Military Medicine Research Unit

Tokyo, Japan

Military Medicine Research Unit

Tokyo, Japan
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Satoh Y.,National Defense Medical College | Sato S.,National Defense Medical College | Tokuno S.,National Defense Medical College | Hatano B.,Military Medicine Research Unit | And 3 more authors.
Lasers in Surgery and Medicine | Year: 2010

Background and Objectives: Primary blast injury is produced by shock waves. Blast injuries to lungs are extremely critical threats to survival, but their etiology is largely undefined. The majority of animal models for these injuries use explosive or complex experimental settings, limiting the laboratory study of blast injury. The aim of this study was to establish a small-animal model for blast injuries, using laser-induced stress waves (LISWs) with high controllability, high reproducibility, and easy experimental settings. Study Design/Materials and Methods: LISWs were used to produce isolated pulmonary blast effects in mice.An LISW was generated by the irradiation of an elastic laser target with 532-nm nanosecond laser pulses of a Q-switchedNd:YAG laser. Histopathological evaluations of damage to lung tissue were conducted to estimate the relevance between peak pressure and trauma intensity. Blood pressure, heart rate, and percutaneous oxygen saturation were monitored for 60 minutes. Results: We could flexibly control the peak pressure of the shock wave by varying the laser energy. Non-lethal doses of LISWs caused pulmonary contusions with alveolar hemorrhages depending on peak pressure. Pulmonary contusion was observed only in areas that were exposed to LISWs, allowing study of isolated injuries without concomitant ones. These injuries caused decreased blood pressure, heart rate, and percutaneous oxygen saturation, immediately after LISW exposure. Conclusion: Mice exposed to thoracic LISWs showed pathologic and physiologic changes similar to those seen in other studies in this area, and in clinical practice. Our newly developed model allows fine management of trauma intensity, and concomitant injuries of the exposed animals were limited. This novel mouse model of blast injury using LISWs is suitable for detailed studies of blast lung contusion and other blast injuries in the laboratory. © 2010 Wiley-Liss, Inc.


Ito Y.,Military Medicine Research Unit | Kinoshita M.,National Defense Medical College | Yamamoto T.,Military Medicine Research Unit | Sato T.,Military Medicine Research Unit | And 3 more authors.
International Journal of Molecular Sciences | Year: 2013

The development of an effective therapy for radiation-induced gastrointestinal damage is important, because it is currently a major complication of treatment and there are few effective therapies available. Although we have recently demonstrated that pretreatment with ascorbic acid attenuates lethal gastrointestinal damage in irradiated mice, more than half of mice eventually died, thus indicating that better approach was needed. We then investigated a more effective therapy for radiation-induced gastrointestinal damage. Mice receiving abdominal radiation at 13 Gy were orally administered ascorbic acid (250 mg/kg/day) for three days before radiation (pretreatment), one shot of engulfment (250 mg/kg) at 8 h before radiation, or were administered the agent for seven days after radiation (post-treatment). None of the control mice survived the abdominal radiation at 13 Gy due to severe gastrointestinal damage (without bone marrow damage). Neither pretreatment with ascorbic acid (20% survival), engulfment (20%), nor post-treatment (0%) was effective in irradiated mice. However, combination therapy using ascorbic acid, including pretreatment, engulfment and post-treatment, rescued all of the mice from lethal abdominal radiation, and was accompanied by remarkable improvements in the gastrointestinal damage (100% survival). Omitting post-treatment from the combination therapy with ascorbic acid markedly reduced the mouse survival (20% survival), suggesting the importance of post-treatment with ascorbic acid. Combination therapy with ascorbic acid may be a potent therapeutic tool for radiation-induced gastrointestinal damage. © 2013 by the authors; licensee MDPI, Basel, Switzerland.


PubMed | National Defense Medical College and Military Medicine Research Unit
Type: Journal Article | Journal: PloS one | Year: 2015

Ascorbic acid is an effective antioxidant and free radical scavenger. Therefore, it is expected that ascorbic acid should act as a radioprotectant. We investigated the effects of post-radiation treatment with ascorbic acid on mouse survival. Mice received whole body irradiation (WBI) followed by intraperitoneal administration of ascorbic acid. Administration of 3 g/kg of ascorbic acid immediately after exposure significantly increased mouse survival after WBI at 7 to 8 Gy. However, administration of less than 3 g/kg of ascorbic acid was ineffective, and 4 or more g/kg was harmful to the mice. Post-exposure treatment with 3 g/kg of ascorbic acid reduced radiation-induced apoptosis in bone marrow cells and restored hematopoietic function. Treatment with ascorbic acid (3 g/kg) up to 24 h (1, 6, 12, or 24 h) after WBI at 7.5 Gy effectively improved mouse survival; however, treatments beyond 36 h were ineffective. Two treatments with ascorbic acid (1.5 g/kg 2, immediately and 24 h after radiation, 3 g/kg in total) also improved mouse survival after WBI at 7.5 Gy, accompanied with suppression of radiation-induced free radical metabolites. In conclusion, administration of high-dose ascorbic acid might reduce radiation lethality in mice even after exposure.


Suzuki G.,Military Medicine Research Unit | Suzuki G.,Japan Self Defense Force Central Hospital | Tokuno S.,National Defense Medical College | Nibuya M.,National Defense Medical College | And 7 more authors.
PLoS ONE | Year: 2014

Decreased concentrations of plasma brain-derived neurotrophic factor (BDNF) and serum BDNF have been proposed to be a state marker of depression and a biological indicator of loaded psychosocial stress. Stress evaluations of participants in military mission are critically important and appropriate objective biological parameters that evaluate stress are needed. In military circumstances, there are several problems to adopt plasma BDNF concentration as a stress biomarker. First, in addition to psychosocial stress, military missions inevitably involve physical exercise that increases plasma BDNF concentrations. Second, most participants in the mission do not have adequate quality or quantity of sleep, and sleep deprivation has also been reported to increase plasma BDNF concentration. We evaluated plasma BDNF concentrations in 52 participants on a 9-week military mission. The present study revealed that plasma BDNF concentration significantly decreased despite elevated serum enzymes that escaped from muscle and decreased quantity and quality of sleep, as detected by a wearable watch-type sensor. In addition, we observed a significant decrease in plasma vascular endothelial growth factor (VEGF) during the mission. VEGF is also neurotrophic and its expression in the brain has been reported to be up-regulated by antidepressive treatments and down-regulated by stress. This is the first report of decreased plasma VEGF concentrations by stress. We conclude that decreased plasma concentrations of neurotrophins can be candidates for mental stress indicators in actual stressful environments that include physical exercise and limited sleep. © 2014 Suzuki et al.


PubMed | Kansai University of Welfare Sciences, National Defense Medical College, Jikei University School of Medicine, Japan Self Defense Force Central Hospital and 2 more.
Type: Journal Article | Journal: Biochemical and biophysical research communications | Year: 2016

Fatigue reduces productivity and is a risk factor for lifestyle diseases and mental disorders. Everyone experiences physiological fatigue and recovers with rest. Pathological fatigue, however, greatly reduces quality of life and requires therapeutic interventions. It is therefore necessary to distinguish between the two but there has been no biomarker for this. We report on the measurement of salivary human herpesvirus (HHV-) 6 and HHV-7 as biomarkers for quantifying physiological fatigue. They increased with military training and work and rapidly decreased with rest. Our results suggested that macrophage activation and differentiation were necessary for virus reactivation. However, HHV-6 and HHV-7 did not increase in obstructive sleep apnea syndrome (OSAS), chronic fatigue syndrome (CFS) and major depressive disorder (MDD), which are thought to cause pathological fatigue. Thus, HHV-6 and HHV-7 would be useful biomarkers for distinguishing between physiological and pathological fatigue. Our findings suggest a fundamentally new approach to evaluating fatigue and preventing fatigue-related diseases.


Yamamoto T.,National Defense Medical College | Yamamoto T.,Military Medicine Research Unit | Kinoshita M.,National Defense Medical College | Shinomiya N.,National Defense Medical College | And 6 more authors.
Journal of Radiation Research | Year: 2010

While bone marrow or stem cell transplantation can rescue bone marrow aplasia in patients accidentally exposed to a lethal radiation dose, radiation-induced irreversible gastrointestinal damage (GI syndrome) is fatal. We investigated the effects of ascorbic acid on radiation-induced GI syndrome in mice. Ascorbic acid (150 mg/kg/day) was orally administered to mice for 3 days, and then the mice underwent whole body irradiation (WBI). Bone marrow transplantation (BMT) 24 h after irradiation rescued mice receiving a WBI dose of less than 12 Gy. No mice receiving 14 Gy-WBI survived, because of radiation- induced GI syndrome, even if they received BMT. However, pretreatment with ascorbic acid significantly suppressed radiation-induced DNA damage in the crypt cells and prevented denudation of intestinal mucosa; therefore, ascorbic acid in combination with BMT rescued mice after 14 Gy-WBI. DNA microarray analysis demonstrated that irradiation up-regulated expressions of apoptosis-related genes in the small intestine, including those related to the caspase-9-mediated intrinsic pathway as well as the caspase-8- mediated extrinsic pathway, and down-regulated expressions of these genes in ascorbic acid-pretreated mice. Thus, pretreatment with ascorbic acid may effectively prevent radiation-induced GI syndrome.


Hatano B.,Japan National Institute of Infectious Diseases | Hatano B.,Military Medicine Research Unit | Kojima A.,Japan National Institute of Infectious Diseases | Sata T.,Japan National Institute of Infectious Diseases | Katano H.,Japan National Institute of Infectious Diseases
Japanese Journal of Infectious Diseases | Year: 2010

Intentional contamination of beverages with microbes is one type of bioterrorist threat. While bacteria and fungus can be easily collected by a centrifuge, viruses are difficult to collect from virus-contaminated beverages. In this study, we demonstrated that Viro-Adembeads, a rapid-capture system for viruses using anionic polymer-coated magnetic beads, collected viruses from beverages contaminated intentionally with vaccinia virus and human herpesvirus 8. Real-time PCR showed that the recovery rates of the contaminated viruses in green tea and orange juice were lower than those in milk and water. Plaque assay showed that green tea and orange juice cut the efficiency of vaccinia virus infection in CV-1 cells. These results suggest that the efficiency of virus detection depends on the kind of beverage being tested. Viro-Adembeads would be a useful tool for detecting viruses rapidly in virus-contaminated beverages used in a bioterrorist attack.


Fukumoto H.,Japan National Institute of Infectious Diseases | Fukumoto H.,Military Medicine Research Unit | Kanno T.,Japan National Institute of Infectious Diseases | Hasegawa H.,Japan National Institute of Infectious Diseases | Katano H.,Japan National Institute of Infectious Diseases
Frontiers in Microbiology | Year: 2011

Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) is a human herpesvirus, classified as a gamma-herpesvirus. KSHV is detected in Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and some cases of multicentric Castleman's disease (MCD). Similar to other herpes viruses, there are two phases of infection, latent and lytic. In KSHV-associated malignancies such as KS and PEL, KSHV latently infects almost all tumor cells. Quantitative PCR analysis revealed that each tumor cell contains one copy of KSHV in KS lesions.The oncogenesis by KSHV has remained unclear. Latency-associated nuclear antigen (LANA)-1 plays an important role in the pathogenesis of KSHV-associated malignancies through inhibition of apoptosis and maintenance of latency. Because all KSHV-infected cells express LANA-1, LANA-1 immunohistochemistry is a useful tool for diagnosis of KSHV infection. KSHV encodes some homologs of cellular proteins including cell-cycle regulators, cytokines, and chemokines, such as cyclin D, G-protein-coupled protein, interleukin-6, and macrophage inflammatory protein-1 and -2. These viral proteins mimic or disrupt host cytokine signals, resulting in microenvironments amenable to tumor growth. Lytic infection is frequently seen in MCD tissues, suggesting a different pathogenesis from KS and lymphoma. © 2011 Fukumoto, Kanno, Hasegawa and Katano.


Otabe H.,National Defense Medical College | Nibuya M.,National Defense Medical College | Shimazaki K.,Jichi Medical School | Toda H.,National Defense Medical College | And 4 more authors.
Progress in Neuro-Psychopharmacology and Biological Psychiatry | Year: 2014

The putative antidepressive mechanisms of a series of electroconvulsive seizures (ECS) are the following: 1) downregulation of monoaminergic receptor expression in several brain regions, 2) upregulation of the expression of brain-derived neurotrophic factor (BDNF), and 3) increased neurogenesis in the hippocampus. In this study, we used Western blot techniques to present another mechanism in which ECS enhances the autophagy signaling that is involved in the machinery related to synaptic and neural plasticity. Antibodies for conjugated Atg5-Atg12 (58. kD) and cleaved light chain protein 3-II (LC3-II; 14 kD) were used to detect autophagy signals. An antibody for cleaved caspase-3 (17 kD) was used to detect alterations in apoptotic signals. Mature BDNF (14. kD) expression in the hippocampus was evaluated in order to qualify the effectiveness of the ECS or stress-loading treatment. While significantly increased autophagy signals and no increases in apoptotic signals were detected in the ECS-treated rat hippocampus, the reverse (increased apoptotic signals and no altered autophagy signals) was observed in stressed rat hippocampus. No neuronal cell loss but new mossy fiber sprouting has been reported to accompany multiple ECS treatments, and recent studies have revealed that autophagy processes regulate the number of specific neurotransmitter receptors and the plasticity of synaptic components. The present study illustrated the neuroplastic and neurotrophic profiles of ECS and the neurotoxic impact of severe stress loading on hippocampal regions. This is the first report to demonstrate increased autophagy signals in ECS-treated rat hippocampus and no alterations in autophagy signals in stress-loaded rat hippocampus. © 2013 Elsevier Inc.


PubMed | National Defense Medical College, Jichi Medical School and Military Medicine Research Unit
Type: | Journal: Progress in neuro-psychopharmacology & biological psychiatry | Year: 2014

The putative antidepressive mechanisms of a series of electroconvulsive seizures (ECS) are the following: 1) downregulation of monoaminergic receptor expression in several brain regions, 2) upregulation of the expression of brain-derived neurotrophic factor (BDNF), and 3) increased neurogenesis in the hippocampus. In this study, we used Western blot techniques to present another mechanism in which ECS enhances the autophagy signaling that is involved in the machinery related to synaptic and neural plasticity. Antibodies for conjugated Atg5-Atg12 (58kD) and cleaved light chain protein 3-II (LC3-II; 14 kD) were used to detect autophagy signals. An antibody for cleaved caspase-3 (17 kD) was used to detect alterations in apoptotic signals. Mature BDNF (14kD) expression in the hippocampus was evaluated in order to qualify the effectiveness of the ECS or stress-loading treatment. While significantly increased autophagy signals and no increases in apoptotic signals were detected in the ECS-treated rat hippocampus, the reverse (increased apoptotic signals and no altered autophagy signals) was observed in stressed rat hippocampus. No neuronal cell loss but new mossy fiber sprouting has been reported to accompany multiple ECS treatments, and recent studies have revealed that autophagy processes regulate the number of specific neurotransmitter receptors and the plasticity of synaptic components. The present study illustrated the neuroplastic and neurotrophic profiles of ECS and the neurotoxic impact of severe stress loading on hippocampal regions. This is the first report to demonstrate increased autophagy signals in ECS-treated rat hippocampus and no alterations in autophagy signals in stress-loaded rat hippocampus.

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