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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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.
doi:10.1293/tox.25.233
PMCID: PMC3517918  PMID: 23345925
magnetite; Fe3O4; nanoparticles; lung; intratracheal spray instillation; Fischer 344 rat
16.  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.
doi:10.1155/2012/680496
PMCID: PMC3505659  PMID: 23213514
17.  Pneumonia after Earthquake, Japan, 2011 
Emerging Infectious Diseases  2012;18(11):1909-1911.
doi:10.3201/eid1811.111660
PMCID: PMC3559172  PMID: 23092559
Tsunami; disaster; earthquake; pneumonia; Haemophilus influenzae; Moraxella catarrhalis; Streptococcus pneumonia; bacteria; Japan
18.  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.
Introduction
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.
Methods
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).
Results
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.
Conclusion
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.
doi:10.1186/ar4063
PMCID: PMC3580535  PMID: 23079134
19.  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.
doi:10.1186/2162-3619-1-28
PMCID: PMC3533870  PMID: 23210523
CLL; T(1;6); Aggressive clinical course
20.  314 GERD Screening by the Use of F-Scale and Allergy Screening for Diagnosis and Treatment of Chronic Cough 
Background
Allergy and gastro-esophageal reflux (GERD) are main causes of chronic cough, and simple, easy and rapid screening is desired for diagnosis of these symptoms.
We used F-scale (Frequency Scale for Symptoms of GERD: FSSG) for GERD screening, developed by Japanese gastro-enterologist, did general allergy screenings, and investigated clinical outcome after treatment retrospectively.
Methods
GERD was screened by F-scale questionnaire, composed in twelve questions concerned with reflux symptoms, and scored 5 grades in each symptom. General allergy screening was defined as asking history of allergy, serum immnogloblin E (IgE) test (total, fourteen kinds of specific allergens) and measuring fraction of exhaled nitric oxide (FeNO),its positive range was greater than or equal to 20 ppb. Allergy positive was defined as at least one positive finding of allergy screening test. GERD was treated with proton pump inhibitor (PPI), and allergy was treated with inhaled corticosteroid or histamine H1 receptor blocker or leukotriene receptor antagonist.
Results
Fifty-four consecutive chronic cough patients were screened in GERD and general allergy screening. Thirty-seven patients (69%) were F-scale positive and 43 patients (80%) were positive in general allergy screening. Thirty patients (56%) were positive in both F-scale and general allergy screening. All patients were treated with allergy medicine or PPI, or both medicines. In all patients screened and treated with both GERD and allergy concurrently, cough improved within 2 weeks, and in patients whose positive finding was either GERD or allergy, cough improved by treatment with PPI or allergy drugs similarly. Delayed screening or treatment of either GERD or allergy was related to delayed improvement of cough. Cough finally improved in all patients in visit within 3 times.
Conclusions
In examination of chronic cough, adding GERD screening by use of F-scale to general allergy screening is beneficial to proper diagnosis, treatment and rapid improvement of symptom.
doi:10.1097/01.WOX.0000412077.68032.ba
PMCID: PMC3512810
21.  A new mutation in the RP1L1 gene in a patient with occult macular dystrophy associated with a depolarizing pattern of focal macular electroretinograms 
Molecular Vision  2012;18:1031-1039.
Purpose
To determine whether a mutation in the RP1-like protein 1 (RP1L1) gene is present in a Japanese patient with sporadic occult macular dystrophy (OMD) and to examine the characteristics of focal macular electroretinograms (ERGs) of the patient with genetically identified OMD.
Methods
An individual with OMD underwent detailed ophthalmic clinical evaluations including focal macular ERGs. Mutation screening of all coding regions and flanking intron sequences of the RP1L1 gene were performed with DNA sequencing analysis in this case with OMD.
Results
A new RP1L1 mutation (c.3596 C>G in exon 4) was identified. The variant c.3596 C>G in exon 4 resulted in the substitution of cysteine for serine at amino acid position 1199. The serine at position 1199 is well conserved among the RP1L1 family in other species. Four out of five computational assessment tools predicted that this mutation is damaging to the protein function. This mutation was not present in 294 control alleles. The waveform of focal macular ERGs recorded from the patient with OMD had a depolarizing pattern, simulating the ERG waveforms observed after the hyperpolarizing bipolar cell activity is blocked.
Conclusions
We have demonstrated in a Japanese patient the possibility that sporadic OMD may also be caused by an RP1L1 mutation. The waveform of focal macular ERGs elicited from the OMD patient with the RP1L1 mutation showed a depolarizing pattern. This characteristic is the same as reported for the focal macular ERGs of OMD.
PMCID: PMC3351429  PMID: 22605915
22.  C5 palsy following anterior decompression and spinal fusion for cervical degenerative diseases 
European Spine Journal  2010;19(10):1702-1710.
Postoperative C5 palsy is a common complication after cervical spine decompression surgery. However, the incidence, prognosis, and etiology of C5 palsy after anterior decompression with spinal fusion (ASF) have not yet been fully established. In the present study, we analyzed the clinical and radiological characteristics of patients who developed C5 palsy after ASF for cervical degenerative diseases. The cases of 199 consecutive patients who underwent ASF were analyzed to clarify the incidence of postoperative C5 palsy. We also evaluated the onset and prognosis of C5 palsy. The presence of high signal changes (HSCs) in the spinal cord was analyzed using T2-weighted magnetic resonance images. C5 palsy occurred in 17 patients (8.5%), and in 15 of them, the palsy developed after ASF of 3 or more levels. Among ten patients who had a manual muscle test (MMT) grade ≤2 at the onset, five patients showed incomplete or no recovery. Sixteen of the 17 C5 palsy patients presented neck and shoulder pain prior to the onset of muscle weakness. In the ten patients with a MMT grade ≤2 at the onset, nine patients showed HSCs at the C3–C4 and C4–C5 levels. The present findings demonstrate that, in most patients with severe C5 palsy after ASF, pre-existing asymptomatic damage of the anterior horn cells at C3–C4 and C4–C5 levels may participate in the development of motor weakness in combination with the nerve root lesions that occur subsequent to ASF. Thus, when patients with spinal cord lesions at C3–C4 and C4–C5 levels undergo multilevel ASF, we should be alert to the possible occurrence of postoperative C5 palsy.
doi:10.1007/s00586-010-1427-5
PMCID: PMC2989233  PMID: 20461418
C5 palsy; Cervical spine; Anterior surgery; Decompression; Fusion
23.  Low level laser therapy (LLLT) for patients with sacroiliac joint pain 
Laser Therapy  2011;20(2):117-121.
Background and Aims: Sacroiliac joint pain not associated with a major etiological factor is a common problem seen in the orthopedic clinical setting, but diagnosis is difficult because of the anatomical area and thus it is sometimes difficult to effect a complete cure. Low level laser therapy (LLLT) has been well-reported as having efficacy in difficult pain types, so the following preliminary study was designed to assess the efficacy of LLLT for sacroiliac pain.
Materials and Methods: Nine patients participated, 4 males and 5 females, average age of 50.4 yrs, who attended the outpatient department with sacroiliac pain. The usual major disorders were ruled out. Pain was assessed subjectively pre-and post-LLLT on a visual analog scale, and trunk range of motion was examined with the flexion test to obtain the pre- and post-treatment finger to floor distance (FFD). The LLLT system used was an 830 nm CW diode laser, 1000 mW, 30 sec/point (20 J/cm2) applied on the bilateral tender points twice/week for 5 weeks. Baseline and final assessment values (after the final treatment session) were compared with the Wilcoxon signed rank test (nonparametric score).
Results: All patients completed the study. Eight of the 9 patients showed significant pain improvement and 6 demonstrated significantly increased trunk mobility (P <0.05 for both).
Conclusions: LLLT was effective for sacroiliac pain, and this may be due to improvement of the blood circulation of the strong ligaments which support the sacroiliac joint, activation of the descending inhibitory pathway, and the additional removal of irregularities of the sacroiliac joint articular surfaces. Further larger-scale studies are warranted.
doi:10.5978/islsm.20.117
PMCID: PMC3799023  PMID: 24155520
Sacroiliac joint; Low Level Laser Therapy; Sacroiliac joint pain
24.  Prediction model for knee osteoarthritis based on genetic and clinical information 
Arthritis Research & Therapy  2010;12(5):R187.
Introduction
Osteoarthritis (OA) is the most common bone and joint disease influenced by genetic and environmental factors. Recent association studies have uncovered the genetic factors behind OA, its susceptibility genes, which would enable us to predict disease occurrence based on genotype information. However, most previous studies have evaluated the effects of only a single susceptibility gene, and hence prediction based on such information is not as reliable. Here, we constructed OA-prediction models based on genotype information from a case-control association study and tested their predictability.
Methods
We genotyped risk alleles of the three susceptibility genes, asporin (ASPN), growth differentiation factor 5 (GDF5), and double von Willebrand factor A domains (DVWA) for a total of 2,158 Japanese subjects (933 OA and 1,225 controls) and statistically analyzed their effects. After that, we constructed prediction models by using the logistic regression analysis.
Results
When the effects of each allele were assumed to be the same and multiplicative, each additional risk allele increased the odds ratio (OR) by a factor of 1.23 (95% confidence interval (CI), 1.12 to 1.34). Individuals with five or six risk alleles showed significantly higher susceptibility when compared with those with zero or one, with an OR of 2.67 (95% CI, 1.46 to 4.87; P = 0.0020). Statistical evaluation of the prediction power of models showed that a model using only genotyping data had poor predictability. We obtained a model with good predictability by incorporating clinical data, which was further improved by rigorous age adjustment.
Conclusions
Our results showed that consideration of adjusted clinical information, as well as increases in the number of risk alleles to be integrated, is critical for OA prediction by using data from case-control studies. To the authors' knowledge, this is the first report of the OA-prediction model combining both genetic and clinical information.
doi:10.1186/ar3157
PMCID: PMC2991022  PMID: 20939878
25.  A 90-day Feeding Toxicity Study of l-Serine in Male and Female Fischer 344 Rats 
A subchronic feeding study of l-serine (l-Ser) was conducted with groups of 10 male and 10 female Fischer 344 rats fed a powder diet containing 0, 0.06, 0.5, 1.5 or 5.0% concentrations of l-Ser for 90 days. There were no toxicologically significant, treatment-related changes with regards to body weight, food intake, water intake or urinalysis data. In several of the hematology, serum biochemistry and organ weight parameters, significant changes were observed between some of the treated groups and the controls. All these changes, however, were subtle and lacked any corresponding pathological findings. In addition, the increased or decreased values remained within the range of the historical control values. In fact, histopathological assessment revealed only sporadic and/or spontaneous lesions. In conclusion, the no-observed-adverse-effect-level (NOAEL) for l-Ser was, therefore, determined to be at least a dietary dose of 5.0% (2765.0 mg/kg body weight/day for males and 2905.1 mg/kg body weight/day for females) under the present experimental conditions.
doi:10.1293/tox.23.39
PMCID: PMC3234656  PMID: 22272010
l-serine; toxicity study; Fischer 344 rat; feed

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