These results suggested that GG activity was closely related to the generation of both SNIP and RSNEP .
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http://dx.doi.org/10.1113/EP086995DOI Listing
December 2018

Graphene as an Imaging Platform of Charged Molecules.

ACS Omega 2018 Mar 15;3(3):3137-3142. Epub 2018 Mar 15.

The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka 567-0047, Japan.

Graphene, a single atom layer of carbon atoms, provides a two-dimensional platform with an extremely high sensitivity to charges due to its unique band structure and high surface-to-volume ratio. Graphene field-effect transistor (G-FET) biosensors have, indeed, demonstrated a detection limit of subnanomolar or even subpicomolar. However, in G-FET, signal is averaged throughout the whole channel, so there remains a need to visualize the spatial distribution of target molecules on a single G-FET, to provide further insight into target molecules and/or biological functions. Here, we made use of graphene as an imaging platform of charged molecules via Raman microscopy. Positively (or negatively) charged microbeads with a diameter of 1 μm were dispersed in a buffer solution and were attached on graphene. We found out that Raman peaks of graphene, where positively (or negatively) charged beads contacted, were up-shifted (or down-shifted) significantly, indicating that the carrier density in the graphene was locally modulated by the charged beads and the charge state of the beads was represented by the peak-shift direction. From the peak shift, the change in the carrier density was calculated to be +1.4 × 10 cm (or -1.0 × 10 cm). By taking Raman peak-shift images, we visualized distribution of charged molecules on graphene with a spatial resolution below 1 μm. The technique described here overcomes the limitation of spatial resolution of G-FET and provides a new route to graphene-based chemical and biosensors.
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http://dx.doi.org/10.1021/acsomega.7b02008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044899PMC
March 2018

Parental questionnaire study showed that annular ligament displacement was common in three-year-old children and almost a half had reoccurring episodes.

Acta Paediatr 2018 11 14;107(11):1983-1985. Epub 2018 Jun 14.

Faculty of Medicine, Division of Health Administration and Promotion, Department of Social Medicine, Tottori University, Yonago, Japan.

Aim: This study sought to determine the incidence of annular ligament displacement (ALD), also known as nursemaid's elbow, in the first 3 years of life.

Methods: A questionnaire was sent to 1098 families between August 2014 and July 2015 before their child attended a routine health check at 3 years of age in Izumo, Shimane prefecture, Japan. The questionnaire included a brief description about ALD, the age when ALD occurred and how the condition was managed.

Results: We received 784 (71.4%) responses and these showed that 61 (7.8%) children had a history of ALD and 31 (51%) were girls. The incidence was 2.6%, calculated by multiplying the number of children by the 3-year observation period. The mean and median ages of the first ALD occurrence were both 25 months. In addition, 28 (46%) children with ALD had a recurrence and the mean number of ALD episodes was 1.8 (range 1-5). The total number of ALD episodes was 108, and of these, 33 (30%) were seen at the hospital emergency department and 17 (16%) spontaneously resolved.

Conclusion: This study confirmed that ALD was a common occurrence in 3-year-old children and that there was a high rate of recurrence.
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http://dx.doi.org/10.1111/apa.14422DOI Listing
November 2018

High prevalence of anemia in 10-month-old breast-fed Japanese infants.

Pediatr Int 2018 Jul 20;60(7):651-655. Epub 2018 Jun 20.

Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Japan.

Background: Anemia in infancy is still prevalent in developing countries. Commercial iron-fortified complementary foods or iron drops are not available in Japan, and breast-fed infants have a higher risk of anemia. We studied anemia screening in 10-month-old infants to determine whether breast-feeding is a risk factor for anemia.

Methods: Anemia screening was performed during regular health check for 10-month-old children at four local pediatric clinics in Shimane Prefecture, Japan. Venous blood was obtained for complete blood count. The clinical characteristics of each child were obtained via questionnaire. Anemia was defined as hemoglobin <11.0 g/dL. Children were categorized into anemia and no-anemia groups, and univariate analysis was conducted on comparison of the clinical variables. Multivariate logistic regression analysis for anemia was performed to adjust for several clinical variables.

Results: We analyzed data in 325 children. On univariate analysis, anemia was associated with breast-feeding, monthly bodyweight gain and gestational week. On multivariate logistic regression analysis, anemia was associated with feeding type and gestational week (OR of partial breast-feeding and formula feeding, 0.446; 95%CI: 0.208-0.957; and 0.223; 95%CI: 0.075-0.660, respectively, compared with exclusive breast-feeding, OR, 1.0; and gestational week, OR, 0.753; 95%CI: 0583-0.972).

Conclusion: Breast-feeding is an important factor for anemia in 10-month-old Japanese infants. Breast-fed infants after 6 months of age may need iron supplements or iron-fortified complimentary foods.
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http://dx.doi.org/10.1111/ped.13588DOI Listing
July 2018

A male case with CDKL5-associated encephalopathy manifesting transient methylmalonic acidemia.

Eur J Med Genet 2018 Aug 3;61(8):451-454. Epub 2018 Mar 3.

Departments of Pediatric, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Mutations in the X-linked gene CDKL5 cause early-onset epileptic encephalopathy and severe developmental delay. Because this disorder predominantly affects females, the full clinical spectrum of male patients remains elusive. We herein report a 16-year-old boy, who suffered from intractable seizures 20 days after birth. Serial electroencephalograms detected recurrent focal epileptiform discharges from age 4 months, which evolved to hypsarrhythmia later in infancy. Mass-spectrometric analyses revealed increase in urinary excretion of methylmalonic acid without perturbed concentrations of propionic acid, homocystein and methionine. Whole-exome sequencing identified a de novo, truncating mutation in CDKL5 (NM_003159.2:c.419dupA, p.Asn140Lysfs*8). Targeted sequencing excluded concomitant mutations in methylmalonic academia-associated genes. No methylmalonic acidemia has been reported in children with CDKL5 disorder. Extensive analyses on organic acid metabolism for males with CDKL5 mutations will gain more insight into their biochemical profiles in infancy.
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http://dx.doi.org/10.1016/j.ejmg.2018.03.003DOI Listing
August 2018

Evaluating effectiveness of infection control efforts in hospitals using information in microbiological laboratory databases.

J Gen Fam Med 2017 12 15;18(6):354-359. Epub 2017 Jun 15.

Department of Laboratory Medicine Hirosaki University Graduate School of Medicine Hirosaki Japan.

Purpose: To analyze the quality of infection control activities, bacteriological data relevant to infection control was evaluated through the microbiological data warehouse networking hospitals in two medical regions.

Methods: Data regarding bacterial test results of 19 hospitals were extracted from two microbiological laboratory information data bases. The rate of MRSA among total was used as a general indicator of infection control activities. The occupancy rate of nasal or pharyngeal swabs among MRSA-positive bacteriological samples was used as an indicator of attention paid for infection control in intensive care wards. The number of blood culture sets per examined patient was utilized as an indicator for life-long vocational education on updated medical practice relevant to infectious diseases.

Results: The rate of MRSA was significantly higher in secondary private hospitals. The occupancy rate of nasal or pharyngeal swabs was significantly higher in tertiary hospitals. The average number of blood culture set per examined patient were 1.55, 1.54 and 1.39 in tertiary, secondary public and secondary private hospitals, respectively; however, there were no statistical differences between groups.

Conclusions: Data bases of microbiological test results shared by hospital laboratories are useful for evaluating regional infection control activities.
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http://dx.doi.org/10.1002/jgf2.93DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729382PMC
December 2017

Acceleration Mechanisms of Skin Wound Healing by Autologous Micrograft in Mice.

Int J Mol Sci 2017 Aug 2;18(8). Epub 2017 Aug 2.

Departments of Plastic, Reconstructive and Aesthetic Surgery, Faculty of Medicine, Fukuoka University, Fukuoka 8140180, Japan.

A micrograft technique, which minces tissue into micro-fragments >50 μm, has been recently developed. However, its pathophysiological mechanisms in wound healing are unclear yet. We thus performed a wound healing study using normal mice. A humanized mouse model of a skin wound with a splint was used. After total skin excision, tissue micro-fragments obtained by the Rigenera protocol were infused onto the wounds. In the cell tracing study, GFP-expressing green mice and SCID mice were used. Collagen stains including Picrosirius red (PSR) and immunohistological stains for α-smooth muscle actin (αSMA), CD31, transforming growth factor-β1 (TGF-β1) and neutrophils were evaluated for granulation tissue development. GFP-positive cells remained in granulation tissue seven days after infusion, but vanished after 13 days. Following the infusion of the tissue micrograft solution onto the wound, TGF-β1 expression was transiently upregulated in granulation tissue in the early phase. Subsequently, αSMA-expressing myofibroblasts increased in number in thickened granulation tissue with acceleration of neovascularization and collagen matrix maturation. On such granulation tissue, regenerative epithelial healing progressed, resulting in wound area reduction. Alternative alteration after the micrograft may have increased αSMA-expressing myofibroblasts in granulation tissue, which may act on collagen accumulation, neovascularization and wound contraction. All of these changes are favorable for epithelial regeneration on wound.
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http://dx.doi.org/10.3390/ijms18081675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578065PMC
August 2017

Antitumour and Apoptotic Effects of a Plant Extract Mixture Containing Rhus verniciflua and Other Herbs in Human Leukaemia Cells.

Drug Res (Stuttg) 2017 Feb 14;67(2):127-130. Epub 2016 Sep 14.

Medicinal Informatics and Research Unit, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.

The apoptotic effects of a novel antitumour agent (Rv-PEM01) prepared from 6 kinds of herbs, including were investigated using flow cytometry and western blot analysis. Rv-PEM01 induced apoptosis but not necrosis in MOLT-3, KG-1, and K562 human leukaemia cell lines. Further, Rv-PEM01-treated cells showed significantly upregulated expression of caspase-3 and 9 and cleaved caspase-3 and 9 compared to the control cells. Taken together, the results suggest that Rv-PEM01 induced apoptosis via the mitochondrial-mediated pathway, and is a potential natural anticancer agent and/or a functional food material.
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http://dx.doi.org/10.1055/s-0042-113458DOI Listing
February 2017

Characterization of the cytotoxic activity of [2]rotaxane (TRO-A0001), a novel supramolecular compound, in cancer cells.

Arch Pharm Res 2016 Jun 6;39(6):825-32. Epub 2016 Apr 6.

Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.

Rotaxanes comprise a class of interlocked molecules containing a wheel threaded onto an axle with blocking groups on the ends to keep the wheel from sliding off. Here, we show that [2][bis(2-(3,5-dimethylphenylcarbonyloxy)ethyl) ammoniumtrifluoromethanesulfonate]-[dibenzo-24-crown-8] rotaxane (TRO-A0001), a rotaxane compound, exerted a growth inhibitory effect on several human cancer cell lines. An MTT assay revealed an IC50 of 14-830 nM for TRO-A0001 in these cells. Neither the wheel nor the axle part alone inhibited tumor cell growth, suggesting that the complete rotaxane molecule with its unique "intramolecular mobility" is required to inhibit cell growth. Annexin-V/PI staining provided evidence of the induction of apoptosis, which was further confirmed by the observation of poly (ADP-ribose) polymerase cleavage. Furthermore, a cell cycle analysis using flow cytometry showed that TRO-A0001 treatment resulted in G1 arrest in glioblastoma T98G and melanoma G361 cells. An immunoblot analysis revealed that in both cell lines, TRO-A0001 treatment caused the induction of p21/Cip1, thereby down-regulating Cdks 2, 4 and 6 and reducing Cyclins D1 and E. The results presented in this study demonstrate cytotoxicity of the rotaxane compound and its potential as a lead compound for the development of a chemotherapeutic agent against cancer.
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http://dx.doi.org/10.1007/s12272-016-0741-9DOI Listing
June 2016

Late-onset Rash in Patients with Group A Beta-hemolytic Streptococcal Pharyngitis Treated with Amoxicillin.

Authors:
Masahiko Kimura

Pediatr Rep 2015 Dec 18;7(4):5951. Epub 2015 Dec 18.

Kimura Children and Family Clinic , Izumo, Japan.

We observed late-onset rashes in patients with group A beta-hemolytic streptococcal (GAS) pharyngitis. Of 1028 patients with GAS pharyngitis, which was principally treated with amoxicillin, we evaluated those who developed a late-onset rash and excluded those with scarlet fever alone. Twenty-one patients developed a rash (2.0%, 95% confidence interval, 1.3-3.1%), 7 to 20 days (median, 8 days) after GAS pharyngitis onset. The rashes were characterized by maculopapules, which increased in size with coalescence and some developing into plaques, with a symmetrical distribution with a propensity for the extremities, including the palms and soles. The clinical courses of the patients were good, and the rashes subsided within 14 days. A non-immediate reaction to β-lactams, which usually manifests as a maculopapular rash, is a possible cause in our patients, however, repeated courses of amoxicillin in 3 patients did not induce the rash. The underlying mechanism of the late-onset rash after GAS pharyngitis with amoxicillin treatment remains unclear.
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http://dx.doi.org/10.4081/pr.2015.5951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689989PMC
December 2015

Possible involvement of reusable towels in the high rate of Bacillus species-positive blood cultures in Japanese hospitals.

J Infect Chemother 2016 Feb 10;22(2):96-101. Epub 2015 Dec 10.

Department of Laboratory Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Clinical Laboratory, Hirosaki University Hospital, Hirosaki, Japan. Electronic address:

Background: A number of outbreaks caused by Bacillus species have been reported to date. Outbreaks reported in the last decade have predominantly arisen in Japanese hospitals.

Aim: To elucidate factors contributing to these real or pseudo outbreaks by Bacillus species, and to evaluate the rate of Bacillus species-positive blood culture samples in Japan.

Methods: A systematic review of the literature was performed. Reports including data on outbreaks caused by Bacillus species were searched for in PubMed, Google Scholar and Evidence-based Medicine BMJ from inception through 10 Aug 2014. Japanese nationwide data on bacteriological tests were collected from Japan Nosocomial Infections Surveillance. Regional bacteriological data for Akita prefecture were collected using the Akita Regional Network for Infection Monitoring/Control System.

Findings: Contamination of reusable towels was suspected as a cause for the high rate of Bacillus-positive blood cultures in Japan. The rate of Bacillus species in blood cultures was much higher in Japan than in reports from other countries.

Conclusions: The high contamination rate of blood culture samples by Bacillus species in Japan is a matter of concern for infection control and medical treatment. Bacteriological investigation of reusable towels should be considered in hospitals with a high frequency of Bacillus-positive blood cultures.
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http://dx.doi.org/10.1016/j.jiac.2015.11.006DOI Listing
February 2016

Potassium Sodium Niobate-Based Lead-Free Piezoelectric Multilayer Ceramics Co-Fired with Nickel Electrodes.

Materials (Basel) 2015 Nov 3;8(11):7423-7438. Epub 2015 Nov 3.

Murata Manufacturing Co., Ltd., Nagaokakyo, Kyoto 617-8555, Japan.

Although lead-free piezoelectric ceramics have been extensively studied, many problems must still be overcome before they are suitable for practical use. One of the main problems is fabricating a multilayer structure, and one solution attracting growing interest is the use of lead-free multilayer piezoelectric ceramics. The paper reviews work that has been done by the authors on lead-free alkali niobate-based multilayer piezoelectric ceramics co-fired with nickel inner electrodes. Nickel inner electrodes have many advantages, such as high electromigration resistance, high interfacial strength with ceramics, and greater cost effectiveness than silver palladium inner electrodes. However, widely used lead zirconate titanate-based ceramics cannot be co-fired with nickel inner electrodes, and silver palladium inner electrodes are usually used for lead zirconate titanate-based piezoelectric ceramics. A possible alternative is lead-free ceramics co-fired with nickel inner electrodes. We have thus been developing lead-free alkali niobate-based multilayer ceramics co-fired with nickel inner electrodes. The normalized electric-field-induced thickness strain (/) of a representative alkali niobate-based multilayer ceramic structure with nickel inner electrodes was 360 pm/V, where denotes the maximum strain and denotes the maximum electric field. This value is about half that for the lead zirconate titanate-based ceramics that are widely used. However, a comparable value can be obtained by stacking more ceramic layers with smaller thicknesses. In the paper, the compositional design and process used to co-fire lead-free ceramics with nickel inner electrodes are introduced, and their piezoelectric properties and reliabilities are shown. Recent advances are introduced, and future development is discussed.
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http://dx.doi.org/10.3390/ma8115389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458925PMC
November 2015

Clinical and genetic investigation of 17 Japanese patients with hyperekplexia.

Dev Med Child Neurol 2015 Apr 30;57(4):372-7. Epub 2014 Oct 30.

Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Japan.

Aim: The aim of the study was to determine clinical and genetic characteristics of Japanese patients with hyperekplexia.

Method: Clinical courses, responses to antiepileptic drugs, outcomes, and genetic testing were investigated in 17 Japanese patients (nine males, eight females, median age 1y, range birth-45y) with hyperekplexia.

Results: In all patients, muscle stiffness and startle responses appeared soon after birth. Only seven patients were diagnosed with hyperekplexia before 1 year of age. Seven patients had been misdiagnosed with other disorders such as epilepsy and adult-onset anxiety neurosis. Umbilical/inguinal hernias were seen in 10 patients. Life-threatening events were noted in four patients. Clonazepam was the most effective drug. Muscle stiffness completely disappeared in 12 patients before 5 years of age, whereas startle responses resolved in only three patients. Mutations in the GLRA1 and GLRB genes were identified in 16 patients and one patient respectively. In 14 patients, the mutation showed autosomal dominant inheritance; in the other three, inheritance was autosomal recessive. p.R271Q of GLRA1 was the most frequent mutation, found in 10 patients. Novel mutations, p.A272P and p.A384P of GLRA1, were detected. Clinical severity and outcome varied even in the same family.

Interpretation: Early correct diagnosis is essential for prevention of accidental injuries and to provide appropriate treatments for hyperekplexia. Clonazepam is effective, although the time taken for startle responses to resolve varied.
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http://dx.doi.org/10.1111/dmcn.12617DOI Listing
April 2015

Effect of balance training on walking speed and cardiac events in elderly patients with ischemic heart disease.

Int Heart J 2014 4;55(5):397-403. Epub 2014 Aug 4.

Graduate School of Medical Sciences, Kitasato University.

The purpose of this study was to clarify the effect of standing balance training on walking speed (short-term outcome) and cardiac events (long-term outcome) in elderly ischemic heart disease (IHD) patients. This was a retrospective cohort study. Ninety-two elderly (≥ 65 years) IHD patients who underwent an inpatient cardiac rehabilitation program were assigned to two groups: a balance group that received standing balance training in addition to conventional (aerobic and resistance) training and a conventional group. Standing balance was assessed by one-leg standing time and a postural stability index reflecting dynamic balance, and normal walking speed was measured at baseline and hospital discharge. Patients were followed for up to 3 years or until a cardiac event occurred. There were no significant differences in clinical characteristics between the groups. Both groups showed a significant change in normal walking speed from baseline to hospital discharge (P < 0.001, respectively), and normal walking speed was significantly higher in the balance group compared to the conventional group (P = 0.001). The postural stability index improved significantly only in the balance group (P = 0.005). Multivariable analyses using Cox proportional hazards model confirmed that standing balance training (hazard ratio [HR]: 0.408; 95% confidence interval [CI]: 0.162-1.029; P = 0.058) and fast walking speed (HR: 0.362; 95% CI: 0.137-0.957; P = 0.041) were associated with cardiac events. These findings show that standing balance training improves walking speed and reduces cardiac events, and suggests that such training can be an effective intervention for elderly IHD patients.
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http://dx.doi.org/10.1536/ihj.14-017DOI Listing
November 2014

[Nationwide surveillance of parenteral antibiotics containing meropenem activities against clinically isolated strains in 2012].

Jpn J Antibiot 2014 Apr;67(2):73-107

The nationwide surveillance of antibacterial susceptibility to meropenem (MEPM) and other parenteral antibiotics against clinical isolates during 2012 in Japan was conducted. A total of 2985 strains including 955 strains of Gram-positive bacteria, 1782 strains of Gram-negative bacteria, and 248 strains of anaerobic bacteria obtained from 31 medical institutions were examined. The results were as follows; 1. MEPM was more active than the other carbapenem antibiotics tested against Gram-negative bacteria, especially against enterobacteriaceae and Haemophilus influenzae. MEPM was also active against most of the species tested in Gram-positive and anaerobic bacteria, except for multi-drug resistant strains including methicillin-resistant Staphylococcus aureus (MRSA). 2. Of all species tested, there were no species, which MIC90 of MEPM was more than 4-fold higher than those in our previous studies in 2009 or 2006. Therefore, the tendency to increase in antimicrobial resistance rates was not observed. 3. MEPM resistance against Pseudomonas aeruginosa was 17.8% (56/315 strains). Compared to our previous results, it was the lowest than that in 2006 and 2009. 4. Carbapenem-resistant Klebsiella pneumoniae, and multi-drug-resistant Acinetobacter species, which emerged in worldwide, were not observed. 5. The proportion of extended-spectrum beta-lactamase (ESBL) strains was 6.2% (59/951 strains) in enterobacteriaceae, which increased compared with that of our previous studies in 2009 or before. Whereas, the proportion of metallo-beta-lactamase strains was 1.6% (5/315 strains) in P. aeruginosa, which was stable. In conclusion, the results from this surveillance suggest that MEPM retains its potent and broad antibacterial activity and therefore is a clinically useful carbapenem for serious infections treatment at present, 17 years passed after available for commercial use in Japan.
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April 2014

Quantum chemical study for radical-induced DNA effects and damage.

Chem Pharm Bull (Tokyo) 2013 ;61(12):1214-9

Nii Bio-plant Research Institute in a Limited Company.

Differences in molecular interaction between bases (adenine (A), guanine (G), and cytosine (C)) and the methyl (Me)-radical were investigated by perturbation analysis using the quantum chemical method. Part of the source of damage to the DNA was elucidated at the molecular level. In the reaction of each of the saccharide derivatives (dA, dG, and dC) with Me-radical, the reactivity of dG (≈dA) is more than about 10 times larger than that of dC. Therefore, it is expected that the base G (and A) was more than about 10 times than the base C in radical-reactivity of the base. For the reaction of dA and dG with the radical, the C(8) site of the partial purine ring of dA and dG, and the C(5) site of the pyrimidine ring of dC were the main reaction sites for methylation. In the reaction of DNA composed of hydrogen-bonded base pairs G-C and A-T with the radical, the purine ring in the constituent base G reacted preferentially with the radical to yield 8-methyl-guanines.
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http://dx.doi.org/10.1248/cpb.c13-00541DOI Listing
July 2014

[Role of university hospitals in regional infection control network].

Rinsho Byori 2013 Aug;61(8):721-7

Department of Laboratory Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8563, Japan.

Activities and the understanding of infection control in healthcare facilities have improved in the past decade since a certification system for medical personnel, such as infection control nurse and infection control doctor, were introduced in Japan. These specialists are distributed among tertiary general hospitals, while many small and mid-scale hospitals have no infection control specialists. In 2012, the Japanese Ministry of Health, Labour and Welfare launched a new strategy for further improvement of infection control by supporting a regional network of infection control activities. Through the infection control network, small or mid-scaled hospitals can utilize infection control specialists in tertiary general hospitals, enter educational programs on infection control and consult in cases of nosocomial infection outbreaks. As part of the regional infection control network, we established an information network system, named ReNICS, to share the bacteriological test results of the hospitals in Akita prefecture. ReNICS offers epidemiological data on bacteria identified in the region. We can identify the spread of multi-drug resistant bacteria and can roughly estimate the quality of infection control activities in each facility. As a similar information network is being prepared in Hirosaki University Hospital Infection Control Center in Aomori, a prefecture neighboring Akita, we discussed the roles of university hospitals for a regional infection control network.
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August 2013

Influence of novel supramolecular substance, [2] rotaxane, on the caspase signaling pathway in melanoma and colon cancer cells in vitro.

J Pharmacol Sci 2013 5;122(2):153-7. Epub 2013 Jun 5.

Medicinal Informatics and Research Unit, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.

We studied the influence of novel supramolecular substance, [2] rotaxane (TRO-A0001), on caspase signaling and cell viability in cancer cell lines. TRO-A0001 suppressed concentration-dependently cell proliferation. Expression of the cleaved-form caspase-3 and PARP was significantly increased in cells exposed to TRO-A0001. The expression of Bax was increased by TRO-A0001. Furthermore, the down-regulation of Bax by siRNA resulted in growth activation significantly. The morphological analysis demonstrated that TRO-A0001 increased the levels of apoptotic cells in human cancer cell lines. These results suggest that TRO-A0001 induces apoptosis in cancer cells and holds potential as a new anti-tumor medicine.
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http://dx.doi.org/10.1254/jphs.12244scDOI Listing
January 2014

[Antitumor effects of a plant extract mixture].

Yakugaku Zasshi 2013 ;133(5):487-91

Medicinal Informatics and Research Unit, Faculty of Pharmaceutical Sciences, Fukuoka University.

Cancer is the most common cause of death in Japan. Fundamental and clinical studies on cancer were conducted from the viewpoint of Western medicine so far. However, a sustained complete remission has not been achieved yet. In order to alleviate the side effects of anticancer drugs, some traditional herbal medicines (Kampo medicines) have been prescribed to cancer patients. We have been studying on antitumor substances in medicinal herbs and found an antitumor medicinal herb named Rhus verniciflua (lacquer, Urushi in Japanese). To investigate the antitumor effect in vitro, a plant extract mixture was prepared from six medicinal herbs containing lacquer. The plant extract mixture containing lacquer (Rv-PEM) inhibited the proliferation of several mouse and human tumor cell lines. Rv-PEM had more potent inhibitory effect on the proliferation of human leukemia cell lines (MOLT-3, KG-1) than on other tumor cell lines. The IC50 values of Rv-PEM on MOLT-3 and KG-1 cells were 0.208 and 0.293 mg/mL, respectively. After treating Rv-PEM to the tumor cells, DNA fragmentation and Caspase-3 and -9 activity increased in the treated cells. The mechanisms of the inhibitory proliferation activity of Rv-PEM would involve apoptosis of human leukemia cells (MOLT-3, KG-1, K-562) by the mitochondrial pathway.
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http://dx.doi.org/10.1248/yakushi.12-00278-1DOI Listing
April 2014
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