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1.  CD4+ T cells in aged or thymectomized recipients of allogeneic stem cell transplantations 
Biological Research  2015;48(1):41.
Background
CD4+CD25highFOXP3+ regulatory T (Treg) cells, which include thymus-derived and peripherally induced cells, play a central role in immune regulation, and are therefore crucial to prevent graft-versus-host disease (GVHD). The increasing use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for elderly patients with thymus regression, and our case of allo-HSCT shortly after total thymectomy, raised questions about the activity of thymus-derived Treg cells and peripherally induced Treg cells, which are otherwise indistinguishable.
Results
We found that despite pre-transplant thymectomy or older age, both naïve and effector Treg cells, as well as naïve and effector conventional T cells, proliferated in allo-HSCT recipients. Higher proportions of total Treg cells 1 month post allo-HSCT, and naïve Treg cells 1 year post allo-HSCT, appeared in patients achieving complete chimera without developing significant chronic GVHD, including our thymectomized patient, compared with patients who developed chronic GVHD.
Conclusions
Treg cells that modulate human allogeneic immunity may arise peripherally as well as in the thymus of allo-HSCT recipients.
doi:10.1186/s40659-015-0033-8
PMCID: PMC4514962  PMID: 26210500
Regulatory T cells; Allogeneic hematopoietic stem cell transplantation; Thymus; Graft-versus-host disease
2.  Characterization of Mucoid and Non-Mucoid Streptococcus pneumoniae Isolated From Outpatients 
Annals of Laboratory Medicine  2015;35(4):410-415.
Background
Streptococcus pneumoniae causes pneumonia, sepsis, and meningitis. This study aimed to investigate the clinical characteristics of mucoid and non-mucoid isolates of S. pneumoniae, and to explore the relationship between the isolate phenotypes and their antibiotic susceptibility.
Methods
Clinical isolates from 3,453 non-repetitive S. pneumoniae (189 mucoid and 3,264 non-mucoid) infections obtained between January 2008 and December 2012 from outpatients at the Kimitsu-Central Hospital were evaluated.
Results
Compared to the non-mucoid isolates, the mucoid phenotypes were more susceptible to certain antibiotics such as erythromycin, clarithromycin, and tetracycline as opposed to clindamycin, chloramphenicol, and rifampicin. The mucoid phenotype was isolated more frequently from schoolchildren, adults, and elderly adults in a variety of clinical sites, including otorrhea, genitalia, pus, and eye discharge than the non-mucoid phenotype. This suggested that mucoid isolates are more likely to be involved than non-mucoid isolates in various local infections. Systemic infection, which indicates invasiveness, was not associated with the mucoid or non-mucoid phenotype.
Conclusions
The results of this study suggest that mucoid isolates tend to have higher susceptibility than non-mucoid isolates to antibiotics. To the best of our knowledge, mucoid and non-mucoid S. pneumoniae isolates considerably differ in terms of clinical isolation site and age-specific prevalence.
doi:10.3343/alm.2015.35.4.410
PMCID: PMC4446579  PMID: 26131412
Streptococcus pneumoniae; Mucoid colony; Antimicrobial susceptibility
3.  Low Level Laser Therapy for chronic knee joint pain patients 
Laser Therapy  2014;23(4):273-277.
Background and Aims: Chronic knee joint pain is one of the most frequent complaints which is seen in the outpatient clinic in our medical institute. In previous studies we have reported the benefits of low level laser therapy (LLLT) for chronic pain in the shoulder joints, elbow, hand, finger and the lower back. The present study is a report on the effects of LLLT for chronic knee joint pain.
Materials and Methods: Over the past 5 years, 35 subjects visited the outpatient clinic with complaints of chronic knee joint pain caused by the knee osteoarthritis-induced degenerative meniscal tear. They received low level laser therapy. A 1000 mW semi-conductor laser device was used to deliver 20.1 J/cm2 per point in continuous wave at 830nm, and four points were irradiated per session (1 treatment) twice a week for 4 weeks.
Results: A visual analogue scale (VAS) was used to determine the effects of LLLT for the chronic pain and after the end of the treatment regimen a significant improvement was observed (p<0.001). After treatment, no significant differences were observed in the knee joint range of motion. Discussions with the patients revealed that it was important for them to learn how to avoid postures that would cause them knee pain in everyday life in order to have continuous benefits from the treatment.
Conclusion: The present study demonstrated that 830 nm LLLT was an effective form of treatment for chronic knee pain caused by knee osteoarthritis. Patients were advised to undertake training involving gentle flexion and extension of the knee.
doi:10.5978/islsm.14-OR-21
PMCID: PMC4331569  PMID: 25705083
Low Level Laser Therapy; knee osteoarthritis; chronic knee joint pain, meniscal tear; posture education; activities of daily living
4.  Prolapse into the bile duct and expansive growth is characteristic behavior of mucinous cystic neoplasm of the liver: report of two cases and review of the literature 
Mucinous cystic neoplasm of the liver (MCN-L) is a very rare tumor whose detailed behavior is still unknown. We describe two cases of MCN-L that exhibited extremely interesting growth patterns, and discuss the characteristics of MCN-Ls. Both cases exhibited MCN-L that originated from the left hepatic lobe (Segment 4) and then prolapsed into the left hepatic duct and common bile duct, resulting in obstructive jaundice due to expansive growth. Endoscopic retrograde cholangiopancreatographies showed the characteristic oval-shaped filling defects in the bile ducts. Endoscopic ultrasound and intraductal ultrasound were useful for differentiating the tumors from stones, since multiple septal formations were observed inside the tumors. A literature search revealed that, over the past 10 years, 15 cases of MCN-L (biliary cystadenomas with ovarian-like stroma) that showed expansive growth in the bile duct had been reported. Prolapse into the bile duct and expansive growth appear to be characteristic behavior of MCN-L. In the future, additional data on more cases needs to be collected to further elucidate MCN-L pathophysiology.
doi:10.1007/s12328-015-0569-8
PMCID: PMC4481294  PMID: 25951998
Mucinous cystic neoplasm of the liver; Biliary cystadenoma; Ovarian-like stroma; ERCP
6.  Liver abscessation and multiple septic pulmonary emboli associated with Lemierre’s syndrome: a case report 
BMC Research Notes  2015;8:65.
Background
In Lemierre’s syndrome, patients first exhibit pharyngitis and peritonsillar abscessation, followed by the development of anaerobic bacterial (usually Fusobacterium necrophorum) septicemia and metastatic infections throughout the body. However, these infections rarely affect the liver. We describe a case of Lemierre’s syndrome, in which the first disease manifestation was liver abscess, for drawing attention of emergency physicians to this rare but fatal disease.
Case presentation
A 28-year-old Asian ethnicity Filipino male, who was previously healthy, entered the emergency department presenting with fever and pharyngeal pain that had persisted for 5 days. Contrast-enhanced abdominal computed tomography revealed a 3-cm area of low density in segment 6 of the liver, consistent with an abscess. Chest computed tomography also revealed that multiple nodes in both lungs were enlarged, and septic emboli were suspected. The patient was hospitalized and antibiotic treatment was initiated. On hospital day 6, blood culture results confirmed Fusobacterium necrophorum septicemia. The patient was diagnosed with Lemierre’s syndrome, as pharyngitis developed into bacteremia associated with hepatic and pulmonary lesions. The patient’s condition improved with antibiotics and he was discharged following three weeks of treatment in the hospital.
Conclusion
With the widespread use of antibiotics, Lemierre’s syndrome is rarely encountered anymore, but it can be fatal if not properly diagnosed. It is a crucial differential diagnosis in young patients exhibiting septicemia or multiple metastatic infection of unknown origin.
doi:10.1186/s13104-015-1028-9
PMCID: PMC4351970  PMID: 25889618
Lemierre’s syndrome; Liver abscess; Fusobacterium necrophorum; Septic pulmonary emboli
7.  Cone Dystrophy in Patient with Homozygous RP1L1 Mutation 
BioMed Research International  2015;2015:545243.
The purpose of this study was to determine whether an autosomal recessive cone dystrophy was caused by a homozygous RP1L1 mutation. A family including one subject affected with cone dystrophy and four unaffected members without evidence of consanguinity underwent detailed ophthalmic evaluations. The ellipsoid and interdigitation zones on the spectral-domain optical coherence tomography images were disorganized in the proband. The proband had a reduced amplitude of cone and flicker full-field electroretinograms (ERGs). Focal macular ERGs and multifocal ERGs were severely reduced in the proband. A homozygous RP1L1 mutation (c.3628T>C, p.S1210P) was identified in the proband. Family members who were heterozygous for the p.S1210P mutation had normal visual acuity and normal results of clinical evaluations. To investigate other putative pathogenic variant(s), a next-generation sequencing (NGS) approach was applied to the proband. NGS identified missense changes in the heterozygous state of the PCDH15, RPGRIP1, and GPR98 genes. None of these variants cosegregated with the phenotype and were predicted to be benign reinforcing the putative pathogenicity of the RP1L1 homozygous mutation. The AO images showed a severe reduction of the cone density in the proband. Our findings indicate that a homozygous p.S1210P exchange in the RP1L1 gene can cause cone dystrophy.
doi:10.1155/2015/545243
PMCID: PMC4322316  PMID: 25692141
8.  New zoonotic cases of Onchocerca dewittei japonica (Nematoda: Onchocercidae) in Honshu, Japan 
Parasites & Vectors  2015;8:59.
Background
Zoonotic infections with Onchocerca species are uncommon, and to date only 25 clinical cases have been reported worldwide. In Japan, five previous zoonotic infections were concentrated in Oita, Kyushu (the southern island), with one previous case in Hiroshima in the western part of Honshu (the main island). The causative agent in Japan was identified as Onchocerca dewittei japonica Uni, Bain & Takaoka, 2001 from Japanese wild boars (Sus scrofa leucomystax Temminck, 1842). Here we report two infections caused by a female and male O. dewittei japonica, respectively, among residents of Hiroshima and Shimane Prefectures in the western part of Honshu.
Methods
In both cases, nodules were surgically removed. The parasites in nodules were identified on the basis of their histopathological characteristics. Identification was confirmed by sequencing the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene from worms in the tissues used in the histological preparations.
Results
Case 1 was a 61-year-old woman from Hiroshima Prefecture who complained of a painful subcutaneous nodule on the back of her right hand. The causative agent was identified as a female O. dewittei japonica owing to transverse ridges on the cuticle and molecular analysis. Case 2 was a 78-year-old woman from Shimane Prefecture who had a painful nodule in the left temporal region. Histopathological characteristics and cox1 sequencing of the worm indicated that the causative agent was a male O. dewittei japonica.
Conclusions
For Cases 1 and 2, we diagnosed the causative agents as a female and male O. dewittei japonica, respectively. These findings indicate the spread of a zoonosis caused by O. dewittei japonica in the western part of Honshu, where wild boars have recently extended their habitats because of decreased annual snowfall, unused rice fields and a decline in the number of hunters in Japan. The O. dewittei japonica infection rate among wild boars was reported as 78% in Shimane Prefecture, in the western part of Honshu. Therefore, in the near future, zoonotic onchocercosis is likely to occur in Honshu as well as Kyushu, where wild boars, blackfly vectors and humans share the same habitat.
doi:10.1186/s13071-015-0655-2
PMCID: PMC4323255  PMID: 25623081
Filarioid; Global warming; Japanese wild boar; Onchocerca dewittei japonica; Vector-borne disease; Zoonosis
9.  High-Resolution Imaging of Patients with Bietti Crystalline Dystrophy with CYP4V2 Mutation 
Journal of Ophthalmology  2014;2014:283603.
The purpose of this study was to determine the retinal morphology of eyes with Bietti crystalline dystrophy (BCD) associated with a CYP4V2 mutation using high-resolution imaging techniques. Three subjects with BCD underwent detailed ophthalmic examinations. High-resolution fundus images were obtained with an adaptive optics (AO) fundus camera. A common homozygous mutation was detected in the three patients. Funduscopic examination of the three patients revealed the presence of crystalline deposits in the retina, and all of the crystalline deposits were also detected in the infrared (IR) images. The crystals observed in the IR images were seen as bright reflective plaques located on the RPE layer in the SD-OCT images. The clusters of hyperreflective signals in the AO images corresponded to the crystals in the IR images. High-magnification AO images revealed that the clusters of hyperreflective signals consisted of circular spots that are similar to the signals of cone photoreceptors. Most of these circular spots were detected in healthy areas in the FAF images. There is a possibility that circular spots observed by AO are residual cone photoreceptors located over the crystals.
doi:10.1155/2014/283603
PMCID: PMC4167809  PMID: 25276414
10.  Increase of nerve growth factor levels in the human herniated intervertebral disc: can annular rupture trigger discogenic back pain? 
Arthritis Research & Therapy  2014;16(4):R159.
Introduction
Nerve growth factor (NGF) has an important role in the generation of discogenic pain. We hypothesized that annular rupture is a trigger for discogenic pain through the action of NGF. In this study, the protein levels of NGF in discs from patients with disc herniation were examined and compared with those from discs of patients with other lumbar degenerative disc diseases.
Methods
Patients (n = 55) with lumbar degenerative disc disease treated by surgery were included. Nucleus pulposus tissue (or herniated disc tissue) was surgically removed and homogenized; protein levels were quantified using an enzyme-linked immunosorbent assay (ELISA) for NGF. Levels of NGF in the discs were compared between 1) patients with herniated discs (herniated group) and those with other lumbar degenerative disc diseases (non-herniated group), and 2) low-grade and high-grade degenerated discs. Patient’s symptoms were assessed using a visual analog scale (VAS) and the Oswestry disability index (ODI); the influence of NGF levels on pre- and post-operative symptoms was examined.
Results
Mean levels of NGF in discs of patients were significantly higher in herniated discs (83.4 pg/mg total protein) than those in non-herniated discs (68.4 pg/mg).
No significant differences in levels of NGF were found between low-grade and high-grade degenerated discs. Multivariate analysis, adjusted for age and sex, also showed significant correlation between the presence of disc herniation and NGF levels, though no significant correlation was found between disc degeneration and NGF levels. In both herniated and non-herniated groups, pre-operative symptoms were not related to NGF levels. In the herniated group, post-operative lower extremity pain and low back pain (LBP) in motion were greater in patients with low levels of NGF; no significant differences were found in the non-herniated group.
Conclusions
This study reports that NGF increased in herniated discs, and may play an important role in the generation of discogenic pain. Analysis of patient symptoms revealed that pre-operative NGF levels were related to post-operative residual lower extremity pain and LBP in motion. The results suggest that NGF in the disc is related to pain generation, however, the impact of NGF on generation of LBP varies in individual patients.
Electronic supplementary material
The online version of this article (doi:10.1186/ar4674) contains supplementary material, which is available to authorized users.
doi:10.1186/ar4674
PMCID: PMC4261264  PMID: 25069717
11.  Evaluation of an Automated Rapid Diagnostic Assay for Detection of Gram-Negative Bacteria and Their Drug-Resistance Genes in Positive Blood Cultures 
PLoS ONE  2014;9(4):e94064.
We evaluated the performance of the Verigene Gram-Negative Blood Culture Nucleic Acid Test (BC-GN; Nanosphere, Northbrook, IL, USA), an automated multiplex assay for rapid identification of positive blood cultures caused by 9 Gram-negative bacteria (GNB) and for detection of 9 genes associated with β-lactam resistance. The BC-GN assay can be performed directly from positive blood cultures with 5 minutes of hands-on and 2 hours of run time per sample. A total of 397 GNB positive blood cultures were analyzed using the BC-GN assay. Of the 397 samples, 295 were simulated samples prepared by inoculating GNB into blood culture bottles, and the remaining were clinical samples from 102 patients with positive blood cultures. Aliquots of the positive blood cultures were tested by the BC-GN assay. The results of bacterial identification between the BC-GN assay and standard laboratory methods were as follows: Acinetobacter spp. (39 isolates for the BC-GN assay/39 for the standard methods), Citrobacter spp. (7/7), Escherichia coli (87/87), Klebsiella oxytoca (13/13), and Proteus spp. (11/11); Enterobacter spp. (29/30); Klebsiella pneumoniae (62/72); Pseudomonas aeruginosa (124/125); and Serratia marcescens (18/21); respectively. From the 102 clinical samples, 104 bacterial species were identified with the BC-GN assay, whereas 110 were identified with the standard methods. The BC-GN assay also detected all β-lactam resistance genes tested (233 genes), including 54 blaCTX-M, 119 blaIMP, 8 blaKPC, 16 blaNDM, 24 blaOXA-23, 1 blaOXA-24/40, 1 blaOXA-48, 4 blaOXA-58, and 6 blaVIM. The data shows that the BC-GN assay provides rapid detection of GNB and β-lactam resistance genes in positive blood cultures and has the potential to contributing to optimal patient management by earlier detection of major antimicrobial resistance genes.
doi:10.1371/journal.pone.0094064
PMCID: PMC3976387  PMID: 24705449
12.  Intravenous administration of granulocyte colony-stimulating factor for treating neuropathic pain associated with compression myelopathy: a phase I and IIa clinical trial 
European Spine Journal  2012;22(1):197-204.
Objective
To confirm the feasibility and safety of granulocyte colony-stimulating factor (G-CSF) for treating spinal neuropathic pain associated with compression myelopathy, we have initiated an open-label single-center prospective clinical trial.
Methods
Between January 2009 and February 2011, 17 patients were accrued and were divided into two groups. One group included 7 patients who complained of pain associated with worsening symptoms of myelopathy (progressing myelopathy-related pain group). The other group included 10 patients who complained of pain that persisted after surgery for compression myelopathy (post-operative persistent pain group). All patients underwent intravenous administration of G-CSF (10 μg/kg/day) for 5 consecutive days. Pain severity was evaluated using a visual analog scale (VAS) before and after G-CSF administration.
Results
In 14 of the 17 patients, pain was relieved within several days after G-CSF administration. Pain disappeared completely in 3 patients. In the progressing myelopathy-related pain group, the mean VAS score was 71.4/100 before G-CSF administration, and decreased to 35.9/100 at 1 week after G-CSF administration (p < 0.05). In the post-operative persistent pain group, the mean VAS score was 72.0/100 before G-CSF administration, and decreased to 51.7/100 at 1 week after G-CSF administration (p < 0.05). No severe adverse events occurred during or after G-CSF administration.
Conclusions
The present results provide us with the possibility that G-CSF has a pain-relieving effect for neuropathic pain in patients with compression myelopathy.
doi:10.1007/s00586-012-2556-9
PMCID: PMC3540322  PMID: 23139012
Neuroprotective therapy; Granulocyte colony-stimulating factor; Myelopathy; Neuropathic pain; Clinical trial
13.  Adeno-associated virus type 8 vector–mediated expression of siRNA targeting vascular endothelial growth factor efficiently inhibits neovascularization in a murine choroidal neovascularization model 
Molecular Vision  2014;20:488-496.
Purpose
To assess the feasibility of a gene therapeutic approach to treating choroidal neovascularization (CNV), we generated an adeno-associated virus type 8 vector (AAV2/8) encoding an siRNA targeting vascular endothelial growth factor (VEGF), and determined the AAV2/8 vector’s ability to inhibit angiogenesis.
Methods
We initially transfected 3T3 cells expressing VEGF with the AAV2/8 plasmid vector psiRNA-VEGF using the H1 promoter and found that VEGF expression was significantly diminished in the transfectants. We next injected 1 μl (3 × 1014 vg/ml) of AAV2/8 vector encoding siRNA targeting VEGF (AAV2/8/SmVEGF-2; n = 12) or control vector encoding green fluorescent protein (GFP) (AAV2/8/GFP; n = 14) into the subretinal space in C57BL/6 mice. One week later, CNV was induced by using a diode laser to make four separate choroidal burns around the optic nerve in each eye. After an additional 2 weeks, the eyes were removed for flat mount analysis of the CNV surface area.
Results
Subretinal delivery of AAV2/8/SmVEGF-2 significantly diminished CNV at the laser lesions, compared to AAV8/GFP (1597.3±2077.2 versus 5039.5±4055.9 µm2; p<0.05). Using an enzyme-linked immunosorbent assay, we found that VEGF levels were reduced by approximately half in the AAV2/8/SmVEGF-2 treated eyes.
Conclusions
These results suggest that siRNA-VEGF can be expressed across the retina and that long-term suppression of CNV is possible through the use of stable AAV2/8-mediated siRNA-VEGF expression. In vivo gene therapy may thus be a feasible approach to the clinical management of CNV in conditions such as age-related macular degeneration.
PMCID: PMC3984039  PMID: 24744609
14.  Small Intestinal Obstruction Caused by Anisakiasis 
Small intestinal anisakiasis is a rare disease that is very difficult to diagnose, and its initial diagnosis is often surgical. However, it is typically a benign disease that resolves with conservative treatment, and unnecessary surgery can be avoided if it is appropriately diagnosed. This case report is an example of small intestinal obstruction caused by anisakiasis that resolved with conservative treatment. A 63-year-old man admitted to our department with acute abdominal pain. A history of raw fish (sushi) ingestion was recorded. Abdominal CT demonstrated small intestinal dilatation with wall thickening and contrast enhancement. Ascitic fluid was found on the liver surface and in the Douglas pouch. His IgE (RIST) was elevated, and he tested positive for the anti-Anisakis antibodies IgG and IgA. Small intestinal obstruction by anisakiasis was highly suspected and conservative treatment was performed, ileus tube, fasting, and fluid replacement. Symptoms quickly resolved, and he was discharged on the seventh day of admission. Small intestinal anisakiasis is a relatively uncommon disease, the diagnosis of which may be difficult. Because it is a self-limiting disease that usually resolves in 1-2 weeks, a conservative approach is advisable to avoid unnecessary surgery.
doi:10.1155/2013/401937
PMCID: PMC3888701  PMID: 24455340
15.  Neuroprotective therapy using granulocyte colony-stimulating factor for acute spinal cord injury: a phase I/IIa clinical trial 
European Spine Journal  2012;21(12):2580-2587.
Objective
Granulocyte colony-stimulating factor (G-CSF) is a cytokine that is clinically used to treat neutropenia. G-CSF also has non-hematopoietic functions and could potentially be used to treat neuronal injury. To confirm the safety and feasibility of G-CSF administration for acute spinal cord injury (SCI), we have initiated a phase I/IIa clinical trial of neuroprotective therapy using G-CSF.
Methods
The trial included a total of 16 SCI patients within 48 h of onset. In the first step, G-CSF (5 μg/kg/day) was intravenously administered for 5 consecutive days to 5 patients. In the second step, G-CSF (10 μg/kg/day) was similarly administered to 11 patients. We evaluated motor and sensory functions of patients using the American Spinal Cord Injury Association (ASIA) score and ASIA impairment scale (AIS) grade.
Results
In all 16 patients, neurological improvement was obtained after G-CSF administration. AIS grade increased by one step in 9 of 16 patients. A significant increase in ASIA motor scores was detected 1 day after injection (P < 0.01), and both light touch and pin prick scores improved 2 days after injection (P < 0.05) in the 10 μg group. No severe adverse effects were observed after G-CSF injection.
Conclusion
These results indicate that intravenous administration of G-CSF (10 μg/kg/day) for 5 days is essentially safe, and suggest that some neurological recovery may occur in most patients. We suggest that G-CSF administration could be therapeutic for patients with acute SCI.
doi:10.1007/s00586-012-2213-3
PMCID: PMC3508205  PMID: 22391867
Spinal cord injury; Neuroprotective therapy; G-CSF; Clinical trial
16.  Long-term Pulmonary Responses to Quadweekly Intermittent Intratracheal Spray Instillations of Magnetite (Fe3O4) Nanoparticles for 52 Weeks in Fischer 344 Rats 
Journal of Toxicologic Pathology  2013;26(4):393-403.
Information about potential risks of iron nanomaterials is still limited, while a wide variety of applications are expected. We recently reported acute phase responses of male and female Fischer 344 rats after a single intratracheal spray instillation of Fe3O4 nanoparticles (magnetite), clearly showing dose-dependent pulmonary inflammatory changes (Tada et al., J Toxicol Pathol 25, 233–239, 2012). The present study assessed long-term responses of male and female Fischer 344 rats to multiple administrations of magnetite. Ten-week-old male and female Fischer 344 rats (n=20/group) were exposed to a total of 13 quadweekly intermittent intratracheal spray instillations of magnetite during the experimental period of 52 weeks, at doses of 0, 0.2 (low), 1.0 (medium) and 5.0 (high-dose) mg/kg body weight per administration. Absolute and relative lung weights of the high-dose group were significantly higher than those of the control group. Macroscopically, slight enlargement and scattered black patches were recognized in the lungs and the lung-associated lymph nodes of the high-dose group. Histopathologically, infiltration of macrophages phagocytosing magnetite (all dose groups) and of chronic inflammatory cells (medium- and high-dose males and high-dose females), alveolar bronchiolization and granuloma (high-dose group) were observed. In addition, alveolar hyperplasias were observed in some rats of the high-dose group, and cytoplasmic overexpression of β-catenin protein was immunohistochemically found in such lesions. The present results clearly show that instilled magnetite causes chronic inflammatory responses in the lung. These responses occur in a dose-dependent manner without apparent differences among sexes
doi:10.1293/tox.2013-0036
PMCID: PMC3921922  PMID: 24526812
magnetite; Fe3O4; nanoparticles; lung; intratracheal spray instillation; Fischer 344 rat
17.  High-Resolution En Face Images of Microcystic Macular Edema in Patients with Autosomal Dominant Optic Atrophy 
BioMed Research International  2013;2013:676803.
The purpose of this study was to investigate the characteristics of microcystic macular edema (MME) determined from the en face images obtained by an adaptive optics (AO) fundus camera in patients with autosomal dominant optic atrophy (ADOA) and to try to determine the mechanisms underlying the degeneration of the inner retinal cells and RNFL by using the advantage of AO. Six patients from 4 families with ADOA underwent detailed ophthalmic examinations including spectral domain optical coherence tomography (SD-OCT). Mutational screening of all coding and flanking intron sequences of the OPA1 gene was performed by DNA sequencing. SD-OCT showed a severe reduction in the retinal nerve fiber layer (RNFL) thickness in all patients. A new splicing defect and two new frameshift mutations with premature termination of the Opa1 protein were identified in three families. A reported nonsense mutation was identified in one family. SD-OCT of one patient showed MME in the inner nuclear layer (INL) of the retina. AO images showed microcysts in the en face images of the INL. Our data indicate that AO is a useful method to identify MME in neurodegenerative diseases and may also help determine the mechanisms underlying the degeneration of the inner retinal cells and RNFL.
doi:10.1155/2013/676803
PMCID: PMC3863472  PMID: 24369534
18.  A combination of anatomical and functional evaluations improves the prediction of cardiac event in patients with coronary artery bypass 
BMJ Open  2013;3(11):e003474.
Objective
To study the usefulness of combined risk stratification of coronary CT angiography (CTA) and myocardial perfusion imaging (MPI) in patients with previous coronary-artery-bypass grafting (CABG).
Design
A retrospective, observational, single centre study.
Setting and patients
204 patients (84.3% men, mean age 68.7±7.6) undergoing CTA and MPI.
Main outcome measures
CTA defined unprotected coronary territories (UCT; 0, 1, 2 or 3) by evaluating the number of significant stenoses which were defined as the left main trunk ≥50% diameter stenosis, other native vessel stenosis ≥70% or graft stenosis ≥70%. Using a cut-off value with receiver-operating characteristics analysis, all patients were divided into four groups: group A (UCT=0, summed stress score (SSS)<4), group B (UCT≥1, SSS<4), group C (UCT=0, SSS≥4) and group D (UCT≥1, SSS≥4).
Results
Cardiac events, as a composite end point including cardiac death, non-fatal myocardial infarction, unstable angina requiring revascularisation and heart-failure hospitalisation, were observed in 27 patients for a median follow-up of 27.5 months. The annual event rates were 1.1%, 2%, 5.7% and 12.9% of patients in groups A, B, C and D, respectively (log rank p value <0.0001). Adding UCT or SSS to a model with significant clinical factors including left ventricular ejection fraction, time since CABG and Euro SCORE II improved the prediction of events, while adding UCT and SSS to the model improved it greatly with increasing C-index, net reclassification improvement and integrated discrimination improvement.
Conclusions
The combination of anatomical and functional evaluations non-invasively enhances the predictive accuracy of cardiac events in patients with CABG.
doi:10.1136/bmjopen-2013-003474
PMCID: PMC3831107  PMID: 24220113
19.  Spontaneous Symptomatic Pseudoarthrosis at the L2-L3 Intervertebral Space with Diffuse Idiopathic Skeletal Hyperostosis: A Case Report 
Case Reports in Orthopedics  2013;2013:497458.
Pseudoarthrosis at the intervertebral space in patients with ankylosing spondylitis has occasionally been reported, but symptomatic pseudoarthrosis at the intervertebral disc level is rare in patients with diffuse idiopathic skeletal hyperostosis (DISH). Here, we report a case of symptomatic pseudoarthrosis at the L2-L3 intervertebral space that was diagnosed based on clinical history. We first performed L1–L5 fixation, but back-out of the pedicle screw occurred in the early postoperative phase and may have been caused by a short fixation range and concomitant Parkinson's disease. However, the prognosis of the case was favorable after a second surgery. This case indicates that a fixation range of at least 3 above and 3 below is necessary for bone fracture of a thoracolumbar vertebra and pseudoarthrosis in patients with DISH.
doi:10.1155/2013/497458
PMCID: PMC3835208  PMID: 24294532
20.  Treatment of Renal Cell Carcinoma with 2-Stage Total en bloc Spondylectomy after Marked Response to Molecular Target Drugs 
Case Reports in Orthopedics  2013;2013:916501.
Metastatic renal cell carcinoma of the bone occurs at a high rate, and the prognosis is poor. In general, total en bloc spondylectomy is considered when there is only one vertebral metastasis and the primary disease is treated. However, palliative surgery is selected when the primary disease is not being treated or metastasis occurs to an important organ. We encountered a patient in whom lung and vertebra metastases were already present at the time of the first examination at our department and the prognosis was considered poor. However, molecular targeted therapy was markedly effective and enabled 2-stage total en bloc spondylectomy. As of one year after total en bloc spondylectomy, the condition has improved to cane gait, and surgery for lung metastasis is planned. Molecular target drugs might markedly change the current therapeutic strategy for renal cell carcinoma.
doi:10.1155/2013/916501
PMCID: PMC3730215  PMID: 23956901
21.  Prediction of lower limb functional recovery after laminoplasty for cervical myelopathy: focusing on the 10-s step test 
European Spine Journal  2012;21(7):1389-1395.
Objective
Operative decompression is indicated for progressive neurological deterioration in patients with cervical compressive myelopathy (CCM). However, the best timing to ensure clinical recovery has not been determined because of the lack of a suitable method. 10 s step (“step”) test is an easily performed physical test to assess the severity of CCM, particularly for the severity of lower limb dysfunction. The purpose of this study was to analyze the predictive value of preoperative step test results in relation to the results of expansive laminoplasty in patients with CCM.
Materials and methods
Clinical and imaging data were prospectively collected from 101 patients who underwent cervical expansive laminoplasty for CCM. The Japanese Orthopedic Association (JOA) score and the lower limb function section of the Japanese Orthopedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ-L) were used to evaluate surgical outcomes. Cutoff value was determined by receiver operating characteristic curve analysis to predict clinical recovery after surgery. JOA recovery rate exceeding 50% was defined as an effective clinical result. The treatment was judged to be effective in 30 patients based on the JOACMEQ-L. The cutoff value of the step test was 14.5 in cases of an effective judgment with JOA and JOACMEQ-L. Multivariate analysis showed that preoperative patient age and duration of symptoms were predictive parameters for effectively judging JOA scores. A preoperative step test result of greater than or equal to 14.5 and male gender were significant predictive parameters for an effective judgment with JOACMEQ-L.
Conclusions
Preoperative step test results significantly reflected the effective results of JOACMEQ-L and were predictive of improved lower limb function after laminoplasty in patients with CCM. Patients with a score of greater than or equal to 14.5 can experience effective lower limb functional recovery.
doi:10.1007/s00586-012-2241-z
PMCID: PMC3389102  PMID: 22407268
Cervical compressive myelopathy; Step test; Laminoplasty; Physical test; Outcome
22.  A Case of Delayed Myelopathy Caused by Atlantoaxial Subluxation without Fracture 
Case Reports in Orthopedics  2013;2013:421087.
We report a case of delayed myelopathy caused by atlantoaxial subluxation without fracture. The patient was a 38-year-old male who became aware of weakness in extremities. The patient had a history of hitting his head severely while diving into a swimming pool at the age of 14 years old. At that time, cervical spine plain X-ray images showed no fracture, and the cervical pain disappeared after use of a collar for several weeks. At his first visit to our department, X-ray images showed an unstable atlantoaxial joint. After surgery, weakness of the extremities gradually improved. At 6 months after surgery, bone union was completed and the symptoms disappeared. This case shows that atlantoaxial ligament injuries are difficult to diagnose and may easily be missed. A high level of suspicion is important in such cases, since neurological compromise or deterioration may occur many years after the injury.
doi:10.1155/2013/421087
PMCID: PMC3628490  PMID: 23607019
23.  Complete response of 7 years’ duration after chemoradiotherapy followed by gefitinib in a patient with intramedullary spinal cord metastasis from lung adenocarcinoma 
Journal of Thoracic Disease  2013;5(2):E65-E67.
Intramedullary spinal cord metastasis is a rare but serious complication which causes rapid progression of neurological deficits. Here we report a 35-year-old man presenting with increasing leg pain and gait disturbance, 8 months after surgery for lung adenocarcinoma. Spinal magnetic resonance imaging revealed an intramedullary tumor at the Th7/8 level. Radiotherapy at 35 Gy resulted in transient symptomatic improvement, but during chemotherapy with vinorelbine and cisplatin, symptoms worsened again. Gefitinib was then administered; the patient improved after 2 weeks and has now maintained a complete response for 7 years.
doi:10.3978/j.issn.2072-1439.2012.12.09
PMCID: PMC3621920  PMID: 23585962
Intramedullary spinal cord metastasis; lung cancer; gefitinib; EGFR; magnetic resonance imaging; positron-emission tomography
24.  Low Level Laser Therapy for Patients with Cervical Disk Hernia 
Laser Therapy  2012;21(3):193-197.
Background and Aims: In previous studies we have reported the benefits of low level laser therapy (LLLT) for chronic shoulder joint pain, elbow, hand and finger pain, and low back pain. The present study is a report on the effects of LLLT for chronic neck pain.
Materials and Methods: Over a 3 year period, 26 rehabilitation department outpatients with chronic neck pain, diagnosed as being caused by cervical disk hernia, underwent treatment applied to the painful area with a 1000 mW semi-conductor laser device delivering at 830 nm in continuous wave, 20.1 J/cm2/point, and three shots were given per session (1 treatment) with twice a week for 4 weeks.
Results:
1. A visual analogue scale (VAS) was used to determine the effects of LLLT for chronic pain and after the end of the treatment regimen a significant improvement was observed (p<0.001).
2. After treatment, no significant differences in cervical spine range of motion were observed.
3. Discussions with the patients revealed that in order to receive continued benefits from treatment, it was important for them to be taught how to avoid postures that would cause them neck pain in everyday life.
Conclusion: The present study demonstrates that LLLT was an effective form of treatment for neck and back pain caused by cervical disk hernia, reinforced by postural training.
doi:10.5978/islsm.12-OR-10
PMCID: PMC3882355  PMID: 24511189
Low Level Laser Therapy; Cervical Disk Hernia; Chronic Pain; Postural training during Activities of Daily Living
25.  Neuroprotective therapy using granulocyte colony-stimulating factor for patients with worsening symptoms of compression myelopathy, part 1: a phase I and IIa clinical trial 
European Spine Journal  2011;21(3):482-489.
Objective
Based on the neuroprotective effects of granulocyte colony-stimulating factor (G-CSF) on experimental spinal cord injury, we initiated a clinical trial that evaluated the safety and efficacy of neuroprotective therapy using G-CSF for patients with worsening symptoms of compression myelopathy.
Methods
We obtained informed consent from 15 patients, in whom the Japanese Orthopaedic Association (JOA) score for cervical myelopathy decreased two points or more during a recent 1-month period. G-CSF (5 or 10 μg/kg/day) was intravenously administered for five consecutive days. We evaluated motor and sensory functions of the patients and the presence of adverse events related to G-CSF therapy.
Results
G-CSF administration suppressed the progression of myelopathy in all 15 patients. Neurological improvements in motor and sensory functions were obtained in all patients after the administration, although the degree of improvement differed among the patients. Nine patients in the 10-μg group (n = 10) underwent surgical treatment at 1 month or later after G-CSF administration. In the 10-μg group, the mean JOA recovery rates 1 and 6 months after administration were 49.9 ± 15.1 and 59.1 ± 16.3%, respectively. On the day following the start of G-CSF therapy, the white blood cell count increased to more than 22,700 cells/mm3. It varied from 12,000 to 50,000 and returned to preadministration levels 3 days after completing G-CSF treatment. No serious adverse events occurred during or after treatment.
Conclusion
The results indicate that G-CSF administration at 10 μg/kg/day is safe for patients with worsening symptoms of compression myelopathy and may be effective for their neurological improvement.
doi:10.1007/s00586-011-2020-2
PMCID: PMC3296845  PMID: 21935680
Neuroprotective therapy; Granulocyte colony-stimulating factor; Compression myelopathy; Clinical trial

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