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1.  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.
PMCID: PMC4322316
2.  New zoonotic cases of Onchocerca dewittei japonica (Nematoda: Onchocercidae) in Honshu, Japan 
Parasites & Vectors  2015;8:59.
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.
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.
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.
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.
PMCID: PMC4323255  PMID: 25623081
Filarioid; Global warming; Japanese wild boar; Onchocerca dewittei japonica; Vector-borne disease; Zoonosis
3.  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.
PMCID: PMC4167809  PMID: 25276414
4.  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.
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.
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.
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.
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.
PMCID: PMC4261264  PMID: 25069717
5.  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.
PMCID: PMC3976387  PMID: 24705449
6.  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.
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.
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.
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.
The present results provide us with the possibility that G-CSF has a pain-relieving effect for neuropathic pain in patients with compression myelopathy.
PMCID: PMC3540322  PMID: 23139012
Neuroprotective therapy; Granulocyte colony-stimulating factor; Myelopathy; Neuropathic pain; Clinical trial
7.  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.
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.
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.
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.
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
8.  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.
PMCID: PMC3888701  PMID: 24455340
9.  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.
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.
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.
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.
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.
PMCID: PMC3508205  PMID: 22391867
Spinal cord injury; Neuroprotective therapy; G-CSF; Clinical trial
10.  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
PMCID: PMC3921922  PMID: 24526812
magnetite; Fe3O4; nanoparticles; lung; intratracheal spray instillation; Fischer 344 rat
11.  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.
PMCID: PMC3863472  PMID: 24369534
12.  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.
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).
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).
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.
The combination of anatomical and functional evaluations non-invasively enhances the predictive accuracy of cardiac events in patients with CABG.
PMCID: PMC3831107  PMID: 24220113
13.  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.
PMCID: PMC3835208  PMID: 24294532
14.  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.
PMCID: PMC3730215  PMID: 23956901
15.  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.
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.
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.
PMCID: PMC3389102  PMID: 22407268
Cervical compressive myelopathy; Step test; Laminoplasty; Physical test; Outcome
16.  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.
PMCID: PMC3628490  PMID: 23607019
17.  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.
PMCID: PMC3621920  PMID: 23585962
Intramedullary spinal cord metastasis; lung cancer; gefitinib; EGFR; magnetic resonance imaging; positron-emission tomography
18.  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.
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.
PMCID: PMC3882355  PMID: 24511189
Low Level Laser Therapy; Cervical Disk Hernia; Chronic Pain; Postural training during Activities of Daily Living
19.  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.
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.
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.
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.
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.
PMCID: PMC3296845  PMID: 21935680
Neuroprotective therapy; Granulocyte colony-stimulating factor; Compression myelopathy; Clinical trial
20.  An ophthalmic solution of a peroxisome proliferator-activated receptor gamma agonist prevents corneal inflammation in a rat alkali burn model 
Molecular Vision  2013;19:2135-2150.
We clarified the effects of an ophthalmic solution of a peroxisome proliferator-activated receptor gamma (PPARγ) agonist on corneal inflammation and wound healing after alkali burn injury in rats.
After alkali exposure, either an ophthalmic solution with 0.1% pioglitazone hydrochloride (the PPARγ group) or vehicle (the vehicle group) was topically applied to the cornea until day 14. Histological, immunohistochemical, and real-time reverse transcription polymerase chain reaction analysis were performed.
After alkali injury, PPARγ expression increased, with the infiltration of many inflammatory cells. The infiltration of neutrophils and macrophages started from the corneal limbus within 6 h, and developed in the corneal center by day 7, with associated neovascularization. The accumulation of α-smooth muscle actin-positive myofibroblasts and the deposition of type III collagen were noted on day 14. The histological changes were suppressed significantly by treatment with the ophthalmic solution of the PPARγ agonist. In addition, the number of infiltrating M2 macrophages in the cornea was increased by PPARγ agonist treatment. In real-time reverse transcription polymerase chain reaction analysis, the messenger ribonucleic acid expression levels of interleukin-1β (IL-1β), IL-6, IL-8, monocyte chemoattractant protein-1, tumor necrosis factor-α, transforming growth factor beta 1, and vascular endothelial growth factor-A were decreased in the PPARγ group compared to the vehicle group in the early periods of corneal inflammation.
The ophthalmic solution of the PPARγ agonist inhibited inflammation, decreased the fibrotic reaction, and prevented neovascularization in the cornea from the early phase after alkali burn injury. The ophthalmic solution of the PPARγ agonist may provide a new treatment strategy with useful clinical applications for corneal inflammation and wound healing.
PMCID: PMC3816991  PMID: 24194635
21.  Acute Phase Pulmonary Responses to a Single Intratracheal Spray Instillation of Magnetite (Fe3O4) Nanoparticles in Fischer 344 Rats 
Journal of Toxicologic Pathology  2012;25(4):233-239.
Iron nanomaterials are of considerable interest for application to nanotechnology-related fields including environmental catalysis, biomedical imaging, drug delivery and hyperthermia, because of their superparamagnetic characteristics and high catalytic abilities. However, information about potential risks of iron nanomaterials is limited. The present study assessed pulmonary responses to a single intratracheal spray instillation of triiron tetraoxide nanoparticles (magnetite) in rats. Ten-week-old male and female Fischer 344 rats (n=5/group) were exposed to a single intratracheal spray instillation of 0 (vehicle), 5.0, 15.0 or 45.0 mg/kg body weight (BW) of magnetite. After 14 days, the rats were sacrificed, and biological consequences were investigated. The lung weights of the 15.0 and 45.0 mg/kg BW male and female groups were significantly higher than those of the control groups. The lungs of treated rats showed enlargement and black patches originating from the color of magnetite. The typical histopathological changes in the lungs of the treated rats included infiltration of macrophages phagocytosing magnetite, inflammatory cell infiltration, granuloma formation and an increase of goblet cells in the bronchial epithelium. The results clearly show that instilled magnetite causes foreign body inflammatory and granulating lesions in the lung. These pulmonary responses occur in a dose-dependent manner in association with the increase in lung weight.
PMCID: PMC3517918  PMID: 23345925
magnetite; Fe3O4; nanoparticles; lung; intratracheal spray instillation; Fischer 344 rat
22.  Evaluation of Nonspecific Low Back Pain Using a New Detailed Visual Analogue Scale for Patients in Motion, Standing, and Sitting: Characterizing Nonspecific Low Back Pain in Elderly Patients 
Pain Research and Treatment  2012;2012:680496.
Because we have a clinical impression that elderly patients have low back pain while in motion and standing, but less pain when sitting, we investigate characteristics of nonspecific low back pain (NSLBP), using a new detailed visual analog scale (VAS) scoring system. One hundred eighty-nine patients with NSLBP were divided into an elderly group (≥65 years old, n = 56) and a young group (<65 years old, n = 133). Low back pain was evaluated by a traditional VAS scoring system, the Oswestry Disability Index (ODI), and a new detailed VAS scoring system in which pain is independently evaluated in three different postural situations (in motion, standing, and sitting). No significant differences were observed in traditional VAS and ODI scores between the two groups. The results of the detailed VAS showed no significant differences between the two groups while in motion and standing. However, the elderly group showed significantly lower VAS score while sitting compared to the young group. In this study of the first use of a new detailed VAS scoring system, differences in characteristics of NSLBP between elderly and young patients were successfully detected. This minor modification of the traditional VAS may be useful for characterizing and evaluating low back pain.
PMCID: PMC3505659  PMID: 23213514
23.  Pneumonia after Earthquake, Japan, 2011 
Emerging Infectious Diseases  2012;18(11):1909-1911.
PMCID: PMC3559172  PMID: 23092559
Tsunami; disaster; earthquake; pneumonia; Haemophilus influenzae; Moraxella catarrhalis; Streptococcus pneumonia; bacteria; Japan
24.  Osteogenesis and osteoclast inhibition in rheumatoid arthritis patients treated with bisphosphonates alone or in combination with pitavastatin over an 18-month follow-up after more than 4 years of treatment with bisphosphonates 
Arthritis Research & Therapy  2012;14(5):R224.
To investigate the effects of bisphosphonates (Bis) (etidronate, alendronate, and risedronate), alone and in combination with statin, on the BMD (bone mineral density) and bone metabolism of rheumatoid arthritis (RA) patients.
Seventy-seven RA patients who had been receiving prednisolone (PSL) and Bis for over 4 years were divided into two groups: Bis and Bis + statin (n = 42 and 35; average age, 66.4 and 65.3 years; average disease duration, 24.9 and 20.8 years; average PSL dose, 2.4 and 2.7 mg, respectively). Serum levels of NTX (N-terminal telopeptide of type I collagen), TRACP-5b (tartrate-resistant acid phosphate-5b), PICP (C-terminal propeptide of type I procollagen), and RANKL (receptor activator of NF-κB ligand) were measured over an 18-month period of treatment and follow-up. The BMD levels of the two groups at the radius, lumbar spine, and femoral neck were compared using DXA (dual-energy x-ray absorptiometry).
A significant increase was only observed in the BMD of the lumbar spine at 18-months, but the BMDs of the radius and femoral neck decreased during the follow-up period in the Bis group. Meanwhile, a significant increase was observed in the BMD of the lumbar spine in the Bis + statin group during administration and the BMDs of the radius and femoral neck stayed at baseline. Among the markers of bone metabolism, serum NTX was up-regulated after 6 months in the Bis + statin group. Serum TRACP-5b was significantly increased during the follow-up period in the Bis + statin group, but only at 18 months in the Bis group. Serum PICP recovered to base line in the Bis + statin group, whereas that in the Bis group did not observably recover during the post-administration follow-up, but rather decreased.
Our findings suggest that both bone resorption and bone formation were inhibited by long-term administration of Bis alone, whereas combination therapy with Bis + statin may be associated with a less marked inhibition of bone metabolism. Cardiovascular disease is highly prevalent in RA patients and some patients are prescribed statins and bisphosphonate. Bis + statin may confer more benefit to the bone metabolism of these patients compared to Bis alone.
PMCID: PMC3580535  PMID: 23079134
25.  A Japanese case of chronic lymphocytic leukemia with t (1;6) 
Chronic lymphocytic leukemia (CLL) rarely exhibits an aggressive clinical course and its patients often have chromosomal deletions or additions. Furthermore, reciprocal translocations are barely observed in CLL. There have only been a few reports of CLL with t(1;6), and here we report the first Asian case of CLL with reciprocal translocation t(1;6). Since our case and previously reported CLL patients with t(1;6) consistently showed aggressive clinical course, t(1;6) may define a distinct type of CLL.
PMCID: PMC3533870  PMID: 23210523
CLL; T(1;6); Aggressive clinical course

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