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author:("nishiwaki, T.")
1.  Prenatal regression of the trophotaenial placenta in a viviparous fish, Xenotoca eiseni 
Scientific Reports  2015;5:7855.
The trophotaenial placenta is a branching, ribbon-like structure that extends from the perianal region of the embryo in viviparous teleost fishes belonging to the family Goodeidae. It is a hindgut-derived pseudoplacenta, which contributes to absorbing maternal nutrients during the prenatal stage. The trophotaeniae are known to reduce at birth; however, no previous study has evaluated the removal mechanisms. We report here the analysis of the trophotaeniae using the goodeid fish species Xenotoca eiseni. The X. eiseni trophotaenia consists of an epidermal cell layer, mesenchyme, vasculature, and circulating erythrocytes. The trophotaeniae had preliminary regressed when the embryo was born. Immunohistochemistry indicated that caspase3-activated cells with fragmented nuclei are present in the regressed processes of the fry immediately after birth, but not in the vasculature and blood cells. This finding suggests that the trophotaenia is rapidly resorbed by apoptosis in the last phase of the pregnancy and that its circulatory pathway is maintained. Such prenatal regression of pseudoplacentae has not been reported in other viviparous vertebrates. On the other hand, similar apoptotic remodeling in the gut has been reported in amphibians, which is regulated by thyroid hormone. Thus, apoptotic regression of the trophotaeniae might occur in a manner similar to amphibian metamorphosis.
PMCID: PMC4297964  PMID: 25598151
2.  Preventive effects of Chlorella on skeletal muscle atrophy in muscle-specific mitochondrial aldehyde dehydrogenase 2 activity-deficient mice 
Oxidative stress is involved in age-related muscle atrophy, such as sarcopenia. Since Chlorella, a unicellular green alga, contains various antioxidant substances, we used a mouse model of enhanced oxidative stress to investigate whether Chlorella could prevent muscle atrophy.
Aldehyde dehydrogenase 2 (ALDH2) is an anti-oxidative enzyme that detoxifies reactive aldehydes derived from lipid peroxides such as 4-hydroxy-2-nonenal (4-HNE). We therefore used transgenic mice expressing a dominant-negative form of ALDH2 (ALDH2*2 Tg mice) to selectively decrease ALDH2 activity in the muscles. To evaluate the effect of Chlorella, the mice were fed a Chlorella-supplemented diet (CSD) for 6 months.
ALDH2*2 Tg mice exhibited small body size, muscle atrophy, decreased fat content, osteopenia, and kyphosis, accompanied by increased muscular 4-HNE levels. The CSD helped in recovery of body weight, enhanced oxidative stress, and increased levels of a muscle impairment marker, creatine phosphokinase (CPK) induced by ALDH2*2. Furthermore, histological and histochemical analyses revealed that the consumption of the CSD improved skeletal muscle atrophy and the activity of the mitochondrial cytochrome c oxidase.
This study suggests that long-term consumption of Chlorella has the potential to prevent age-related muscle atrophy.
PMCID: PMC4200191  PMID: 25305781
Muscle atrophy; Chlorella; Aldehyde dehydrogenase 2; Mitochondrial cytochrome c oxidase; Oxidative stress
3.  Successful treatment of acquired uterine arterial venous malformation using N-butyl-2-cyanoacrylate under balloon occlusion 
Acta Radiologica Short Reports  2014;3(8):2047981614545910.
We present two cases of acquired uterine arterial venous malformation (AVM) which was diagnosed because of massive genital bleeding successfully treated with transcatheter arterial embolization (TAE), using N-butyl-2-cyanoacrylate (NBCA) under balloon occlusion. Balloon occlusion at the uterine artery was performed in both patients for diffuse distribution of NBCA in multiple feeding branches, as well as to the pseudoaneurysm, and for the prevention of NBCA reflux. In one of our patients, balloon occlusion of the draining vein was simultaneously performed to prevent NBCA migration through accompanying high-flow arteriovenous fistula (AVF). Doppler ultrasound at 6 months of both patients documented persistent complete occlusion of AVM. Complete and safe obliteration of acquired uterine AVM was accomplished using NBCA as embolic agent, under balloon occlusion at the communicating vessels of acquired uterine AVM.
PMCID: PMC4207280  PMID: 25346850
Acquired arteriovenous malformation; embolization; obstetrics
4.  Imipenem/cilastatin sodium (IPM/CS) as an embolic agent for transcatheter arterial embolisation: a preliminary clinical study of gastrointestinal bleeding from neoplasms 
SpringerPlus  2013;2:344.
To evaluate the feasibility and usefulness of imipenem/cilastatin sodium (IPM/CS) as an embolic agent for intestinal bleeding from neoplasms.
Materials and methods
Seven patients who underwent 11 transarterial embolisations (TAEs) using IPM/CS as an embolic material for duodenal or small/large intestinal tumour bleeding from January 2004 to December 2011 were retrospectively evaluated. A mixture of IPM/CS and contrast medium was introduced through the microcatheter positioned at the feeding artery to the tumour until extravasation disappeared or stasis of blood flow to the tumour staining was observed.
Haemostasis was obtained in all patients. Therefore, the technical success rate was 100%. Rebleeding was observed in four patients. All of them underwent repeat TAE using IPM/CS, and haemostasis was obtained successfully. No complication was identified following laboratory and clinical examinations. No haemorrhagic death occurred. Haemorrhagic parameters, including blood haemoglobin and the amount of blood transfusion, improved after TAE.
The safety, feasibility, and effectiveness of TAE using IPM/CS as an embolic material for intestinal bleeding from neoplasms were suggested by this study. The mild embolic effect of IPM/CS may be adequate for oozing from tumours. Although rebleeding may occur after embolotherapy using IPM/CS, repeat embolisation is effective as treatment for rebleeding.
PMCID: PMC3731674  PMID: 23961409
Bleeding; Neoplasm; Embolisation; IPM/CS
5.  Lipidomic analysis of brain tissues and plasma in a mouse model expressing mutated human amyloid precursor protein/tau for Alzheimer’s disease 
Alzheimer’s disease (AD), the most common cause of dementia among neurodegenerative diseases, afflicts millions of elderly people worldwide. In addition to amyloid-beta (Aβ) peptide and phosphorylated tau, lipid dysregulation is suggested to participate in AD pathogenesis. However, alterations in individual lipid species and their role in AD disease progression remain unclear.
We performed a lipidomic analysis using brain tissues and plasma obtained from mice expressing mutated human amyloid precursor protein (APP) and tau protein (Tg2576×JNPL3) (APP/tau mice) at 4 (pre-symptomatic phase), 10 (early symptomatic) and 15 months (late symptomatic).
Levels of docosahexaenoyl (22:6) cholesterol ester (ChE) were markedly increased in APP/tau mice compared to controls at all stages examined. Several species of ethanolamine plasmalogens (pPEs) and sphingomyelins (SMs) showed different levels between brains from APP/tau and control mice at various stages of AD. Increased levels of 12-hydroxyeicosatetraenoic acid (12-HETE) during the early symptomatic phase were consistent with previous reports using human AD brain tissue. In addition, 19,20-dihydroxy-docosapentaenoic acid (19,20-diHDoPE) and 17,18-dihydroxy-eicosatetraenoic acid (17,18-diHETE), which are produced from docosahexaenoic acid and eicosapentaenoic acid via 19,20-epoxy-docosapentaenoic acid (19,20-EpDPE) and 17,18-epoxy-eicosatetraenoic acid (17,18-EpETE), respectively, were significantly increased in APP/tau brains during the pre-symptomatic phase, and concomitant increases occurred in plasma. Several arachidonic acid metabolites such as prostaglandin D2 (PGD2) and 15-hydroxyeicosatetraenoic acid (15-HETE), which have potential deteriorating and protective actions, respectively, were decreased in the early symptomatic phase of APP/tau mice. Significant decreases in phosphatidylcholines and PEs with polyunsaturated fatty acids were also detected in the late symptomatic phase, indicating a perturbation of membrane properties.
Our results provide fundamental information on lipid dysregulation during various stages of human AD.
PMCID: PMC3668217  PMID: 23659495
Lipidomic analysis; Alzheimer’s disease; Mice model; Ethanolamine plasmalogens; Oxidative fatty acids
6.  Acute phlegmonous esophagitis as a rare but threatening complication of chemoradiotherapy: report of a case 
Surgery Today  2013;44(6):1147-1151.
Phlegmonous infection involving the digestive tract has been reported to have a poor prognosis. However, the pathogenesis and clinical features of acute phlegmonous esophagitis have remained unclear due to the rarity of the disease. We herein report a case of acute phlegmonous esophagitis that showed a fulminant course during chemoradiotherapy for uterine cancer. The patient developed septic shock 10 h after postprandial nausea and vomiting, and a computed tomographic scan showed diffuse thickening of the esophageal wall. Severe leukopenia that was refractory to the administration of granulocyte colony-stimulating factor persisted during the first few days. The patient fortunately survived after intensive treatment. The acute phlegmonous esophagitis of the present case might have been evoked and worsened by chemoradiotherapy due to its emetic and myelosuppressive adverse effects, respectively. Although its incidence is extremely rare, acute phlegmonous esophagitis may occur as a life-threatening complication of chemoradiotherapy.
PMCID: PMC4019822  PMID: 23467978
Acute phlegmonous esophagitis; Chemoradiotherapy; Adverse event
7.  Tuberculous Lymphadenopathy Mimicking Pancreatic Neoplasm 
Case Reports in Medicine  2012;2012:579297.
Abdominal tuberculosis (TB) is the sixth most common location of extrapulmonary TB involvement. Because its symptoms and signs are often nonspecific, laboratory and imaging findings mimic other diseases including carcinoma. Therefore, the diagnosis of abdominal TB is challenging. We herein report a case of 74-year-old woman who presented with abdominal pain, anorexia, and weight loss. She had been given a diagnosis of pancreatic head carcinoma. Laboratory data was unremarkable except for elevated erythrocyte sedimentation rate, CA125, and sIL-2R. CT scan revealed multiple enlarged peripancreatic lymph nodes and concentric thickening of the ileocecal wall. Colonoscopy demonstrated deformed ileocecal valve and erosions. Histological examination showed epithelioid granulomas. Laparoscopy revealed numerous white tubercles diffusely covering the parietal peritoneum. Histopathological images of peripancreatic lymph node revealed large multiple caseating granulomas surrounded by Langhans_giant cells and epithelioid cells. Polymerase chain reaction and culture of the specimens were positive for Mycobacterium tuberculosis. Tuberculous lymphadenopathy, colitis, and peritonitis were finally diagnosed. She responded well to the antitubercular treatment.
PMCID: PMC3407625  PMID: 22851977
8.  The increase in surface CXCR4 expression on lung extravascular neutrophils and its effects on neutrophils during endotoxin-induced lung injury 
Inflammatory stimuli, such as a microbes or lipopolysaccharides, induce a rapid release of neutrophils from the bone marrow and promote neutrophil migration into inflamed sites to promote host defense. However, an excess accumulation and retention of neutrophils in inflamed tissue can cause severe tissue injuries in the later stages of inflammation. Recent studies have reported that both CXCL12 levels in injured lungs and its receptor, CXCR4, on accumulated neutrophils in injured lungs, increased; furthermore, these studies showed that the CXCL12/CXCR4 signaling pathway participated in neutrophil accumulation in the later stages of lipopolysaccharide (LPS)-induced lung injury. However, the mechanisms underlying this increase in surface CXCR4 expression in neutrophils remain unclear. In this study, we found that surface CXCR4 expression increased in extravascular, but not intravascular, neutrophils in the lungs of LPS-induced lung injury model mice. Furthermore, ex vivo studies revealed that CXCL12 acted not only as a chemoattractant, but also as a suppressor of cell death for the lung neutrophils expressing CXCR4. Sulfatide, one of the native ligands for L-selectin, induced the increase of surface CXCR4 expression on isolated circulating neutrophils, suggesting that the activation of L-selectin may be involved in the increase in surface CXCR4. Our findings show that surface CXCR4 levels on neutrophils increase after extravasation into injured lungs, possibly through the activation of L-selectin. The CXCL12/CXCR4 signaling pathway plays an important role in the modulation of neutrophil activity during acute lung injury, not only by promoting chemotaxis but also by suppressing cell death.
PMCID: PMC4002449  PMID: 21460863
CXCL12; CXCR4; lipopolysaccharides; lung injury; neutrophils
9.  Transient neonatal diabetes mellitus in an extremely preterm infant 
BMJ Case Reports  2009;2009:bcr11.2008.1185.
The present report concerns transient neonatal diabetes mellitus in an extremely preterm infant (gestational age 27 weeks, birth weight 718 g). The patient had intrauterine growth retardation and developed hyperglycaemia on the first day of life. Insulin administration was discontinued on the 89th day of life, which was 1 day before the original due date. This case suggests that (a) insufficient insulin secretion started at least from the second trimester of the pregnancy, and (b) the duration needed for recovery of insulin secretion was not dependent on the maturity.
PMCID: PMC3027502  PMID: 21686427
10.  Clinical significance of GLUT-1 expression in patients with esophageal cancer treated with concurrent chemoradiotherapy 
Oncology Letters  2010;2(1):21-28.
This study aimed to investigate whether glucose transporter-1 (GLUT-1) expression in a pretreatment esophageal cancer biopsy was predictive of clinical outcomes in patients with esophageal cancer undergoing concurrent chemoradiotherapy (CRT). A total of 25 patients with esophageal cancer treated with concurrent CRT were reviewed. Radiotherapy was administered up to total doses of 40–66.6 Gy (median 66.6 Gy) with a single fraction of 1.8–2 Gy. Regarding chemotherapy, cisplatin (80 mg/m2 on day 1) and 5-fluorouracil (800 mg/m2 on days 2–6) were used concurrently with radiotherapy, every 3–4 weeks for a total of 1–2 courses. Tissue samples from esophageal carcinoma were obtained from the 25 patients by biopsy prior to concurrent CRT, and a semiquantitative analysis of GLUT-1 expression was performed using immunohistochemical staining. High GLUT-1 expression was observed in 7 of 25 (28%) patients, and GLUT-1 expression was significantly correlated with clinical T stage (p=0.0454), clinical N stage (p=0.0324) and initial response to CRT (p=0.0185). Patients with a high GLUT-1 expression had significantly poorer local control (LC) (5-year LC 28.6%) than those with a low expression (5-year LC 73.4%, p<005). Multivariate analysis revealed that GLUT-1 and the number of chemotherapy courses were independent prognostic factors for LC. Patients with a high GLUT-1 expression had significantly lower recurrence-free survival (RFS) compared to those with a low GLUT-1 expression (p=0.0405). Multivariate analysis revealed that GLUT-1, the number of chemotherapy courses and clinical M stage were independent prognostic factors for RFS. GLUT-1 expression was significantly correlated with clinical T stage, clinical N stage and initial response to concurrent CRT, and was predictive of LC and RFS for patients with esophageal cancer treated with concurrent CRT.
PMCID: PMC3412522  PMID: 22870123
glucose-transporter-1; esophageal neoplasm; radiotherapy; chemotherapy
11.  Aortic thrombus in a patient with myeloproliferative thrombocytosis, successfully treated by pharmaceutical therapy: a case report 
Thrombosis in myeloproliferative thrombocytosis occurs usually in the microvessels and medium-sized arteries and veins and only rarely in the aorta. Aortic thrombosis is usually treated with thrombectomy. Reported here is a rare case that was treated pharmacologically.
Case presentation
A 60-year-old Japanese woman presented with numbness of both lower extremities. Her platelet count was 1787 × 103/μl. Through bone marrow examination, we diagnosed her condition as myelodysplastic and/or myeloproliferative disorder-unclassifiable. Abdominal ultrasonography and computed tomographic scan revealed aortic thrombosis. Her platelet count was controlled with hydroxyurea and ranimustine. Aspirin and ticlopidine improved the numbness in both lower limbs on the second day. Aortic thrombosis was not observed in a computed tomographic scan on the seventh day.
For aortic thrombosis, surgical management is usually adopted, but pharmacological management is also an option because of its immediate curative effects.
PMCID: PMC2919551  PMID: 20663173
12.  Successful treatment for esophageal carcinoma with lung metastasis by induction chemotherapy followed by salvage esophagectomy: Report of a case 
We here report a case of a 51-year-old man with lung metastasis from esophageal carcinoma that was initially treated by combination chemotherapy consisting of fluorouracil and nedaplatin. Because metastatic disease disappeared, salvage esophagectomy was performed. Although chest wall recurrence developed at the thoracotomy wound, prolonged survival of 48 months was achieved by local tumor resection and additional chemotherapy. This combination chemotherapy is regarded as a promising and considerable treatment for metastatic esophageal carcinoma.
PMCID: PMC4087733  PMID: 16810771
Esophageal carcinoma; Lung metastasis; Induction chemotherapy; Fluorouracil; Nedaplatin; Salvage esophagectomy
13.  Characterisation of T cell clonotypes that accumulated in multiple joints of patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  1999;58(9):546-553.
OBJECTIVE—To investigate whether identical T cell clonotypes accumulate in multiple rheumatoid joints, the clonality of T cells that had infiltrated into synovial tissue (ST) samples simultaneously obtained from multiple joints of patients with rheumatoid arthritis (RA) was analysed.
METHODS—T cell receptor (TCR) β gene transcripts, amplified by reverse transcription-polymerase chain reaction from ST and peripheral blood lymphocytes of five RA patients, were subjected to single strand conformation polymorphism analysis and DNA sequencing.
RESULTS—Approximately 40% of accumulated T cell clonotypes found in one joint of a patient were found in multiple joints in the same patient. Furthermore, identical amino acid sequences were found in TCR β junctional regions of these clonotypes from different patients with at least one HLA molecule match.
CONCLUSIONS—The T cell clonotypes accumulating in multiple rheumatoid joints may be involved in the perpetuation of polyarthritis by reacting to antigens common to these multiple joints.

PMCID: PMC1752942  PMID: 10460187
14.  Evaluation of Local Intra-Arterial Fibrinolytic Therapy for Acute Middle Cerebral Artery Occlusion 
Interventional Neuroradiology  2001;6(2):125-133.
Fibrinolytic therapy for acute ischaemic stroke has been investigated in several clinical trials, with various protocols. This retrospective study was undertaken to evaluate the efficacy and limitation of local intra-arterial fibrinolytic therapy using urokinase (UK) in patients with acute middle cerebral artery occlusion.
Fifty patients were treated with local intra-arterial fibrinolytic therapy within six hours after onset of symptoms. The median National Institutes of Health Stroke Scale (NIHSS) score was 17 (range, 6 to 28). Two hundred and forty thousand IU of UK was administered through a microcatheter for 20 minutes. When arterial recanalization was not achieved, a second or third infusion was performed. Maximum dosage of UK was 0.96 × 106 IU. Recanalization efficacy was evaluated at the end of fibrinolytic therapy and intracranial haemorrhage was assessed within 24 hours. Clinical outcome was evaluated three months after ictus with modified Rankin scale (RS).
Thirty-nine patients (78%) obtained recanalization. Twenty-nine of 39 (74%) showed clinical improvement just after treatment. On the other hand, only 18% patients (2/11) who did not recanalize demonstrated improvement. Twenty-five of 50 (50%) patients recovered to RS score 0 or 1, however; only 28% of patients (5/18) with proximal Ml occlusion obtained good outcome and 39% of them (7/18) died. The mean time interval from onset to treatment did not affect outcome. The overall incidence of haemorrhagic event (HE) within 24 hours was 36%, however; 78% of patients with proximal Ml occlusion showed HE. Only one patient with HE clinically deteriorated.
In conclusion, local intra-arterial fibrinolytic therapy could be a safe and effective method for acute middle cerebral artery occlusion, however; indication of this therapy for patients with proximal Ml occlusion should be carefully decided.
PMCID: PMC3679587  PMID: 20667190
stroke, fibrinolysis, intraarterial, middle cerebral artery
15.  Complement activating properties of monoreactive and polyreactive IgM rheumatoid factors. 
Annals of the Rheumatic Diseases  1993;52(11):795-800.
OBJECTIVES--To estimate the complement activating properties of monoclonal, monoreactive, and polyreactive IgM rheumatoid factors derived from Epstein-Barr virus transformed B cells isolated from peripheral blood and synovial tissue of patients with rheumatoid arthritis (RA). METHODS--An enzyme linked immunosorbent assay (ELISA) was used to measure the activation of the classical pathway of complement by monoclonal IgM rheumatoid factor. Monoclonal IgM rheumatoid factor was bound to IgG Fc adsorbed onto microtitre plates and then reacted with diluted normal human serum as a source of complement. The activation and binding of C4 were measured with F(ab')2 antibody to human C4. The complement activating property of IgM rheumatoid factor bound to IgG Fc was tentatively expressed as the ratio of the amount of bound C4 to the amount of bound IgM rheumatoid factor. RESULTS--The complement activating property of monoreactive IgM rheumatoid factor was shown to be about three times higher than that of polyreactive IgM rheumatoid factor. CONCLUSIONS--Monoreactive IgM rheumatoid factor with the higher complement activating property would result in a greater degree of complement dependent inflammation and might have a more important pathogenic role in RA than polyreactive IgM rheumatoid factor.
PMCID: PMC1005191  PMID: 8250611
16.  Effects and virulences of recombinant vaccinia viruses derived from attenuated strains that express the human T-cell leukemia virus type I envelope gene. 
Journal of Virology  1988;62(12):4474-4480.
We constructed recombinant vaccinia viruses (RVVs) that expressed human T-cell leukemia virus type I (HTLV-I) envelope glycoproteins by using attenuated vaccinia viruses (VVs) which have much lower neurovirulence than the WR strain that is extensively used as a vector. The RVV produced from the LC16mO strain, one of the attenuated VVs, elicited a high titer of anti-HTLV-I antibody in rabbits and protected them against HTLV-I infection. The env gene was inserted into the VV hemagglutinin gene. The resultant inactivation of the hemagglutinin gene led to the attenuation of VVs, but the extent of their attenuation depended on the VV strain. The propagation of LC16mO and its RVV in rabbit brain was poorer than that of LO-1, a cloned derivative of Lister strain, and its RVV, although LC16mO replicated in other organs better than did LO-1. Taken together, these results suggest that LC16mO is a good candidate as a vector for vaccination of humans.
PMCID: PMC253556  PMID: 3184271
17.  Live imaging of calcium spikes during double fertilization in Arabidopsis 
Nature Communications  2014;5:4722.
Ca2+ waves and oscillation are key signalling elements during the fertilization process of animals, and are involved, for example, in egg activation. In the unique double fertilization process in flowering plants, both the egg cell and the neighbouring central cell fuse with a sperm cell each. Here we succeeded in imaging cytosolic Ca2+ in these two cells, and in the two synergid cells that accompany the gametes during semi-in vivo double fertilization. Following pollen tube discharge and plasmogamy, the egg and central cells displayed transient Ca2+ spikes, but not oscillations. Only the events in the egg cell correlated with the plasmogamy. In contrast, the synergid cells displayed Ca2+ oscillations on pollen tube arrival. The two synergid cells showed distinct Ca2+ dynamics depending on their respective roles in tube reception. These Ca2+ dynamics in the female gametophyte seem to represent highly specific signatures that coordinate successful double fertilization in the flowering plants.
Intracellular calcium waves are key signalling elements during the fertilization process of animals, involved in egg activation. Here the authors image calcium oscillations during the fertilization process in flowering plants, revealing specific signatures involved in the success of this process.
PMCID: PMC4143913  PMID: 25146889

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