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1.  Effects of GABA on pancreatic exocrine secretion of rats. 
Journal of Korean Medical Science  2000;15(Suppl):S24-S26.
Since GABA and its related enzymes had been determined in beta-cells of pancreas islets, effects of GABA on pancreatic exocrine secretion were investigated in the isolated perfused rat pancreas. GABA, given intra-arterially at concentrations of 3, 10, 30 and 100 microM, did not exert any influence on spontaneous or secretin (12 pM)-induced pancreatic exocrine secretion. However, GABA further elevated cholecystokinin (10 pM)-, gastrin-releasing peptide (100 pM)- or electrical field stimulation-induced pancreatic secretions of fluid and amylase, dose-dependently. The GABA-enhanced CCK-induced pancreatic secretions were completely blocked by bicuculline (10 microM), a GABAA receptor antagonist but not affected by saclofen (10 microM), a GABA(B) receptor antagonist. The enhancing effects of GABA (30 microM) on CCK-induced pancreatic secretions were not changed by tetrodotoxin (1 microM) but partially reduced by cyclo-(7-aminoheptanonyl-Phe-D-Trp-Lys-Thr[BZL]) (10 microM), a somatostatin antagonist. In conclusion, GABA enhances pancreatic exocrine secretion induced by secretagogues, which stimulate enzyme secretion predominantly, via GABA(A) receptors in the rat pancreas. The enhancing effect of GABA is partially mediated by inhibition of islet somatostatin release. GABA does not modify the activity of intrapancreatic neurons.
PMCID: PMC3202176  PMID: 10981502
2.  Papillary ependymoma: its differential diagnosis from choroid plexus papilloma. 
Journal of Korean Medical Science  1996;11(5):415-421.
Papillary ependymoma is a rare variant of ependymoma and often gives rise to confusion with choroid plexus papilloma because of topographic, light microscopic and ultrastructural similarities. Here, we report two cases of papillary ependymomas regarding their unique clinicopathologic features and differential points from choroid plexus papilloma. Brain MRI revealed a large mass in the left lateral ventricle in one case and a 3cm sized mass in the pineal area and the 3rd ventricle in the other. Microscopically, the tumor was characterized by papillary and tubular structures. Immunohistochemically, the tumor cells in both cases expressed cytokeratins(CK22 and CAM 5.2) but did not express glial fibrillary acidic protein(GFAP), vimentin, epithelial membrane antigen, and S100 protein. This is a very unusual immunohistochemical feature for papillary ependymoma. Ultrastructurally, the tumor showed a mosaic pattern of tumor cells with frequent intercellular microrosettes having a few stubby microvilli, a few cilia and zonulae adherentes. The cytoplasmic processes were markedly reduced compared to conventional ependymoma. The cytoplasm did not contain intermediate filaments. Interestingly, the mitochondria showed abnormal features with a pleomorphic shape and abnormal cristae in both cases. These ultrastructural features enabled differentiation between papillary ependymoma and choroid plexus papilloma in addition to the light microscopic findings.
PMCID: PMC3054185  PMID: 8934397
3.  Inclusion body myositis--a case report. 
Journal of Korean Medical Science  1996;11(4):358-363.
Inclusion body myositis is a rare myopathy that clinically resembles a chronic polymyositis and histopathologically is characterized by the presence of rimmed vacuoles containing ultrastructural cytoplasmic degradation products with filamentous intranuclear and cytoplasmic inclusions. Since clinical features are not uniform, histopathologic and ultrastructural studies are necessary to confirm the diagnosis. We report a typical case of inclusion body myositis with histopathologic and ultrastructural study. The patient was a 31 year old male who presented with progressive weakness of both forearms, hands and lower extremities for 10 years.
PMCID: PMC3054092  PMID: 8878808
4.  Spinal meningeal melanocytoma. 
A case of spinal meningeal melanocytoma is reported along with clinicopathologic, immunohistochemical and ultrastructural studies. This patient presented clinically with paraparesis, tingling sensation and numbness of both lower extremities of 4 months duration. No mucocutaneous pigmented nevi were found. On operation, scattered coal-black pigmented lesions were found in the meninges between T3 and T4-5 interspace level. Nearly total removal was carried out. The tumor was composed of spindle and epithelioid cells with heavy brown-black pigmentation. There was no pleomorphism, mitosis, hemorrhage, necrosis or invasion to the underlying cord tissue. In Korea, this case appears to be the first example of this disease. Neurologic deficit improved after surgical excision.
PMCID: PMC3053837  PMID: 1299241
5.  Nanometer scale thermometry in a living cell 
Nature  2013;500(7460):54-58.
Sensitive probing of temperature variations on nanometer scales represents an outstanding challenge in many areas of modern science and technology1. In particular, a thermometer capable of sub-degree temperature resolution over a large range of temperatures as well as integration within a living system could provide a powerful new tool for many areas of biological, physical and chemical research; possibilities range from the temperature-induced control of gene expression2–5 and tumor metabolism6 to the cell-selective treatment of disease7,8 and the study of heat dissipation in integrated circuits1. By combining local light-induced heat sources with sensitive nanoscale thermometry, it may also be possible to engineer biological processes at the sub-cellular level2–5. Here, we demonstrate a new approach to nanoscale thermometry that utilizes coherent manipulation of the electronic spin associated with nitrogen-vacancy (NV) color centers in diamond. We show the ability to detect temperature variations down to 1.8 mK (sensitivity of 9mK/Hz) in an ultra-pure bulk diamond sample. Using NV centers in diamond nanocrystals (nanodiamonds, NDs), we directly measure the local thermal environment at length scales down to 200 nm. Finally, by introducing both nanodiamonds and gold nanoparticles into a single human embryonic fibroblast, we demonstrate temperature-gradient control and mapping at the sub-cellular level, enabling unique potential applications in life sciences.
PMCID: PMC4221854  PMID: 23903748
6.  Phase II study of pazopanib monotherapy in metastatic gastroenteropancreatic neuroendocrine tumours 
British Journal of Cancer  2013;109(6):1414-1419.
Treatment options for patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP NETs) are still limited. We investigated the antitumour activity and safety profile of pazopanib – a multitarget drug with anti-angiogenic activity in patients with metastatic GEP NETs.
This was a nonrandomised, open-labeled, single-center phase II study. Pazopanib was orally administered at a dose of 800 mg daily continuously with a 28-day cycle. The primary end point was an objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST). The secondary end points were progression-free survival (PFS), overall survival (OS) and safety. An independent review of objective response was planned. The trial is registered with, NCT number 01099540. Correlative biomarker analyses were performed.
Between April 2010 and February 2012, a total of 37 patients were enrolled. Thirty-two percent of the enrolled patients had pancreatic primary and 22% of the patients had colorectal primary NETs. This phase II study demonstrated an objective response rate of 18.9% (7 of the 37, 95% CI 8.0–35.2) and a disease control rate (CR+confirmed PR+stable disease) of 75.7% (28 of the 37, 95% CI, 58.8–88.2) in metastatic GEP NETs. The independent review demonstrated a higher overall response rate of 24.3% (95% CI, 11.8–41.2%) with nine confirmed PRs.
Pazopanib showed a comparable efficacy to other targeted agents not only in pancreatic NETs but also in NETs originating from gastrointestinal (GI) tract.
PMCID: PMC3776983  PMID: 23989950
neuroendocrine tumours; pazopanib; chemotherapy; chromogranin A; positron-emission tomography
7.  Differential Effects of Pneumococcal Vaccines against Serotypes 6A and 6C 
The Journal of infectious diseases  2008;198(12):1818-1822.
Because classical pneumococcal serotyping cannot distinguish between serotypes 6A and 6C, the effects of pneumococcal vaccines against serotype 6C are unknown. Pneumococcal vaccines contain 6B, but do not contain 6A and 6C.
We used a phagocytic killing assay to estimate the immunogenicity of 7-valent conjugate vaccine (PCV7) in children and 23-valent polysaccharide vaccine (PPV23) in adults against serotypes 6A and 6C. We evaluated trends in invasive pneumococcal disease (IPD) caused by serotypes 6A and 6C using active surveillance in the U.S.
Sera from PCV7-immunized children had median opsonization indices of 150 and <20 for serotypes 6A and 6C, respectively. Similarly, only 52% (25/48) of adults vaccinated with PPV23 showed opsonic indices greater than 20 against serotype 6C. During 1999–2006, the incidence (cases per 100,000) of serotype 6A IPD declined from 4.9 to 0.46 (−91%, P<0.05) among children aged <5 years, and from 0.86 to 0.36 (−58%, P<0.05) among persons aged ≥5 years. Although incidence of 6C IPD showed no consistent trend (range 0–0.6) among <5 year-olds, it increased from 0.25 to 0.62 (P<0.05) among persons aged ≥5 years.
PCV7 introduction has led to reductions in serotype 6A IPD, but not serotype 6C IPD in the U.S.
PMCID: PMC4159939  PMID: 18983249
Pneumococcus; vaccine; cross-protection; serotype; herd immunity
8.  Focal nodular hyperplasia: characterisation at gadoxetic acid-enhanced MRI and diffusion-weighted MRI 
The British Journal of Radiology  2013;86(1028):20130299.
The aim of this study was to assess the enhancement patterns of hepatic focal nodular hyperplasia (FNH) on gadoxetic acid-enhanced MRI and diffusion-weighted (DW) MRI.
This retrospective study had institutional review board approval. Gadoxetic acid-enhanced and DW MR images were evaluated in 23 patients with 30 FNHs (26 histologically proven and 4 radiologically diagnosed). The lesion enhancement patterns of the hepatobiliary phase images were classified as heterogeneous or homogeneous signal intensity (SI), and as dominantly high/iso or low SI compared with those of adjacent liver parenchyma. Heterogeneous (any) SI lesions and homogeneous low SI lesions were categorised into the fibrosis group, whereas homogeneous high/iso SI lesions were categorised into the non-fibrosis group. Additionally, lesion SI on T2 weighted images, DW images and apparent diffusion coefficient (ADC) values were compared between the two groups.
The lesions showed heterogeneous high/iso SI (n=16), heterogeneous low SI (n=5), homogeneous high/iso SI (n=7) or homogeneous low SI (n=2) at the hepatobiliary phase MR images. The fibrosis group lesions were more likely to show high SI on DW images and T2 weighted images compared with those in the non-fibrosis group (p<0.05). ADC values tended to be lower in the fibrosis group than those in the non-fibrosis group without significance.
FNH showed variable enhancement patterns on hepatobiliary phase images during gadoxetic acid-enhanced MRI. SI on DW and T2 weighted images differed according to the fibrosis component contained in the lesion.
Advances in knowledge:
FNH shows a wide spectrum of imaging findings on gadoxetic acid-enhanced MRI and DW MRI.
PMCID: PMC3745063  PMID: 23873903
9.  Statins and prostate cancer recurrence following radical prostatectomy or radiotherapy: a systematic review and meta-analysis 
Annals of Oncology  2013;24(6):1427-1434.
In this meta-analysis, we evaluated associations between statins and recurrence-free survival (RFS) following treatment of localized prostate cancer, with attention to potential benefits among patients treated primarily with radiotherapy (RT) versus radical prostatectomy.
Patients and methods
We identified original studies examining the effect of statins on men who received definitive treatment of localized prostate cancer using a systematic search of the PubMed and EMBASE databases through August 2012. Our search yielded 17 eligible studies from 794 references; 13 studies with hazard ratios (HRs) for RFS were included in the formal meta-analysis.
Overall, statins did not affect RFS (HR 0.90, 95% CI 0.74–1.08). However, in RT patients (six studies), statins were associated with a statistically significant improvement in RFS (HR 0.68; 95% CI 0.49–0.93); this benefit was not observed in radical prostatectomy patients (seven studies). Sensitivity analyses suggested that primary treatment modality may impact the effect of statins on prostate cancer recurrence.
Our meta-analysis suggests a potentially beneficial effect of statins on prostate cancer patients treated with RT but not among radical prostatectomy patients. Although limited by the lack of randomized data, these results suggest that primary treatment modality should be considered in future studies examining associations between statins and oncologic outcomes.
PMCID: PMC3660083  PMID: 23508824
meta-analysis; prostate cancer; radical prostatectomy; radiotherapy; recurrence; statin
10.  Elevated Id2 expression results in precocious neural stem cell depletion and abnormal brain development 
Stem cells (Dayton, Ohio)  2013;31(5):1010-1021.
Id2 is a helix-loop-helix (HLH) transcription factor essential for normal development and its expression is dysregulated in many human neurological conditions. Although it is speculated that elevated Id2 levels contribute to the pathogenesis of these disorders, it is unknown whether dysregulated Id2 expression is sufficient to perturb normal brain development or function. Here, we show that mice with elevated Id2 expression during embryonic stages develop microcephaly, and that females in particular are prone to generalized tonic-clonic seizures. Analyses of Id2 transgenic brains indicate that Id2 activity is highly cell context specific: elevated Id2 expression in naive NSCs in early neuroepithelium induces apoptosis and loss of NSCs and intermediate progenitors. Activation of Id2 in maturing neuroepithelium results in less severe phenotypes and is accompanied by elevation of G1 Cyclin expression and p53 target gene expression. In contrast, activation of Id2 in committed intermediate progenitors has no significant phenotype. Functional analysis with Id2 over-expressing and Id2-null NSCs shows that Id2 negatively regulates NSC self-renewal in vivo, in contrast to previous cell culture experiments. Deletion of p53 function from Id2-transgenic brains rescues apoptosis and results in increased incidence of brain tumors. Furthermore, Id2 over-expression normalizes the increased self-renewal of p53-null NSCs, suggesting that Id2 activates and modulates the p53 pathway in NSCs. Together, these data suggest that elevated Id2 expression in embryonic brains can cause deregulated NSC self-renewal, differentiation and survival that manifest in multiple neurological outcomes in mature brains, including microcephaly, seizures, and brain tumors.
PMCID: PMC3637429  PMID: 23390122
neural stem cells; Id2; brain tumor; glioma; medulloblastoma; self-renewal; apoptosis; seizure; CyclinG1; Rett syndrome
11.  Distant metastasis of intraosseous dentinogenic ghost cell tumour to the donor site of a bone graft 
Dentomaxillofacial Radiology  2013;42(5):20120172.
A dentinogenic ghost cell tumour (DGCT) is an extremely rare odontogenic tumour which is considered as a solid, neoplastic variant of calcifying odontogenic cyst. Intraosseous DGCTs are more aggressive than extraosseous DGCTs and have a high propensity for local recurrence. This report describes a case of a diagnosis of recurrent DGCT at the primary site and a distant donor site. A 25-year-old female patient visited a dental hospital for a complaint of facial swelling for the previous month. Incisional biopsy was performed and the specimen was diagnosed as DGCT. Partial mandibulectomy for tumour resection and iliac bone graft was performed. 2 years later, the tumour recurred on the mandible and iliac bone. The recurrent lesion on the donor site was diagnosed as metastasized DGCT. This report highlights the possibility of distant metastasis occurring at a graft donor site.
PMCID: PMC3635771  PMID: 23420853
odontogenic tumours; neoplasm metastasis; neoplasm seeding; diagnostic imaging
12.  Clinical correlation of a new practical MRI method for assessing central lumbar spinal stenosis 
The British Journal of Radiology  2013;86(1025):20120180.
To evaluate interobserver agreement and determine whether a new MRI grading system agrees with symptoms and neurological signs.
We examined 160 patients (72 males and 88 females; mean age 57 years) who underwent MRI of the lumbar spine at our institution and were evaluated by two musculoskeletal radiologists. The presence and grade of central lumbar spinal stenosis (CLSS) at L3–4, L4–5 and L5–S1 were assessed according to a new grading system, the Lee system. The results were correlated with clinical manifestations and neurological examinations [positive neurological manifestation (PNM) and negative neurological manifestation (NNM)]. Statistical analyses were performed using kappa statistics and non-parametric correlation analysis (Spearman’s correlation).
Interobserver agreement in the grading of CLSS between the two readers was substantial (κ=0.780). Interobserver agreement of the L4–5 level and older age group was high (0.789, 0.814). The correlation coefficient (R) of Reader 1 between MRI Grades 0, 1, 2 or 3 and neurological manifestations (negative or positive) was 0.654; the R of Reader 2 was 0.591. In the younger age group (<57 years), the R of Reader 1 was 0.634 and the R of Reader 2 was 0.500. In the older age group (≥57 years), the R of Reader 1 was 0.650 and the R of Reader 2 was 0.645. Correlation coefficients were higher at the L3–4 level (0.612–0.678) than at other levels but did not show statistical significance (p>0.05).
Interobserver agreement for the new CLSS grading system was substantial. Grade 0 was associated with NNMs and Grade 3 with PNMs in this cohort. Grade 2 demonstrates more cases of PNM than NNM but requires further evaluation. Correlations between MRI grades and clinical manifestations were moderate and slightly higher in older patients.
Advances in knowledge:
The new practical MRI grading method can be useful in the categorisation of CLSS and shows strong clinical correlation.
PMCID: PMC3635794  PMID: 23426848
13.  A practical MRI grading system for cervical foraminal stenosis based on oblique sagittal images 
The British Journal of Radiology  2013;86(1025):20120515.
To propose a new and practical MRI grading method for cervical neural foraminal stenosis and to evaluate its reproducibility.
We evaluated 50 patients (37 males and 13 females, mean age 49 years) who visited our institution and underwent oblique sagittal MRI of the cervical spine. A total of 300 foramina and corresponding nerve roots in 50 patients were qualitatively analysed from C4–5 to C6–7. We assessed the grade of cervical foraminal stenosis at the maximal narrowing point according to the new grading system based on T2 weighted oblique sagittal images. The incidence of each of the neural foraminal stenosis grades according to the cervical level was analysed by χ2 tests. Intra- and interobserver agreements between two radiologists were analysed using kappa statistics. Kappa value interpretations were poor (κ<0.1), slight (0.1≤κ≤0.2), fair (0.2<κ≤0.4), moderate (0.4<κ≤0.6), substantial (0.6<κ≤0.8) and almost perfect (0.8<κ≤1.0).
Significant stenoses (Grades 2 and 3) were rarely found at the C4–5 level. The incidence of Grade 3 at the C5–6 level was higher than that at other levels, a difference that was statistically significant. The overall intra-observer agreement according to the cervical level was almost perfect. The agreement at each level was almost perfect, except for only substantial agreement at the right C6–7 by Reader 2. No statistically significant differences were seen according to the cervical level. Overall kappa values of interobserver agreement according to the cervical level were almost perfect. In addition, the agreement of each level was almost perfect. Overall intra- and interobserver agreement for the presence of foraminal stenosis (Grade 0 vs Grades 1, 2 and 3) and for significant stenosis (Grades 0 and 1 vs Grades 2 and 3) showed similar results and were almost perfect. However, only substantial agreement was seen in the right C6–7.
A new grading system for cervical foraminal stenosis based on oblique sagittal MRI provides reliable assessment and good reproducibility. This new grading system is a useful and easy method for the objective evaluation of cervical neural foraminal stenosis by radiologists and clinicians.
Advances in knowledge:
The use of the new grading system for cervical foraminal stenosis based on oblique sagittal MRI can be a useful method for evaluating cervical neural foraminal stenosis.
PMCID: PMC3635796  PMID: 23410800
14.  Evaluation of anatomical landmark position differences between respiration-gated MRI and four-dimensional CT for radiation therapy in patients with hepatocellular carcinoma 
The British Journal of Radiology  2013;86(1021):20120221.
To measure the accuracy of position differences in anatomical landmarks in gated MRI and four-dimensional CT (4D-CT) fusion planning for radiation therapy in patients with hepatocellular carcinoma (HCC).
From April to December 2009, gated MR and planning 4D-CT images were obtained from 53 inoperable HCC patients accrued to this study. Gated MRI and planning 4D-CT were conducted on the same day. Manual image fusions were performed by matching the vertebral bodies. Liver volumes and three specific anatomical landmarks (portal vein conjunction, superior mesenteric artery bifurcation, and other noticeable points) were contoured from each modality. The points chosen nearest the centre of the four landmark points were compared to measure the accuracy of fusion.
The average distance differences (±standard deviation) of four validation points were 5.1 mm (±4.6 mm), 5.6 mm (±6.2 mm), 5.4 mm (±4.5 mm) and 5.1 mm (±4.8 mm). Patients who had ascites or pulmonary disease showed larger discrepancies. MRI–CT fusion discrepancy was significantly correlated with positive radiation response (p<0.05).
Approximately 5-mm anatomical landmark positional differences in all directions were found between gated MRI and 4D-CT fusion planning for HCC patients; the gap was larger in patients with ascites or pulmonary disease.
Advances in knowledge
There were discrepancies of approximately 5 mm in gated MRI–CT fusion planning for HCC patients.
PMCID: PMC3615390  PMID: 23239694
15.  Marker-free registration for the accurate integration of CT images and the subject's anatomy during navigation surgery of the maxillary sinus 
Dentomaxillofacial Radiology  2012;41(8):679-685.
This study compared three marker-free registration methods that are applicable to a navigation system that can be used for maxillary sinus surgery, and evaluated the associated errors, with the aim of determining which registration method is the most applicable for operations that require accurate navigation.
The CT digital imaging and communications in medicine (DICOM) data of ten maxillary models in DICOM files were converted into stereolithography file format. All of the ten maxillofacial models were scanned three dimensionally using a light-based three-dimensional scanner. The methods applied for registration of the maxillofacial models utilized the tooth cusp, bony landmarks and maxillary sinus anterior wall area. The errors during registration were compared between the groups.
There were differences between the three registration methods in the zygoma, sinus posterior wall, molar alveolar, premolar alveolar, lateral nasal aperture and the infraorbital areas. The error was smallest using the overlay method for the anterior wall of the maxillary sinus, and the difference was statistically significant.
The navigation error can be minimized by conducting registration using the anterior wall of the maxillary sinus during image-guided surgery of the maxillary sinus.
PMCID: PMC3528203  PMID: 22499127
registration; image-guided surgery; navigation; maxillary sinus
16.  The Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin increases cisplatin antitumor activity by inducing p53-mediated apoptosis in head and neck cancer 
Cell Death & Disease  2013;4(12):e956-.
The tumor suppressor p53 is often inactivated in head and neck cancer (HNC) through TP53 mutations or overexpression of mouse double minute 2 or mouse double minute X. Restoration of p53 function by counteracting these p53 repressors is a promising strategy for cancer treatment. The present study assessed the ability of a heat shock protein 90 (Hsp90) inhibitor, 17-(Allylamino)-17-demethoxygeldanamycin (17AAG), to induce apoptosis in HNC by restoring p53 function. The effect of 17AAG, alone or in combination with Nutlin-3a or cisplatin, was assessed in HNC cells using growth and apoptosis, immunoblotting, quantitative reverse transcription-polymerase chain reaction, and preclinical tumor xenograft models. 17AAG activated and stabilized p53 in HNC cells bearing wild-type TP53 by disrupting the p53–MDMX interaction. 17AAG upregulated p21 and proapoptotic gene expression, and promoted apoptosis in a concentration-dependent manner. Growth inhibition by 17AAG was highest in tumor cells with MDMX overexpression. The apoptotic response was blocked by inhibition of p53 expression, demonstrating that the effect of 17AAG depended on p53 and MDMX. 17AAG synergized in vitro with Nutlin-3a and in vitro and in vivo with cisplatin to induce p53-mediated apoptosis. 17AAG effectively induced p53-mediated apoptosis in HNC cells through MDMX inhibition and increased the antitumor activity of cisplatin synergistically, suggesting a promising strategy for treating HNC.
PMCID: PMC3877559  PMID: 24336076
17AAG; p53; MDMX; head and neck cancer; apoptosis
17.  Mycobacterial HBHA induces endoplasmic reticulum stress-mediated apoptosis through the generation of reactive oxygen species and cytosolic Ca2+ in murine macrophage RAW 264.7 cells 
Cell Death & Disease  2013;4(12):e957-.
Mycobacterial heparin-binding haemagglutinin antigen (HBHA) is a virulence factor that induces apoptosis of macrophages. Endoplasmic reticulum (ER) stress-mediated apoptosis is an important regulatory response that can be utilised to study the pathogenesis of tuberculosis. In the present study, HBHA stimulation induced ER stress sensor molecules in a caspase-dependent manner. Pre-treatment of RAW 264.7 cells with an IκB kinase 2 inhibitor reduced not only C/EBP homology protein expression but also IL-6 and monocyte chemotactic protein-1 (MCP-1) production. BAPTA-AM reduced both ER stress responses and caspase activation and strongly suppressed HBHA-induced IL-6 and MCP-1 production in RAW 264.7 cells. Enhanced reactive oxygen species (ROS) production and elevated cytosolic [Ca2+]i levels were essential for HBHA-induced ER stress responses. Collectively, our data suggest that HBHA induces cytosolic [Ca2+]i, which influences the generation of ROS associated with the production of proinflammatory cytokines. These concerted and complex cellular responses induce ER stress-associated apoptosis during HBHA stimulation in macrophages. These results indicate that the ER stress pathway has an important role in the HBHA-induced apoptosis during mycobacterial infection.
PMCID: PMC3877560  PMID: 24336077
ER stress; macrophage; mycobacteria
18.  Medial meniscal root tears and meniscal extrusion transverse length ratios on MRI 
The British Journal of Radiology  2012;85(1019):e1032-e1037.
To evaluate the clinical utility of the meniscal extrusion transverse ratio of the medial meniscus in the diagnosis of meniscal root tear compared with the gold standard of arthroscopic diagnosis.
This retrospective study sample included 32 males and 35 females who underwent MRI at our institution. There were 24 meniscal root tear cases. The control groups were 18 cases of medial meniscal tears without root tears and 25 cases of negative meniscal findings on arthroscopy. Meniscal extrusion (L) and maximal transverse lengths (T) of the medial meniscus were measured, and L/T ratios were calculated. These results were correlated with arthroscopic findings and analysed statistically. With arthroscopic findings used as the standard of reference, the sensitivity and specificity of 10%, 11% and 12% extrusion thresholds, and 3 mm of medial meniscal extrusion (MME) as diagnostic thresholds, were calculated.
The mean length of the meniscal extrusions of meniscal root tears was twice as long as the control group. The mean L/T ratio of the meniscal root tears was approximately 13%, while those of the control groups were 5%. The differences in the L and L/T between the meniscal root tears and normal and meniscal root tears and other meniscal tears were statistically significant (p<0.001), but those between normal and other meniscal tears were not. The best diagnostic discrimination was achieved using an extrusion ratio threshold of 10% (79% sensitivity, 86% specificity). The 3 mm of MME threshold demonstrated high specificity (98%), but not high sensitivity (54%).
The mean L/T ratio of the meniscal root tears was approximately 13% and was statistically significant. The best diagnostic discrimination was achieved using an extrusion ratio threshold of 10%.
Advances in knowledge
The use of the L/T ratio in combination with MME can be a useful method for evaluating medial meniscal root tears.
PMCID: PMC3500800  PMID: 23091292
19.  The Possibility of TBC1D21 as a Candidate Gene for Teat Numbers in Pigs 
Based on a quantitative traits locus (QTL) study using a F2 intercross between Landrace and Korean native pigs, a significant QTL affecting teat numbers in SSC7 was identified. The strong positional candidate gene, TBC1D21, was selected due to its biological function for epithelial mesenchymal cell development. Sequence analysis revealed six single nucleotide polymorphisms (SNPs) in the TBC1D21 gene. Among these, two SNP markers, one silent mutation (SNP01) for g.13,050A>G and one missense mutation (SNP04) for c.829A>T (S277C), were genotyped and they showed significant associations with teat number traits (p value = 6.38E-05 for SNP01 and p value = 1.06E-07 for SNP04 with total teat numbers). Further functional validation of these SNPs could give valuable information for understanding the teat number variation in pigs.
PMCID: PMC4093071  PMID: 25049720
QTL; SNP; SSC7; TBC1D21; Teat Number; Pig
20.  Non-Typeable Streptococcus Pneumoniae Carriage Isolates Genetically Similar to Invasive and Carriage Isolates Expressing Capsular Type 14 in Brazilian Infants 
The Journal of infection  2010;61(4):314-322.
We have recently found a high prevalence of non-typeable pneumococcal isolates (NTPn) circulating in day-care centers in Central Brazil, besides serotype 14 isolates. We therefore examined the genetic relationship among NTPn and serotype 14 from carriage and invasive pneumococcal isolates obtained from children attending emergency rooms enrolled in a population-based surveillance.
The isolates were characterized by Quellung reaction serotyping, PCR for the presence of pneumolysin and the loci for a capsule gene (cpsA) and the type 14 gene (cps14H) in all NTPn, and by multilocus sequence typing and pulsed field gel electrophoresis.
87.2% of the isolates were clustered into nine clusters. The major cluster included 41 pneumococcal serotype 14 (28 carriage and 13 invasive isolates) and two NTPn related to the global pneumococcal clone Spain 9V-3. Overall, 95.4% of the NTPn carriage strains were genetically related to carriage or invasive strains expressing serotype 14. A dominant NTPn lineage was found, that grouped 14 pneumococcal strains. Almost half of the multidrug-resistant isolates grouped into the NTPn cluster.
These findings provide baseline data to assess the impact of the pneumococcal vaccination on the molecular epidemiology of S. pneumoniae. Changes in frequency of NTPn isolates and also genetic changes should be carefully monitored post vaccination, to detect potential vaccine-escape or replacement disease by capsule switched strains, especially in areas where colonization with NTPn has been frequently observed.
PMCID: PMC3769134  PMID: 20637229
molecular epidemiology; non-typeable Streptococcus pneumoniae; carriage; invasive pneumococcal disease
21.  Serial intracameral visualization of the Ahmed glaucoma valve tube by anterior segment optical coherence tomography 
Eye  2012;26(9):1256-1262.
To investigate serial changes of the Ahmed glaucoma valve (AGV) implant tube in the anterior chamber by anterior segment optical coherence tomography (AS-OCT).
Patients who had received AGV implantation without complications (n=48) were included in this study. Each patient received follow-up examinations including AS-OCT at days 1 and 2, week 1, and months 1, 3, 6, and 12. Tube parameters were defined to measure its length and position. The intracameral length of the tube was from the tip of the bevel-edged tube to the sclerolimbal junction. The distance between the extremity of the tube and the anterior iris surface (T–I distance), and the angle between the tube and the posterior endothelial surface of the cornea (T–C angle) were defined. Factors that were related to tube parameters were analysed by multiple regression analysis.
The mean change in tube length was −0.20±0.17 mm, indicating that the tube length shortened from the initial inserted length. The mean T–I distance change was 0.11±0.07 mm and the mean T–C angle change was −6.7±5.6°. Uveitic glaucoma and glaucoma following penetrating keratoplasty showed the most changes in tube parameters. By multiple regression analysis, diagnosis of glaucoma including uveitic glaucoma (P=0.049) and glaucoma following penetrating keratoplasty (P=0.008) were related to the change of intracameral tube length.
These results suggest that the length and position of the AGV tube changes after surgery. The change was prominent in uveitic glaucoma and glaucoma following penetrating keratoplasty.
PMCID: PMC3443837  PMID: 22744388
Ahmed glaucoma valve; anterior segment optical coherence tomography; glaucoma surgery
22.  Correlation of the apparent diffusion coefficiency values on diffusion-weighted imaging with prognostic factors for breast cancer 
The British Journal of Radiology  2012;85(1016):e474-e479.
The aim of this study was to correlate the apparent diffusion coefficient (ADC) value of breast cancer with prognostic factors.
335 patients with invasive ductal carcinoma not otherwise specified (IDC NOS) and ductal carcinoma in situ (DCIS) who underwent breast MRI with diffusion-weighted imaging were included in this study. ADC of breast cancer was calculated using two b factors (0 and 1000 s mm–2). Mean ADCs of IDC NOS and DCIS were compared and evaluated. Among cases of IDC NOS, mean ADCs were compared with lymph node status, size and immunochemical prognostic factors using Student's t-test. ADC was also correlated with histological grade using the Kruskal–Wallis test.
Mean ADC of IDC NOS was significantly lower than that of DCIS (p<0.001). However, the mean ADC of histological grade of IDC NOS was not significantly different (p=0.564). Mean ADC of oestrogen receptor (ER)-positive or progesterone receptor (PR)-positive cancer was significantly lower than that of ER-negative or PR-negative cancer (p=0.003 vs p=0.032). Mean ADC of Ki-67 index-positive cancer was significantly lower than that of Ki-67 index-negative cancer (p=0.028). Mean ADC values of cancers with increased microvascular density (MVD) were significantly lower than those of cancer with no MVD increase (p=0.009). No correlations were observed between mean ADC value and human growth factor receptor 2 expression, tumour size and lymph node metastasis.
Low ADC value was correlated with positive expression of ER, PR, increased Ki-67 index, and increased MVD of breast cancer.
PMCID: PMC3587081  PMID: 22128125
23.  Production of a unique pneumococcal capsule serotype belonging to serogroup 6 
Microbiology (Reading, England)  2009;155(0 2):576-583.
Serogroup 6 of Streptococcus pneumoniae contains three serotypes named 6A, 6B and 6C with highly homologous capsule gene loci. The 6A and 6B capsule gene loci consistently differ from each other by only one nucleotide in the wciP gene. The 6A capsule gene locus has a galactosyl transferase, which has been replaced with a glucosyl transferase in the 6C capsule gene locus. We considered that a new serotype named “6X1” would be possible if the galactosyl transferase of the 6B capsule gene locus is replaced with the glucosyl transferase of 6C. We demonstrate that this gene transfer yields a viable pneumococcal strain and the capsular polysaccharide from this strain has the predicted chemical structure and serologic similarity to the capsular polysaccharide of the 6B serotype. The new strain (i.e., serotype 6X1) is typed as 6B by the quellung reaction but it can be distinguished from 6B strains with monoclonal antibodies to 6B polysaccharide. Reexamination of 264 pneumococcal isolates that were previously typed as 6B with classical typing methods revealed no isolates expressing serotype 6X1. Nevertheless, this study shows this capsular polysaccharide is biochemically possible and could exist/emerge in nature.
PMCID: PMC3706093  PMID: 19202106
pneumococcus; serotype; vaccine
24.  Ultrasonography-guided ethanol ablation of predominantly solid thyroid nodules: a preliminary study for factors that predict the outcome 
The British Journal of Radiology  2012;85(1015):930-936.
The aim of this study was to evaluate the success rate in ultrasonography-guided ethanol ablation (EA) of benign, predominantly solid thyroid nodules and to assess the value of colour Doppler ultrasonography in prediction of its success.
From January 2008 to June 2009, 30 predominantly solid thyroid nodules in 27 patients were enrolled. Differences in the success rate of EA were assessed according to nodule vascularity, nodule size, ratio of cystic component, amount of injected ethanol, degree of intranodular echo-staining just after ethanol injection and the number of EA sessions.
On follow-up ultrasonography after EA for treatment of thyroid nodules, 16 nodules showed an excellent response (90% or greater decrease in volume) and 2 nodules showed a good response (50–90% decrease in volume) on follow-up ultrasonography. However, 5 nodules showed an incomplete response (10–50% decrease in volume) and 7 nodules showed a poor response (10% or less decrease in volume). Statistical analysis revealed a significant association of nodule vascularity (p = 0.002) and degree of intranodular echo-staining just after ethanol injection (p = 0.003) with a successful outcome; however, no such association was observed with regard to nodule size, ratio of cystic component, amount of infused ethanol and the number of EA sessions. No serious complications were observed during or after EA.
The success rate of EA was 60%, and nodule vascularity and intranodular echo-staining on colour Doppler ultrasonography were useful in predicting the success rate of EA for benign, predominantly solid thyroid nodules.
PMCID: PMC3474049  PMID: 22167503
25.  Randomised phase II trial of docetaxel and sunitinib in patients with metastatic gastric cancer who were previously treated with fluoropyrimidine and platinum 
British Journal of Cancer  2012;106(9):1469-1474.
Docetaxel is widely used as a chemotherapeutic agent for gastric cancer treatment. A combined regimen with sunitinib demonstrated a synergistic antitumour effect in a preclinical model. The aim of this study was to evaluate the efficacy and safety of this combination in patients with unresectable or metastatic advanced gastric cancer following failure of treatment with a fluoropyrimidine and platinum combination.
This open-label, phase II, randomised trial enrolled patients with unresectable or metastatic gastric cancer. Patients were assigned to either a docetaxel monotherapy arm (D only arm: 60 mg m−2, every 3 weeks) or a combination arm (DS arm: docetaxel+sunitinib 37.5 mg every day). The primary end point of the study was time to progression and the secondary end points were overall response rate, disease control rate, overall survival, and toxicity profile. A pharmacokinetic study was also performed.
A total of 107 patients were entered into the study. The TTP was not significantly prolonged in the DS arm when compared with the D only arm (DS vs D only arm: 3.9 months (95% confidence interval (CI) 2.9–4.9) vs 2.6 months (95% CI 1.8–3.5) (P=0.206). The hazard ratio for TTP was 0.77 (95% CI 0.52–1.16). However, the objective response rate was significantly higher in the DS arm (41.1% vs 14.3%, P=0.002). Patients in the DS arm experienced stomatitis, diarrhoea, and hand–foot syndrome more frequently.
The addition of sunitinib to docetaxel did not significantly prolong TTP, although it significantly increased response.
PMCID: PMC3341944  PMID: 22460270
gastric cancer; second-line chemotherapy; docetaxel; sunitinib

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