Publications by authors named "Kenji Dohi"

61 Publications

A novel mouse model of heatstroke accounting for ambient temperature and relative humidity.

J Intensive Care 2021 Apr 16;9(1):35. Epub 2021 Apr 16.

Department of Emergency, Critical Care and Disaster Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.

Background: Heatstroke is associated with exposure to high ambient temperature (AT) and relative humidity (RH), and an increased risk of organ damage or death. Previously proposed animal models of heatstroke disregard the impact of RH. Therefore, we aimed to establish and validate an animal model of heatstroke considering RH. To validate our model, we also examined the effect of hydration and investigated gene expression of cotransporter proteins in the intestinal membranes after heat exposure.

Methods: Mildly dehydrated adult male C57/BL6J mice were subjected to three AT conditions (37 °C, 41 °C, or 43 °C) at RH > 99% and monitored with WetBulb globe temperature (WBGT) for 1 h. The survival rate, body weight, core body temperature, blood parameters, and histologically confirmed tissue damage were evaluated to establish a mouse heatstroke model. Then, the mice received no treatment, water, or oral rehydration solution (ORS) before and after heat exposure; subsequent organ damage was compared using our model. Thereafter, we investigated cotransporter protein gene expressions in the intestinal membranes of mice that received no treatment, water, or ORS.

Results: The survival rates of mice exposed to ATs of 37 °C, 41 °C, and 43 °C were 100%, 83.3%, and 0%, respectively. From this result, we excluded AT43. Mice in the AT 41 °C group appeared to be more dehydrated than those in the AT 37 °C group. WBGT in the AT 41 °C group was > 44 °C; core body temperature in this group reached 41.3 ± 0.08 °C during heat exposure and decreased to 34.0 ± 0.18 °C, returning to baseline after 8 h which showed a biphasic thermal dysregulation response. The AT 41 °C group presented with greater hepatic, renal, and musculoskeletal damage than did the other groups. The impact of ORS on recovery was greater than that of water or no treatment. The administration of ORS with heat exposure increased cotransporter gene expression in the intestines and reduced heatstroke-related damage.

Conclusions: We developed a novel mouse heatstroke model that considered AT and RH. We found that ORS administration improved inadequate circulation and reduced tissue injury by increasing cotransporter gene expression in the intestines.
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http://dx.doi.org/10.1186/s40560-021-00546-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052643PMC
April 2021

Hypovolemic shock induced by a large chest wall hematoma caused by a single rib fracture in an elderly patient.

Trauma Case Rep 2021 Apr 17;32:100459. Epub 2021 Mar 17.

Department of Emergency and Disaster Medicine, Showa University.

Displaced rib fractures can injure intercostal vessels leading to chest wall hematomas. As the bleeding occurs within the vessel, compression of the vessel wall helps in preventing further bleeding. Therefore, chest wall hematomas rarely result in shock. A thin 78-year-old man transferred to the emergency department with complaints of left dorsal pain due to an injury. He had a history of hypertension and aorta dissection. He arrived at the ED in a state of shock and presented with a large left dorsal wall mass. Subsequent imaging using computed tomography angiography revealed a large hyperdense hematoma at the left dorsal-flank wall along with rib fracture (11th intercostal artery). Moreover, a large fusiform aneurysm was detected from the abdominal aorta to the iliac arteries. Extravasation of the contrast agent was detected at the branch of the 11th intercostal artery, and hence, embolization was performed. The dermis, which comprises collagen and elastin fibers, plays an important role in vessel compression to prevent bleeding. The aortic media also comprises collagen and elastin fibers. Cell turnover, loss of collagen, and excessive elastolysis are associated with the formation of abdominal aortic aneurysms. The systemic degeneration of connecting tissue (collagen and elastin fiber) appears to be progress in patients with an aortic aneurysms and history of aortic dissection compared with other healthy older individuals. Physicians should be cognizant of the potential unexpected large hematoma complications if a risk of systemic connecting tissue degradation exists, as seen in patients with aortic aneurysm or aortic dissection.
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http://dx.doi.org/10.1016/j.tcr.2021.100459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010857PMC
April 2021

High early phase hemoglobin level is associated with favorable neurological outcome in patients with severe traumatic brain injury.

Am J Emerg Med 2020 May 6. Epub 2020 May 6.

Yamaguchi Prefectural University, 3-2-1 Sakurabatake, Yamaguchi City, Yamaguchi 753-8502, Japan.

Background: The appropriate hemoglobin (Hb) level threshold for the early phase (i.e. from Emergency Department to ICU admission) in patients with severe traumatic brain injury (TBI) is still unknown. Therefore, we aimed to examine the association between Hb levels during the early phase and neurological outcomes in patients with severe TBI using data from the Brain Hypothermia (B-HYPO) Study Group.

Methods: We performed a post-hoc analysis of the B-HYPO study (a prospective, multicenter, randomized controlled trial on patients with severe TBI who received either mild therapeutic hypothermia [MTH; 32.0 °C-34.0 °C] or fever control [35.5 °C-37.0 °C]). We calculated Hb levels during early phase by the formula: (admission Hb + Hb on day 1) / 2. The primary outcome was the association between during early phase Hb levels and 6-month neurological outcome after the TBI based on the Glasgow Outcome Scale scores (a measure of functional recovery defined as moderate disability or good recovery).

Results: We reviewed data from 130 patients and found favorable neurological outcomes in 48.5% of them. We found significant differences between the favorable and unfavorable neurological outcome groups in terms of their Hb levels on admission and on day 1. But, we found no Hb level differences after day 3 (including 1 day after rewarming). Our multivariable analysis showed that Hb levels during early phase were significantly associated with favorable neurological outcomes (odds ratio, 1.387; 95% confidence interval, 1.057-1.858; P = 0.018).

Conclusions: High early phase Hb levels are associated with favorable neurological outcomes after severe TBI.
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http://dx.doi.org/10.1016/j.ajem.2020.04.065DOI Listing
May 2020

Mistaking an Auto-injector for a Ballpoint Pen.

Intern Med 2020 09 2;59(17):2201. Epub 2020 Jun 2.

Department of Emergency and Disaster Medicine, Showa University, Japan.

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http://dx.doi.org/10.2169/internalmedicine.4489-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516324PMC
September 2020

Diagnosis of neurofibromatosis type 1 after rupture of aneurysm and consequent fatal hemothorax.

Am J Emerg Med 2020 07 7;38(7):1543.e3-1543.e5. Epub 2020 Apr 7.

Department of Emergency and Disaster Medicine, Showa University, Fujigaoka Hospital, 1-30 Fujigaoka Aoba-ku, Yokohama 227-8501, Japan; Department of Emergency and Disaster Medicine, Showa University, 1-5-8 Hatanodai Shinagawa-ku, Tokyo 142-8666, Japan.

Patients with neurofibromatosis type 1 (NF1) can develop both benign and malignant tumors throughout their lives. A 49-year-old man was transferred to the emergency department with complaints of sudden right dorsal pain and respiratory discomfort. He was in shock on arrival. On finding significantly decreased permeability of the left lung field in chest X-ray, drainage was immediately performed. Subsequent computed tomography (CT; Lammert et al., 2005) angiography revealed the extravasation of contrast media from the deep carotid artery, a branch of subclavian artery. It suggested rupture of an aneurysm located at a rare site; the ruptured aneurysm penetrated the pleura, causing shock. The patient was resuscitated. Transcatheter arterial embolization (TAE; Evans et al., 2010) was successfully performed. Immediate drainage, resuscitation, and TAE 2 improved his condition. Most NF1 patients have café-au-lait macules; café-au-lait macules tend to fade with age. Importantly, café-au-lait macules, neurofibromas, and Lisch nodules were noticed at admission. NF1 patients are likely to have a malignant neoplasm when they are young. The patient had been diagnosed with thyroid cancer when he was young. As his deceased mother was an NF1 patient, we diagnosed him with NF1. Detailed patient history and early-stage examination led to the early diagnosis. NF1 should be considered as an early differential diagnosis to improve the outcome of patients in such cases.
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http://dx.doi.org/10.1016/j.ajem.2020.04.004DOI Listing
July 2020

The enhancement of CCL2 and CCL5 by human bone marrow-derived mesenchymal stem/stromal cells might contribute to inflammatory suppression and axonal extension after spinal cord injury.

PLoS One 2020 10;15(3):e0230080. Epub 2020 Mar 10.

Department of Anatomy, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan.

Human bone marrow-derived mesenchymal stem/stromal cells (hMSCs) have shown potential in facilitating recovery from spinal cord injury (SCI) through communicating with microglia/macrophages (MG/MΦ). We here focused on chemokines as a candidate for the communication. Selected MG/MΦ-related chemokines were determined gene expression after SCI and further focused CCL2/CCR2 and CCL5/CCR5 to estimate role of the chemokines by hMSCs. Male C57/BL6 mice were subjected to spinal cord transection. Gene expression was assayed in the spinal cords following SCI for selected MG/MΦ-related chemokines and their receptors. hMSCs (5×105 cells) were then transplanted into parenchyma of the spinal cord, and the expressions of the Ccl2/Ccr2 and Ccl5/Ccr5 axes, inflammation, MG/MΦ-polarization, and axonal regeneration were evaluated to measure the influence of the hMSCs. Finally, mouse CCL5 was injected into the spinal cords. Acute increases in gene expression after SCI were observed for most chemokines, including Ccl2; chronic increases were observed for Ccl5. CCL2+-cells merged with NeuN+-neurons. CCR2+ immunoreactivity was principally observed in Ly-6G+/iNOS+-granulocytes on postoperative day (pod) 1, and CCL5+ and CCR5+ immunoreactivity overlapped with NeuN+-neurons and F4/80+-MG/MΦ on pod 14. The hMSC transplantation enhanced Ccl2 and Ccl5 and improved locomotor activity. The hMSC implantation did not alter the number of Ly-6G+/CCR2+ but decreased Il1, Elane, and Mpo on pod 3. Conversely, hMSC transplantation increased expression of Zc3h12a (encodes MCP-1-induced protein) on pod 14. Moreover, hMSC increased the Aif1, and two alternatively activated macrophage (AAM)-related genes, Arg1 and Chil3 (Ym1), as well as axonal regenerative markers, Dpysl2 and Gap43. Gene expression indicative of AAM polarization and axonal regeneration were partially recovered by CCL5 injection. These results suggest that hMSC implantation increases Ccl2 and Ccl5, improves locomotor activity, enhances MG/MΦ polarization to AAM, and increases the gene expression of axonal regenerative markers. These functions of hMSCs might be partially mediated by the CCL2/CCR2 and CCL5/CCR5 axes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230080PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064230PMC
June 2020

Prognostic Significance of the Difference Between Mixed and Jugular Venous Oxygen Saturation After Severe Traumatic Brain Injury: A Post Hoc Analysis of the Brain Hypothermia Study.

World Neurosurg 2020 05 10;137:e68-e74. Epub 2020 Jan 10.

Yamaguchi Prefectural Grand Medical Center, Yamaguchi, Japan.

Background: In patients postcardiac arrest, it has been reported that the small value of the difference between mixed venous oxygen saturation (Svo) and jugular venous oxygen saturation (Sjvo) is associated with poor neurologic outcome. However, the importance of the difference between mixed venous oxygen saturation and jugular venous oxygen saturation (ΔSo [v - jv]) remains unknown in severe traumatic brain injury (TBI). The aim of this study was to examine whether ΔSo (v - jv) is associated with neurologic outcome and mortality in patients with severe TBI.

Methods: We conducted post hoc analyses of the Brain Hypothermia Study, a multicenter randomized controlled trial of mild therapeutic hypothermia for the treatment of severe TBI. The value of ΔSo(v - jv) on day 1 and day 3 was compared between survivors (n = 65) and nonsurvivors (n = 25) or between patients with favorable (n = 47) and unfavorable (n = 43) neurologic outcomes.

Results: The reduction in ΔSo (v - jv) on day 3 was -2.0% (range, -6.9% to 6.5%) in the nonsurvivor group and 6.3% (range, -2.5% to 16.7%) in the survivor group. The difference was statistically significant (P = 0.03). The same tendencies were observed in the nonsurvivor group on day 1 and in the unfavorable neurologic outcome group on day 1 and day 3, but the difference was not significant.

Conclusions: The reduction in ΔSo(v - jv) on day 3 was associated with high mortality in patients with severe TBI.
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http://dx.doi.org/10.1016/j.wneu.2020.01.004DOI Listing
May 2020

Usefulness of bounce-back admission in monitoring the quality of practice in the emergency department.

Ther Clin Risk Manag 2019 6;15:647-658. Epub 2019 May 6.

Department of Emergency, Disaster and Critical Care Medicine, Showa University, Tokyo 142-8555, Japan.

Recently, unscheduled readmissions after discharge from the emergency department (ED) (bounce-back admissions, BBAs) have been monitored as a hospital performance measure in countries other than Japan. It has been suggested that BBAs may be caused by errors in diagnoses or treatments. This retrospective cohort study aimed to evaluate BBAs and improve the quality of medical care in the ED of Showa University Hospital by analyzing the data of adult patients (≥18 years) with index visits to the ED of Showa University Hospital between June 2011 and May 2013 (n=15,069). Patients were registered and followed up for unscheduled admissions to this hospital within 7 days. In order to understand the reasons for BBAs, individual diagnoses upon BBA were compared to the corresponding diagnoses upon discharge. Among the 11,669 discharged patients, 180 patients were admitted within 3 days after discharge (3-day BBAs), and 257 were admitted within 7 days after discharge (7-day BBAs). The main diagnoses upon admission (BBA) were pneumonia or exacerbation of chronic obstructive pulmonary disease (COPD) or asthma (n=40, 16%), cholecystitis or cholangitis (n=21, 8.2%), and urinary tract infection (n=16, 6.2%). Among the 7-day BBA cases, 117 patients had similar and 110 patients had different diagnoses upon discharge and admission; in the remaining 30 cases, the results could not be ascertained owing to incomplete diagnostic data. In the cases of pneumonia, exacerbation of COPD or asthma, and colitis or enterocolitis, there was a significantly higher "similar" diagnoses than "different", while the reverse was true for cases of stroke, ileus or bowel obstruction, and meningitis. These results were shared with the ED staff, and similar surveillances were periodically conducted. The frequency of admission within 7 days after discharge continuously declined from 2013 to 2016. Analyzing the discharge and admission diagnoses may help ED staff to understand the reasons for common errors in order to follow the plan-do-check-act cycle of medical care in the ED.
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http://dx.doi.org/10.2147/TCRM.S193863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511631PMC
May 2019

Mild decrease in heart rate during early phase of targeted temperature management following tachycardia on admission is associated with unfavorable neurological outcomes after severe traumatic brain injury: a post hoc analysis of a multicenter randomized controlled trial.

Crit Care 2018 12 19;22(1):352. Epub 2018 Dec 19.

Yamaguchi Prefectural University, 3-2-1 Sakurabatake, Yamaguchi City, Yamaguchi, 753-8502, Japan.

Background: The association between isolated admission heart rate (HR) and prognosis has been discussed, but not that between gross HR change and neurological outcome in patients with severe traumatic brain injury (TBI). In the acute phase of severe TBI, HR is influenced by several factors (e.g., pain, sympathetic activation, hypovolemia, fever, body temperature). Therefore, admission HR and gross HR change should be examined in patients with TBI treated with a well-designed protocol, such as was done in the Brain Hypothermia (B-HYPO) Study.

Methods: This was a post hoc analysis of the B-HYPO Study, which was conducted as a prospective, multicenter, randomized controlled trial in patients with severe TBI receiving mild therapeutic hypothermia (MTH; 32.0 °C-34.0 °C) or fever control (35.5 °C-37.0 °C) in Japan. Patients with MTH were examined, and HR change (%HR) in the early MTH phase was calculated as follows: [admission HR - HR at day 1]/admission HR × 100. Patients were divided into six groups, using admission HR (< 80, 80-99, ≤ 100) and median of %HR; i.e., group (Admission HR < 80 and %HR ≥ 18.6); group (Admission HR < 80 and %HR < 18.6); group (Admission HR 80-99 and %HR ≥ 18.6); group (Admission HR 80-99 and %HR < 18.6); group (Admission HR ≥100 and %HR ≥ 18.6); and group (Admission HR ≥100 and %HR < 18.6). The primary outcome was an adjusted predicted probability of unfavorable neurological outcome at 6 months after TBI according to Glasgow Outcome Scale score, which is a measure of functional recovery and defined as severe disability, persistent vegetative state, and death.

Results: Overall, 79 patients with MTH (52.7% of the original trial) were examined; among these, unfavorable neurological outcomes were observed in 53.2%. Among all the groups, group (Admission HR ≥100 and %HR < 18.6) exhibited the highest proportion of unfavorable outcomes, and 82.3% of patients had an adjusted predicted probability of unfavorable outcomes, whereas those in group (Admission HR < 80 and %HR ≥ 18.6) developed only 22.8% (p = 0.04).

Conclusions: Mild HR decrease during the early phase of targeted temperature management following tachycardia at admission can be associated with unfavorable neurological outcomes after severe TBI.
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http://dx.doi.org/10.1186/s13054-018-2276-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300018PMC
December 2018

The exploration of population pharmacokinetic model for meropenem in augmented renal clearance and investigation of optimum setting of dose.

J Infect Chemother 2018 Oct 4;24(10):834-840. Epub 2018 Aug 4.

Division of Pharmacotherapeutics, Department of Clinical Pharmacy, Showa University School of Pharmacy, Tokyo, Japan.

In recent years, augmented renal clearance (ARC), in which renal function is excessively enhanced, has been reported, and its influence on β-lactam antibiotics has been investigated. In this study, we aimed to determine the optimum population pharmacokinetic model of meropenem in patients with sepsis with ARC, and evaluated dosing regimens based on renal function. Seventeen subjects (6 with ARC and 11 without) were enrolled in this study. Predicted meropenem concentrations were evaluated for bias and precision using the Bland-Altman method. To examine the dosing regimen, Monte Carlo simulation was performed to calculate the cumulative fraction of response (CFR). In patients with ARC, the bias (average of the predicted value and measured value residuals) of models constructed by Crandon et al. (2011), Roberts et al. (2009), and Jaruratanasirikul et al. (2015) were 5.96 μg/mL, 10.91 μg/mL, and 4.41 μg/mL, respectively. Following 2 g meropenem every 8 h (180 min infusion), CFR ≥ 90%, a criterion of success for empirical therapy, was achieved, even with creatinine clearance of 130-250 mL/min. For patients with sepsis and ARC, the model of Jaruratanasirikul et al. showed the highest degree of accuracy and precision and confirmed the efficacy of the meropenem dosing regimen in this patient population.
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http://dx.doi.org/10.1016/j.jiac.2018.07.007DOI Listing
October 2018

Slow rewarming improved the neurological outcomes of prolonged mild therapeutic hypothermia in patients with severe traumatic brain injury and an evacuated hematoma.

Sci Rep 2018 08 2;8(1):11630. Epub 2018 Aug 2.

Yamaguchi Prefectural Grand Medical Center, 77 Osaki, Hofu, Yamaguchi, 747-8511, Japan.

Mild therapeutic hypothermia (MTH) is expected to improve the neurological outcomes of patients with severe traumatic brain injury (TBI). However, there are no standard protocols for managing the temperature of patients with severe TBI in order to improve their neurological outcomes. We conducted a post hoc analysis of the B-HYPO study, a randomized controlled trial of MTH in patients with TBI in Japan. We evaluated the impact of MTH methods on neurological outcomes. Ninety-seven patients who received MTH were included in the present analyses. The neurological outcomes were compared among subgroups of patients divided by cutoff values for the induction, maintenance, and rewarming times of MTH in all patients, in patients with diffuse injury, and in patients with an evacuated hematoma. The proportion of patients with a good neurological outcome was significantly different between patients with an evacuated hematoma divided into subgroups by the cutoff value of rewarming time of 48 h (>48 h vs. ≤ 48 h: 65% vs. 22%; odds ratio: 6.61; 95% confidence interval: 1.13-38.7, P = 0.0498). Slow rewarming for >48 h might improve the neurological outcomes of prolonged MTH in patients with TBI and an evacuated hematoma. Further studies are needed to investigate the optimal rewarming protocol in patients with TBI.
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http://dx.doi.org/10.1038/s41598-018-30119-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072739PMC
August 2018

Therapeutic hypothermia in patients with coagulopathy following severe traumatic brain injury.

Scand J Trauma Resusc Emerg Med 2017 Dec 20;25(1):120. Epub 2017 Dec 20.

Yamaguchi Prefectural Grand Medical Center, 77 Osaki, Boufu, Yamaguchi, 747-8511, Japan.

Background: Coagulopathy in traumatic brain injury (TBI) has been associated with poor neurological outcomes and higher in-hospital mortality. In general principle of trauma management, hypothermia should be prevented as it directly worsens coagulopathy. Therefore, we examined the safety of mild therapeutic hypothermia (MTH) in patients with coagulopathy following severe TBI.

Methods: We re-evaluated the brain hypothermia (B-HYPO) study data based on coagulopathy and compared the Glasgow Outcome Scale scores and survival rates at 6 months using per protocol analyses. Coagulopathy was defined as an activated partial thromboplastin time (APTT) > 60 s and/or fibrin/fibrinogen degradation product levels (FDP) > 90 μg/mL on admission. Baseline characteristics, coagulation parameters, and outcomes were compared between the control and MTH groups with or without coagulopathy.

Results: In patients with coagulopathy, 12 patients were allocated to the control group (35.5-37.0 °C) and 20 patients to the MTH group (32-34 °C). In patients without coagulopathy, 28 were allocated to the control group and 59 patients were allocated to the MTH group. In patients with coagulopathy, favorable neurological outcomes and survival rates were comparable between the control and MTH groups (33.3% vs. 35.0%, P = 1.00; 50.0% vs. 60.0%, P = 0.72) with no difference in complication rates. On admission, no significant differences in APTT or FDP levels were observed between the two groups; however, APTT was significantly prolonged in the MTH group compared to the control group on day 3.

Discussion: Based on our study, MTH did not seem to negatively affect the outcomes in patients with coagulopathy following severe TBI on admission; therefore, the present study indicates that MTH may be applicable even in patients with severe TBI and coagulopathy.

Conclusions: Our study suggests that in comparison to control, MTH does not worsen the outcome of patients with coagulopathy following severe TBI.

Trial Registration: UMIN-CTR, No. C000000231 , Registered 13 September 2005.
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http://dx.doi.org/10.1186/s13049-017-0465-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738813PMC
December 2017

Molecular hydrogen in the treatment of acute and chronic neurological conditions: mechanisms of protection and routes of administration.

J Clin Biochem Nutr 2017 07 15;61(1):1-5. Epub 2017 Jun 15.

Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Rm 810A, Bldg 1 VAPSHCS/GRECC S-182, 1660 S, Columbian Way, Seattle, WA 98108, USA.

Oxidative stress caused by reactive oxygen species is considered a major mediator of tissue and cell injuries in various neuronal conditions, including neurological emergencies and neurodegenerative diseases. Molecular hydrogen is well characterized as a scavenger of hydroxyl radicals and peroxynitrite. Recently, the neuroprotective effects of treatment with molecular hydrogen have been reported in both basic and clinical settings. Here, we review the effects of hydrogen therapy in acute neuronal conditions and neurodegenerative diseases. Hydrogen therapy administered in drinking water may be useful for the prevention of neurodegenerative diseases and for reducing the symptoms of acute neuronal conditions.
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http://dx.doi.org/10.3164/jcbn.16-87DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525017PMC
July 2017

Elevated Serum High-Mobility Group Box-1 Protein Level Is Associated with Poor Functional Outcome in Ischemic Stroke.

J Stroke Cerebrovasc Dis 2017 Oct 20;26(10):2404-2411. Epub 2017 Jun 20.

Japan Organization of Occupational Health and Safety, Tokyo, Japan.

Background: In experimental models, inhibition of high-mobility group box-1 (HMGB1) signaling has been reported to protect against the sequelae of ischemic stroke. Here, we determined the clinical significance of serum HMGB1 levels in patients with acute ischemic stroke.

Methods: We enrolled 183 patients (114 men, 69 women; mean age: 72.7 years) over 6 consecutive months. On admission and day 7, we recorded the National Institutes of Health Stroke Scale scores and measured serum high-sensitivity C-reactive protein (hs-CRP) and HMGB1 levels. Stroke volumes were estimated using diffusion-weighted magnetic resonance imaging performed on admission. One year later, clinical outcome was assessed using the modified Rankin Scale (mRS).

Results: Serum hs-CRP and HMGB1 levels in patients with ischemic stroke were increased relative to healthy controls (both P < .01). On day 7, hs-CRP, but not HMBG1, levels had increased significantly relative to levels at admission (P < .01 and .54, respectively). Higher HMGB1, but not hs-CRP, levels at day 7 correlated with larger stroke volumes (P < .01 and .28, respectively). HMGB1 levels did not significantly differ between stroke subtypes. Multiple logistic regression analysis indicated that a serum HMGB1 level higher than 7.5 ng/mL was an independent risk factor for poor prognosis, defined as a 1-year mRS score of 3-6 (odds ratio, 2.34; 95% confidence interval, 1.02-5.38).

Conclusions: Acute ischemic stroke is associated with elevated serum HMGB1 levels, and HMGB1 levels at admission independently predict poor outcome at 1 year. These results suggest that HMGB1 quantification provides more accurate prognostic information after ischemic stroke.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.05.033DOI Listing
October 2017

Early-Stage Hyperoxia Is Associated with Favorable Neurological Outcomes and Survival after Severe Traumatic Brain Injury: A Post-Hoc Analysis of the Brain Hypothermia Study.

J Neurotrauma 2017 Apr 19;34(8):1565-1570. Epub 2017 Jan 19.

Yamaguchi Prefectural Grand Medical Center, Yamaguchi, Japan.

The effects of hyperoxia on the neurological outcomes of patients with severe traumatic brain injury (TBI) are still controversial. We examined whether the partial pressure of arterial oxygen (PaO) and hyperoxia were associated with neurological outcomes and survival by conducting analyses of the Brain Hypothermia (B-HYPO) study, a multi-center randomized controlled trial of mild therapeutic hypothermia for severe TBI. The differences in PaO and PaO/fraction of inspiratory oxygen (P/F) ratio on the 1st day of admission were compared between patients with favorable ( = 64) and unfavorable ( = 65) neurological outcomes and between survivors ( = 90) and deceased patients ( = 39). PaO and the P/F ratio were significantly greater in patients with favorable outcomes than in patients with unfavorable neurological outcomes (PaO: 252 ± 122 vs. 202 ± 87 mm Hg, respectively,  = 0.008; P/F ratio: 455 ± 171 vs. 389 ± 155, respectively,  = 0.022) and in survivors than in deceased patients (PaO: 242 ± 117 vs. 193 ± 75 mm Hg, respectively,  = 0.005; P/F ratio: 445 ± 171 vs. 370 ± 141, respectively,  = 0.018). Similar tendencies were observed in subgroup analyses in patients with fever control and therapeutic hypothermia, and in patients with an evacuated mass or other lesions (unevacuated lesions). PaO was independently associated with survival (odds ratio 1.008,  = 0.037). These results suggested that early-stage hyperoxia might be associated with favorable neurological outcomes and survival following severe TBI.
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http://dx.doi.org/10.1089/neu.2016.4753DOI Listing
April 2017

Association between Blood Glucose Levels the Day after Targeted Temperature Initiation and Outcome in Traumatic Brain Injury: A Post-Hoc Analysis of the B-HYPO Study.

J Neurotrauma 2017 03 27;34(5):987-995. Epub 2016 Oct 27.

8 Yamaguchi Prefectural Grand Medical Center , Yamaguchi, Japan .

We investigated associations between blood glucose levels and clinical outcomes in participants of the multi-center randomized controlled Brain-Hypothermia (B-HYPO) study. Patients with severe traumatic brain injury (TBI, Glasgow Coma Scale 4-8) were assigned to therapeutic hypothermia (TH, 32-34°C, n = 98) or fever control (35.5-37.0°C, n = 50) groups. TH patients were cooled as soon as possible for ≥72 h and rewarmed at a rate of <1°C/d. We recorded blood glucose (BG) levels on days 0, 1, and 3 after treatment initiation, and day 1 after rewarming. The Glasgow Outcome Scale was assessed at 6 months. Median BG levels decreased from day 0 to day 1 (163 vs. 132 mg/dL, p = 0.0062) in the fever control group. In contrast, a decrease was observed from day 1 to day 3 (157.5 vs. 126 mg/dL, p < 0.001) in the TH group. Day 1 BG was higher in the TH group compared with the fever control group (p = 0.0252). At day 0, BG levels were higher in non-survivors compared with survivors across all patients (p = 0.0035), the TH group (p = 0.0125), and the non-surgical group (p = 0.0236). Higher day 1 BG levels were observed in non-survivors compared with survivors across all patients (p = 0.0071), the fever control group (p = 0.0495), and the surgical group (p = 0.0364). In the TH group, the initial stress hyperglycemia was sustained the next day after TH induction. Day 1 BG predicted outcome in TBI patients with TH and fever control. Our findings indicate the significance of BG control particularly during TH treatment.
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http://dx.doi.org/10.1089/neu.2016.4662DOI Listing
March 2017

Plasma Potassium Concentration on Admission Correlates with Neurologic Outcome in Traumatic Brain Injury Patients Treated with Targeted Temperature Management: A Post Hoc Analysis of a Multicenter Randomized Controlled Trial.

World Neurosurg 2016 Oct 19;94:437-441. Epub 2016 Jul 19.

Yamaguchi Prefectural Grand Medical Center, Yamaguchi, Japan.

Background: Recent studies have focused on the association between plasma electrolytes, particularly potassium level and neurologic outcomes in patients with traumatic brain injury (TBI). We hypothesized that potassium level on admission is an indicator for initiation of targeted temperature management in patients with severe TBI.

Methods: We re-evaluated the Brain Hypothermia Study data based on the potassium levels on admission (i.e., hypokalemia [<3.5 mEq/L] or normokalemia [3.5-5 mEq/L]) and compared these values and Glasgow Outcome Scale scores at 6 months by per protocol analysis. Consequently, 135 patients were enrolled. Finally, groups 50 and 23 patients with hypokalemia and 34 and 23 patients with normokalemia were allocated to mild therapeutic hypothermia (MTH) and fever control groups, respectively. Baseline characteristics, complication rates, and favorable neurologic outcome rates were compared between the two groups.

Results: In the normokalemia patients, fever control management was associated with a significant increase in favorable neurologic outcome compared with those in the MTH group (68.2% vs. 35.3%; P = 0.03). The complication rate was significantly higher in the MTH group than in the fever control group for patients with normokalemia (23.4% vs. 0%; P = 0.03). Conversely, hypokalemia patients in the MTH group revealed relatively better favorable neurologic outcomes compared with those in the fever control group (52.0% vs. 39.1%; P = 0.33).

Conclusions: The initial potassium level may be an indicator in determining appropriate targeted temperature management for patients with TBI. Fever control may be considered instead of MTH for normokalemia patients with TBI on admission.
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http://dx.doi.org/10.1016/j.wneu.2016.07.040DOI Listing
October 2016

Assessing blood granulocyte colony-stimulating factor as a potential biomarker of acute traumatic brain injury in mice and humans.

Brain Behav Immun 2016 Feb 9;52:81-87. Epub 2015 Oct 9.

Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Department of Biobehavioral Nursing & Health Systems, School of Nursing, University of Washington, Seattle, WA 98195, USA; Harborview Injury Prevention and Research Center, University of Washington, Seattle, WA 98104, USA. Electronic address:

Previous work has found that serum G-CSF was acutely elevated in mice 24h but not one week after controlled cortical impact (CCI). The purpose of this study was to investigate whether blood G-CSF correlates with the elevated brain cytokines in mice after CCI and also if it correlates with traumatic brain injury (TBI) in humans. Here, we found in mice undergoing CCI, a procedure that induces direct injury to the brain, that serum G-CSF correlated directly or indirectly with several brain cytokines, indicating it is a useful marker for the neuroinflammation of TBI. A pilot study in humans (phase I, n=19) confirmed that plasma G-CSF is acutely elevated on day 1 (p<0.001) of TBI and has returned to baseline by one week. In a second human sample (phase II) (n=80), we found plasma G-CSF peaks about 12h after arriving in the emergency department (41.6+/-5.4 pg/ml). Aging was weakly associated (p<0.05) with a less robust elevation in serum G-CSF, but there was no difference with gender. ISS, a measure of total severity of injury, correlated with the degree of elevation in serum G-CSF (r=.419; p<0.05), but severity of head injury (via AIS) did not. The latter may have been because of the statistically narrow range of head injuries among our cases and the high number of cases diagnosed with closed head injury (a non-codable diagnosis). In conclusion, plasma G-CSF may be a useful biomarker of TBI, correlating with neuroinflammation in the animal model and in the human studies with time since injury and total severity of injury. As such, it may be useful in determining whether TBI has occurred within the last 24h.
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http://dx.doi.org/10.1016/j.bbi.2015.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873950PMC
February 2016

Fever Control Management Is Preferable to Mild Therapeutic Hypothermia in Traumatic Brain Injury Patients with Abbreviated Injury Scale 3-4: A Multi-Center, Randomized Controlled Trial.

J Neurotrauma 2016 06 20;33(11):1047-53. Epub 2015 Oct 20.

5 Yamaguchi Prefectural Grand Medical Center , Yamaguchi, Japan .

In our prospective, multi-center, randomized controlled trial (RCT)-the Brain Hypothermia (B-HYPO) study-we could not show any difference on neurological outcomes in patients probably because of the heterogeneity in the severity of their traumatic condition. We therefore aimed to clarify and compare the effectiveness of the two therapeutic temperature management regimens in severe (Abbreviated Injury Scale [AIS] 3-4) or critical trauma patients (AIS 5). In the present post hoc B-HYPO study, we re-evaluated data based on the severity of trauma as AIS 3-4 or AIS 5 and compared Glasgow Outcome Scale score and mortality at 6 months by per-protocol analyses. Consequently, 135 patients were enrolled. Finally, 129 patients, that is, 47 and 31 patients with AIS 3-4 and 36 and 15 patients with AIS 5 were allocated to the mild therapeutic hypothermia (MTH) and fever control groups, respectively. No significant intergroup differences were observed with regard to age, gender, scores on head computed tomography (CT) scans, and surgical operation for traumatic brain injury (TBI), except for Injury Severity Score (ISS) in AIS 5. The fever control group demonstrated a significant reduction of TBI-related mortality compared with the MTH group (9.7% vs. 34.0%, p = 0.02) and an increase of favorable neurological outcomes (64.5% vs. 51.1%, p = 0.26) in patients with AIS 3-4, although the latter was not statistically significant. There was no difference in mortality or favorable outcome in patients with AIS 5. Fever control may be considered instead of MTH in patients with TBI (AIS 3-4).
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http://dx.doi.org/10.1089/neu.2015.4033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892213PMC
June 2016

Early initiation of steroid pulse therapy for neuromyelitis optica in an emergency room setting.

Acute Med Surg 2016 04 27;3(2):171-173. Epub 2015 Aug 27.

Department of Emergency Tokyo Jikei University School of Medicine Tokyo Japan.

Case: A 40-year-old man presented to the emergency room with visual impairment, dysesthesia of lower legs, and urinary retention. Two days before admission, he was consulted to the neurology department due to bilateral optic neuritis and scheduled the magnetic resonance imaging of spine. However, the urinary retention deteriorated acutely and he came to the emergency room. On arrival, the plain magnetic resonance image of his spine showed diffuse hyperintensity signals of the spinal cord in T2-weighted images. He was diagnosed with neuromyelitis optica and steroid pulse therapy was initiated.

Outcome: We began treatment immediately in the emergency room, cooperating with the neurology team. After admission, plasmapheresis was added for his fluctuating symptoms. On hospital day 7, he was discharged without complication.

Conclusion: It is important to understand the various clinical manifestations of neuromyelitis optica. In emergency settings, immediate steroid therapy is necessary for better outcomes.
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http://dx.doi.org/10.1002/ams2.155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667370PMC
April 2016

Human mesenchymal stem/stromal cells suppress spinal inflammation in mice with contribution of pituitary adenylate cyclase-activating polypeptide (PACAP).

J Neuroinflammation 2015 Feb 22;12:35. Epub 2015 Feb 22.

Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.

Background: Adult human mesenchymal stem/stromal cells (hMSCs) from bone marrow have been reported to exhibit beneficial effects on spinal cord injury (SCI). A neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP) is known to decrease neuronal cell death and inflammatory response after ischemia, SCI, and other neuronal disorders. Recently, we found that expression of the gene for mouse PACAP (Adcyap1) was greater in animals receiving hMSCs with neural injury such as ischemia. However, the association of PACAP with hMSCs to protect nerve cells against neural injuries is still unclear.

Methods: Wild-type and PACAP-gene-deficient (Adcyap1 (+/-) ) mice were subjected to spinal cord transection, and hMSCs (5 × 10(5) cells) were injected into the intervertebral spinal cord on day 1 post-operation (p.o.). Locomotor activity, injury volume, retention of hMSCs, mouse and human cytokine genes (which contribute to macrophage (MΦ) and microglial activation), and Adcyap1 were evaluated.

Results: hMSCs injected into wild-type mice improved locomotor activity and injury volume compared with vehicle-treated mice. In contrast, non-viable hMSCs injected into wild-type mice, and viable hMSCs injected into Adcyap1 (+/-) mice, did not. Wild-type mice injected with hMSCs exhibited increased Adcyap1 expression, and observed PACAP immunoreaction in neuron-like cells. Gene expression levels for IL-1, tumor necrosis factor α (TNFα), interleukin-10 (IL-10), and transforming growth factor β (TGFβ) decreased, while that for interleukin-4 (IL-4) increased, in hMSC-injected wild-type mice. In contrast, IL-1, TGFβ, and IL-4 gene expression levels were all abolished in hMSC-injected Adcyap1 (+/-) mice on day 7 post-operation. Moreover, the mice-implanted hMSCs increased an alternative activating macrophage/microglial marker, arginase activity. The human gene profile indicated that hMSCs upregulated the gene of IL-4 and growth factors which were reported to enhance Adcyap1 expression. Finally, we demonstrated that hMSCs express human ADCYAP1 and its receptor gene after the inflammation-related interferon-γ (IFNγ) in vitro.

Conclusions: These results suggest that hMSCs attenuate the deleterious effects of SCI by reducing associated inflammatory responses and enhancing IL-4 production. This effect could be mediated in part by cell-cell cross-talk involving the neuropeptide PACAP.
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http://dx.doi.org/10.1186/s12974-015-0252-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346126PMC
February 2015

Molecular hydrogen in drinking water protects against neurodegenerative changes induced by traumatic brain injury.

PLoS One 2014 24;9(9):e108034. Epub 2014 Sep 24.

Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States of America; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, United States of America.

Traumatic brain injury (TBI) in its various forms has emerged as a major problem for modern society. Acute TBI can transform into a chronic condition and be a risk factor for neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, probably through induction of oxidative stress and neuroinflammation. Here, we examined the ability of the antioxidant molecular hydrogen given in drinking water (molecular hydrogen water; mHW) to alter the acute changes induced by controlled cortical impact (CCI), a commonly used experimental model of TBI. We found that mHW reversed CCI-induced edema by about half, completely blocked pathological tau expression, accentuated an early increase seen in several cytokines but attenuated that increase by day 7, reversed changes seen in the protein levels of aquaporin-4, HIF-1, MMP-2, and MMP-9, but not for amyloid beta peptide 1-40 or 1-42. Treatment with mHW also reversed the increase seen 4 h after CCI in gene expression related to oxidation/carbohydrate metabolism, cytokine release, leukocyte or cell migration, cytokine transport, ATP and nucleotide binding. Finally, we found that mHW preserved or increased ATP levels and propose a new mechanism for mHW, that of ATP production through the Jagendorf reaction. These results show that molecular hydrogen given in drinking water reverses many of the sequelae of CCI and suggests that it could be an easily administered, highly effective treatment for TBI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108034PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176020PMC
June 2015

PACAP38 suppresses cortical damage in mice with traumatic brain injury by enhancing antioxidant activity.

J Mol Neurosci 2014 Nov 8;54(3):370-9. Epub 2014 Jun 8.

Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.

The production of reactive oxygen species (ROS) and the resulting oxidative stress in mice in response to a controlled cortical impact (CCI) are typical exacerbating factors associated with traumatic brain injury (TBI). Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) is a multifunctional peptide that has been shown to exhibit neuroprotective effects in response to a diverse range of injuries to neuronal cells. We recently reported that PACAP38 might regulate oxidative stress in mice. The aim of the present study was to determine whether PACAP38 exerts neuroprotective effects by regulating oxidative stress in mice with TBI. Reactive oxidative metabolites (ROMs) and biological antioxidant potential (BAP) were measured in male C57Bl/6 mice before and 3, 4, and 24 h after CCI. PACAP38 was administered intravenously immediately following CCI, and immunostaining for the oxidative stress indicator nitrotyrosine (NT), and for neuronal death as an indicator of the area affected by TBI, was measured 24 h later. Western blot experiments to determine antioxidant activity [as indicated by superoxide dismutase-2 (SOD-2) and glutathione peroxidase 1 (GPx-1)] in the neocortical region were also performed 3 h post-CCI. Results showed that plasma BAP and ROM levels were dramatically increased 3 h after CCI. PACAP38 suppressed the extent of TBI and NT-positive regions 24 h after CCI, and increased SOD-2 and GPx-1 levels in both hemispheres. Taken together, these results suggest that increasing antioxidant might be involving in the neuroprotective effect of PACAP38 in mice subjected to a CCI.
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http://dx.doi.org/10.1007/s12031-014-0309-4DOI Listing
November 2014

Status of systemic oxidative stress during therapeutic hypothermia in patients with post-cardiac arrest syndrome.

Oxid Med Cell Longev 2013 26;2013:562429. Epub 2013 Aug 26.

Department of Emergency and Critical Care Medicine, Showa University Fujigaoka Hospital, Aoba-ku, Yokohama, Kanagawa 227-8501, Japan.

Therapeutic hypothermia (TH) is thought to be due to the downregulation of free radical production, although the details of this process remain unclear. Here, we investigate changes in oxidative stress and endogenous biological antioxidant potential during TH in patients with post-cardiac arrest syndrome (PCAS). Nineteen PCAS patients were enrolled in the study. Brain temperature was decreased to the target temperature of 33°C, and it was maintained for 24 h. Patients were rewarmed slowly (0.1°C/h, <1°C/day). The generation of reactive oxygen metabolites (ROMs) was evaluated in plasma samples by d-ROM test. Plasma antioxidant capacity was measured by the biological antioxidant potential (BAP) test. Levels of d-ROMs and BAP levels during the hypothermic stage (33°C) were suppressed significantly compared with pre-TH induction levels (P < 0.05), while both d-ROM and BAP levels increased with rewarming (33-36°C) and were correlated with brain temperature. Clinical monitoring of oxidative stress and antioxidant potential is useful for evaluating the redox state of patients undergoing TH after PCAS. Additional therapy to support the antioxidant potential in the rewarming stage following TH may reduce some of the observed side effects associated with the use of TH.
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http://dx.doi.org/10.1155/2013/562429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770059PMC
February 2014

Edaravone increases regional cerebral blood flow after traumatic brain injury in mice.

Acta Neurochir Suppl 2013 ;118:103-9

Department of Anatomy, Showa University School of Medicine, Shinagawa-Ku, Tokyo, Japan.

Traumatic brain injury (TBI) is a major cause of preventable death and serious morbidity, with subsequent low cerebral blood flow (CBF) considered to be associated with poor prognosis. In the present study, we demonstrated the effect of the free radical scavenger edaravone on regional CBF (rCBF) after TBI. Male mice (C57/BL6) were subjected to TBI using a controlled cortical impactor device. Immediately after TBI, the animals were intravenously administered 3.0 mg/kg of edaravone or a vehicle saline solution. Two-dimensional rCBF images were acquired before and 24 h post-TBI, and were quantified in the ipsilateral and contralateral hemispheres (n = 5 animals per group). CBF in the vehicle-treated animals decreased broadly over the ipsilateral hemisphere, with the region of low rCBF spreading from the frontal cortex to the occipital lobe. The zone of lowest rCBF matched that of the contusion area. The mean rCBF at 24 h for a defined elliptical region between the bregma and lambda was 73.7 ± 5.8 %. In comparison, the reduction of rCBF in edaravone-treated animals was significantly attenuated (93.4 ± 5.7 %, p < 0.05). The edaravone-treated animals also exhibited higher rCBF in the contralateral hemisphere compared with that seen in -vehicle-treated animals. It is suggested that edaravone reduces neuronal damage by scavenging reactive oxygen species (ROS) and by maintaining intact the autoregulation of the cerebral vasculature.
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http://dx.doi.org/10.1007/978-3-7091-1434-6_18DOI Listing
August 2013

Establishment and characterization of primary adult microglial culture in mice.

Acta Neurochir Suppl 2013 ;118:49-54

Department of Anatomy, Showa University School of Medicine, Shinagawa-Ku, Tokyo, Japan.

Microglial cells account for approximately 12-15 % of the cells in the central nervous system (CNS). Microglial cells are polarized by pathological stimuli such as cytokines, chemokines, and growth factors, and play important roles in the deterioration and repair of the CNS. Here, we established cultures of primary microglial cells isolated from the brains of adult C57/BL6 mice using Percoll density gradients. The cells were cultured and stained with antibodies against CD11b, glial fibrillary acidic protein, myelin basic protein and NeuN to determine microglial, astroglial, oligodendroglial, and neuronal cells respectively. Moreover, the cells were exposed to interferon-γ (IFNγ) plus interleukin-1β (IL-1β) or IL-4 for 24 h to demonstrate the activating phenotypes with inducible nitric oxide synthase (iNOS), Ym1, and Iba-1 immunoblotting. At least 95 % of the cultured cells were CD11b-positive and -negative for astroglial, neuronal, and oligodendrocyte markers. IFNγ plus IL-1β treatment resulted in classical activation, which was represented by an increase in iNOS. The cells also displayed alternative activation, which increased Ym1 when treated with IL-4. The present study indicates that the microglial cells isolated as described here are a useful tool for elucidating adult microglial function.
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http://dx.doi.org/10.1007/978-3-7091-1434-6_8DOI Listing
August 2013

Therapeutic time window for edaravone treatment of traumatic brain injury in mice.

Biomed Res Int 2013 10;2013:379206. Epub 2013 Apr 10.

Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.

Traumatic brain injury (TBI) is a major cause of death and disability in young people. No effective therapy is available to ameliorate its damaging effects. Our aim was to investigate the optimal therapeutic time window of edaravone, a free radical scavenger which is currently used in Japan. We also determined the temporal profile of reactive oxygen species (ROS) production, oxidative stress, and neuronal death. Male C57Bl/6 mice were subjected to a controlled cortical impact (CCI). Edaravone (3.0 mg/kg), or vehicle, was administered intravenously at 0, 3, or 6 hours following CCI. The production of superoxide radicals (O2 (∙-)) as a marker of ROS, of nitrotyrosine (NT) as an indicator of oxidative stress, and neuronal death were measured for 24 hours following CCI. Superoxide radical production was clearly evident 3 hours after CCI, with oxidative stress and neuronal cell death becoming apparent after 6 hours. Edaravone administration after CCI resulted in a significant reduction in the injury volume and oxidative stress, particularly at the 3-hour time point. Moreover, the greatest decrease in O2 (∙-) levels was observed when edaravone was administered 3 hours following CCI. These findings suggest that edaravone could prove clinically useful to ameliorate the devastating effects of TBI.
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http://dx.doi.org/10.1155/2013/379206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654699PMC
December 2013

Accumulation of autofluorescent storage material in brain is accelerated by ischemia in chloride channel 3 gene-deficient mice.

J Neurosci Res 2012 Nov 30;90(11):2163-72. Epub 2012 Jul 30.

Department of Anatomy, Showa University School of Medicine, Tokyo, Japan.

Autofluorescent storage material (ASM) is an aging pigment that accumulates during the normal course of senescence. Although the role of ASM has yet to be fully elucidated, ASM has been implicated in age-related neurodegeneration. In this study, we determined the level of ASM in chloride channel 3 (ClC-3) gene-deficient (KO) mice both in response to aging and following mild global ischemia. To understand the mechanism of action of the ASM, mice subjected to ischemia were treated with the cyclooxygenase (COX) inhibitor indomethacin or with the noncompetitive glutamate receptor antagonist MK-801. ClC-3 KO mice displayed age-related neurodegeneration of the neocortex as well as the hippocampus. The cortical layers in particular granular layers became thinner with aging. ASM accumulated in the brains of ClC-3 KO mice was increased seven- to 50-fold over that observed in the corresponding regions of their wild-type littermates. Young wild-type mice survived longer than age-matched ClC-3 KO mice after permanent global ischemia. However, in the case of older animals, the survival curves were similar. The ASM also increased four- to fivefold 10 days after mild global ischemia, an effect that was suppressed by treatment with indomethacin and MK-801. These results suggest that temporary ischemia might trigger a process similar to aging in the brain, mimicking the effect of age-related neurodegenerative diseases.
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http://dx.doi.org/10.1002/jnr.23110DOI Listing
November 2012

[Aggressive endoscopic removal of bezoars effective for the treatment of acute poisoning].

Chudoku Kenkyu 2012 Jun;25(2):113-6

Department of Emergency and Critical Care Medicine, Showa University.

A 37-year-old female presented with acute chlorpromazine and phenobarbital poisoning. Contrast enhanced abdominal CT on admission revealed a high density area at the gastric fundus and residual drugs were suspected. Activated charcoal and cathartics were administered following the gastric lavage under the intubation. As the plasma concentration of phenobarbital was high, urinary alkalinization and crystalloid infusion were carried out to reduce it. However, at 3 days after admission, the plasma concentration level had increased and the consciousness disturbance and respiratory depression continued. Abdominal CT was performed again and bezoars formation was suspected. Endoscopy was carried out to remove the bezoars. After the removal, the plasma concentration level significantly decreased. Her consciousness disturbance and respiratory depression also improved and high density area at the gastric fundus disappeared. Acute endoscopy is seldom advocated in cases of drug overdose. However, aggressive endoscopic removal should be considered in the case of acute poisoning of drugs with form bezoars.
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June 2012

Neuroinflammation: a common pathway in CNS diseases as mediated at the blood-brain barrier.

Neuroimmunomodulation 2012 11;19(2):121-30. Epub 2012 Jan 11.

Geriatrics Research Education and Clinical Center, Puget Sound Health Care System, Seattle, Wash., USA.

The blood-brain barrier (BBB) is not simply a physical barrier but a regulatory interface between the central nervous system (CNS) and immune system. The BBB both affects and is affected by the immune system and connects at many levels with the CNS, including the following: (1) the BBB transports cytokines and secretes various substances with neuroinflammatory properties; (2) transporters are altered in disease states including traumatic injury, Alzheimer's disease and inflammatory processes; (3) cytokines and other immune secretions from the cells comprising the BBB are both constitutive and inducible; (4) immune cells are transported across the BBB by the highly regulated process termed diapedesis, which involves communication and interactions between the brain endothelial cells and the immune cells; (5) the neuroimmune system has various effects on the BBB, including modulation of important transport systems and in extreme pathological conditions even disruption of the BBB, and (6) the brain-to-blood efflux transporter P-glycoprotein is altered in inflammatory conditions, thus affecting drug delivery to the brain. In summary, the BBB is an interactive interface that regulates and defines many of the ways that the CNS and the immune system communicate with one another.
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http://dx.doi.org/10.1159/000330247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707010PMC
July 2012