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1.  Developmental Changes in Organization of Structural Brain Networks 
Khundrakpam, Budhachandra S. | Reid, Andrew | Brauer, Jens | Carbonell, Felix | Lewis, John | Ameis, Stephanie | Karama, Sherif | Lee, Junki | Chen, Zhang | Das, Samir | Evans, Alan C. | Ball, William S. | Byars, Anna Weber | Schapiro, Mark | Bommer, Wendy | Carr, April | German, April | Dunn, Scott | Rivkin, Michael J. | Waber, Deborah | Mulkern, Robert | Vajapeyam, Sridhar | Chiverton, Abigail | Davis, Peter | Koo, Julie | Marmor, Jacki | Mrakotsky, Christine | Robertson, Richard | McAnulty, Gloria | Brandt, Michael E. | Fletcher, Jack M. | Kramer, Larry A. | Yang, Grace | McCormack, Cara | Hebert, Kathleen M. | Volero, Hilda | Botteron, Kelly | McKinstry, Robert C. | Warren, William | Nishino, Tomoyuki | Robert Almli, C. | Todd, Richard | Constantino, John | McCracken, James T. | Levitt, Jennifer | Alger, Jeffrey | O'Neil, Joseph | Toga, Arthur | Asarnow, Robert | Fadale, David | Heinichen, Laura | Ireland, Cedric | Wang, Dah-Jyuu | Moss, Edward | Zimmerman, Robert A. | Bintliff, Brooke | Bradford, Ruth | Newman, Janice | Evans, Alan C. | Arnaoutelis, Rozalia | Bruce Pike, G. | Louis Collins, D. | Leonard, Gabriel | Paus, Tomas | Zijdenbos, Alex | Das, Samir | Fonov, Vladimir | Fu, Luke | Harlap, Jonathan | Leppert, Ilana | Milovan, Denise | Vins, Dario | Zeffiro, Thomas | Van Meter, John | Lange, Nicholas | Froimowitz, Michael P. | Botteron, Kelly | Robert Almli, C. | Rainey, Cheryl | Henderson, Stan | Nishino, Tomoyuki | Warren, William | Edwards, Jennifer L. | Dubois, Diane | Smith, Karla | Singer, Tish | Wilber, Aaron A. | Pierpaoli, Carlo | Basser, Peter J. | Chang, Lin-Ching | Koay, Chen Guan | Walker, Lindsay | Freund, Lisa | Rumsey, Judith | Baskir, Lauren | Stanford, Laurence | Sirocco, Karen | Gwinn-Hardy, Katrina | Spinella, Giovanna | McCracken, James T. | Alger, Jeffry R. | Levitt, Jennifer | O'Neill, Joseph
Cerebral Cortex (New York, NY)  2012;23(9):2072-2085.
Recent findings from developmental neuroimaging studies suggest that the enhancement of cognitive processes during development may be the result of a fine-tuning of the structural and functional organization of brain with maturation. However, the details regarding the developmental trajectory of large-scale structural brain networks are not yet understood. Here, we used graph theory to examine developmental changes in the organization of structural brain networks in 203 normally growing children and adolescents. Structural brain networks were constructed using interregional correlations in cortical thickness for 4 age groups (early childhood: 4.8–8.4 year; late childhood: 8.5–11.3 year; early adolescence: 11.4–14.7 year; late adolescence: 14.8–18.3 year). Late childhood showed prominent changes in topological properties, specifically a significant reduction in local efficiency, modularity, and increased global efficiency, suggesting a shift of topological organization toward a more random configuration. An increase in number and span of distribution of connector hubs was found in this age group. Finally, inter-regional connectivity analysis and graph-theoretic measures indicated early maturation of primary sensorimotor regions and protracted development of higher order association and paralimbic regions. Our finding reveals a time window of plasticity occurring during late childhood which may accommodate crucial changes during puberty and the new developmental tasks that an adolescent faces.
doi:10.1093/cercor/bhs187
PMCID: PMC3729193  PMID: 22784607
adolescence; connectivity; connector hub; cortical thickness; maturation
2.  Effect of methylglyoxal on multidrug-resistant Pseudomonas aeruginosa 
Honey has a complex chemistry, and its broad-spectrum antimicrobial activity varies with floral source, climate, and harvesting conditions. Methylglyoxal was identified as the dominant antibacterial component of manuka honey. Although it has been known that methylglyoxal has antibacterial activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus, there is not much information describing its activity against gram-negative bacteria. In this study, we report the effect of methylglyoxal against multidrug-resistant Pseudomonas aeruginosa (MDRP) using 53 clinically isolated strains. We also assessed the effect of deleting the five multidrug efflux systems in P. aeruginosa, as well as the efflux systems in Escherichia coli and Salmonella enterica serovar Typhimurium, on MICs of methylglyoxal. Our results indicate that methylglyoxal inhibits the growth of MDRP at concentrations of 128–512 μg/ml (1.7–7.1 mM) and is not recognized by drug efflux systems.
doi:10.3389/fmicb.2014.00180
PMCID: PMC4029012  PMID: 24860556
manuka honey; methylglyoxal; drug efflux system; multidrug resistance; Pseudomonas aeruginosa
3.  Cooperation of the multidrug efflux pump and lipopolysaccharides in the intrinsic antibiotic resistance of Salmonella enterica serovar Typhimurium 
Objectives
In Gram-negative bacteria, drug susceptibility is associated with multidrug efflux systems and an outer membrane (OM) barrier. Previous studies revealed that Salmonella enterica serovar Typhimurium has 10 functional drug efflux pumps. Among them, AcrB is a major factor to maintain the intrinsic drug resistance in this organism. The lipopolysaccharide (LPS) content of OM is also important for resistance to lipophilic drugs; however, the interplay between the multidrug efflux pump and LPS in the intrinsic antibiotic resistance of Salmonella remains to be studied in detail. The aim of this study was to investigate the relationship between AcrB and LPS in the intrinsic drug resistance of this organism.
Methods
The genes encoding LPS core biosynthetic proteins and AcrB were disrupted from the wild-type S. enterica strain ATCC 14028s. The plasmid carrying acrB was transformed into these mutants and then the drug susceptibilities of the mutants and transformants were determined.
Results
Our results showed that the levels of Salmonella intrinsic antibiotic resistance were decreased when the length and branches of core oligosaccharide were lost. Furthermore, the deletion of acrB reduced multidrug resistance of all LPS mutants and AcrB production from the plasmid complemented this phenotype. However, AcrB production could not completely compensate for LPS function in intrinsic resistance.
Conclusions
Both pump inactivation and shortened LPS enhanced drug susceptibility, although the maximum susceptibility was achieved when the two were combined. Hence, these results indicated that the multidrug efflux system and OM barrier are both essential for maintaining intrinsic antibiotic resistance in Salmonella.
doi:10.1093/jac/dks528
PMCID: PMC3625434  PMID: 23378414
AcrB; LPS; multidrug resistance
4.  Impact of Hfq on the Intrinsic Drug Resistance of Salmonella Enterica Serovar Typhimurium 
Salmonella enterica is an important enteric pathogen, and its various serovars cause both systemic and intestinal diseases in humans and domestic animals. The emergence of multidrug-resistant strains of Salmonella, leading to increased morbidity and mortality, has further complicated its management. Hfq is an RNA chaperon that mediates the binding of small RNAs to mRNA and assists in post-transcriptional gene regulation in bacteria. Although Hfq is related to important phenotypes including virulence in Salmonella, its role in the drug resistance of this organism is unknown. The aim of this study was to investigate the role of Hfq in intrinsic drug resistance of S. enterica serovar Typhimurium. hfq Mutant was susceptible to acriflavine. Although there is a relationship between the production of the AcrB multidrug efflux pump and Hfq in Escherichia coli, the deletion of the drug efflux acrB did not impair the effect of hfq deletion on Salmonella susceptibility. In contrast, the deletion of another drug efflux gene, smvA, impaired the effect of hfq deletion on acriflavine susceptibility. These results indicate that Hfq regulates the intrinsic drug resistance, and it may influence drug susceptibility by regulating SmvA in Salmonella.
doi:10.3389/fmicb.2012.00205
PMCID: PMC3366549  PMID: 22675323
drug efflux system; drug resistance; Hfq, Salmonella; small RNA
5.  Effect of NlpE Overproduction on Multidrug Resistance in Escherichia coli▿  
NlpE, an outer membrane lipoprotein, functions during envelope stress responses in Gram-negative bacteria. In this study, we report that overproduction of NlpE increases multidrug and copper resistance through activation of the genes encoding the AcrD and MdtABC multidrug efflux pumps in Escherichia coli.
doi:10.1128/AAC.01677-09
PMCID: PMC2863614  PMID: 20211889
6.  H-NS Modulates Multidrug Resistance of Salmonella enterica Serovar Typhimurium by Repressing Multidrug Efflux Genes acrEF▿  
Screening of Salmonella mutants for the ability to increase β-lactam resistance has led to the identification of a mutation in hns, which codes for the histone-like nucleoid structuring protein (H-NS). In this study, we report that H-NS modulates multidrug resistance through repression of the genes that encode the AcrEF multidrug efflux pump in Salmonella enterica serovar Typhimurium.
doi:10.1128/AAC.00371-09
PMCID: PMC2715579  PMID: 19506059
7.  Revisiting the relationship between tumour volume and diameter in advanced NSCLC patients: An exercise to maximize the utility of each measure to assess response to therapy 
Clinical radiology  2014;69(8):841-848.
AIM
To revisit the presumed relationship between tumour diameter and volume in advanced non-small-cell lung cancer (NSCLC) patients, and determine whether the measured volume using volume-analysis software and its proportional changes during therapy matches with the calculated volume obtained from the presumed relationship and results in concordant response assessment.
MATERIALS AND METHODS
Twenty-three patients with stage IIIB/IV NSCLC with a total of 53 measurable lung lesions, treated in a phase II trial of erlotinib, were studied with institutional review board approval. Tumour volume and diameter were measured at baseline and at the first follow-up computed tomography (CT) examination using volume-analysis software. Using the measured diameter (2r) and the equation, calculated volume was obtained as (4/3) πr3 at baseline and at the follow-up. Percent volume change was obtained by comparing to baseline for measured and calculated volumes, and response assessment was assigned.
RESULTS
The measured volume was significantly smaller than the calculated volume at baseline (median 11,488.9 mm3 versus 17,148.6 mm3; p < 0.0001), with a concordance correlation coefficient (CCC) of 0.7022. At follow-up, the measured volume was once again significantly smaller than the calculated volume (median 6573.5 mm3 versus 9198.1 mm3; p = 0.0022), with a CCC of 0.7408. Response assessment by calculated versus measured volume changes had only moderate agreement (weighted κ = 0.545), with discordant assessment results in 20% (8/40) of lesions.
CONCLUSION
Calculated volume based on the presumed relationship significantly differed from the measured volume in advanced NSCLC patients, with only moderate concordance in response assessment, indicating the limitations of presumed relationship.
doi:10.1016/j.crad.2014.03.020
PMCID: PMC4105980  PMID: 24857677
8.  Relationship between environment factors and the number of outpatient visits at a clinic for nonallergic rhinitis in Japan, extracted from electronic medical records 
Background
The objective of this study was to evaluate the influence of the environmental factors (meteorological factors, air pollutant levels, etc.) on the number of clinic consultations for nonallergic rhinitis (NAR).
Methods
Among the 9056 outpatients visiting a general internal medicine clinic in Japan between August 2012 and the end of July 2013 (counting return visitors as multiple cases), the total daily number of first visits for NAR plus the number of extraordinary visits by patients with NAR for acute exacerbation of the disease was investigated using electronic medical records and analyzed.
Results
Major parameters with significant Spearman’s correlation coefficients and significant correlation coefficients also in the multiple regression analysis were the mean vapor pressure (coefficient of determination 27.3 %) throughout the year, mean vapor pressure (58.4 %), mean temperature (44.4 %), maximum 10-min precipitation (12.0 %) only during the autumn-winter period, and temperature difference (13.3 %) only during the spring-summer period.
Conclusions
The mean vapor pressure is the most important environmental factor associated with acute exacerbation of NAR.
doi:10.1186/s40001-015-0151-3
PMCID: PMC4502595  PMID: 26152217
Nonallergic rhinitis; Electronic medical records; Weather; Environment; Biometeorology
9.  Intrathymic cyst: clinical and radiological features in surgically resected cases 
Clinical radiology  2014;69(7):732-738.
AIM
To investigate radiological and clinical characteristics of pathologically proven cases of intrathymic cysts.
MATERIALS AND METHODS
The study population consisted of 18 patients (five males, 13 females; median age 56 years) with pathologically confirmed intrathymic cysts who underwent thymectomy and had preoperative chest computed tomography (CT) available for review. The patient demographics, clinical presentation, and preoperative radiological diagnoses were reviewed. CT images were evaluated for shape, contour, location of the cysts and the presence of adjacent thymic tissue, mass effect, calcifications, and septa. The size and CT attenuations of the cysts were measured.
RESULTS
The most common CT features of intrathymic cysts included oval shape (9/18; 50%), smooth contour (12/18; 67%), midline location (11/18; 61%), the absence of visible adjacent thymic tissue (12/18; 67%), and the absence of calcification (16/18; 89%). The mean longest diameter and the longest perpendicular diameter were 25 mm (range 17–49 mm) and 19 mm (range 10–44 mm), respectively. The mean CT attenuation was 38 HU (range 6–62 HU) on contrast-enhanced CT, and was 45 HU (range 26–64 HU) on unenhanced CT (p=0.41). The CT attenuation was >20 HU in 15 of 18 patients (83%). Preoperative radiological diagnosis included thymoma in 11 patients.
CONCLUSION
In surgically removed, pathologically proven cases of intrathymic cyst, the CT attenuation was >20 HU in most cases, leading to the preoperative diagnosis of thymoma. Awareness of the spectrum of imaging findings of the entity is essential to improve the diagnostic accuracy and patient management.
doi:10.1016/j.crad.2014.03.002
PMCID: PMC4068340  PMID: 24824976
10.  Tetraploid Embryonic Stem Cells Maintain Pluripotency and Differentiation Potency into Three Germ Layers 
PLoS ONE  2015;10(6):e0130585.
Polyploid amphibians and fishes occur naturally in nature, while polyploid mammals do not. For example, tetraploid mouse embryos normally develop into blastocysts, but exhibit abnormalities and die soon after implantation. Thus, polyploidization is thought to be harmful during early mammalian development. However, the mechanisms through which polyploidization disrupts development are still poorly understood. In this study, we aimed to elucidate how genome duplication affects early mammalian development. To this end, we established tetraploid embryonic stem cells (TESCs) produced from the inner cell masses of tetraploid blastocysts using electrofusion of two-cell embryos in mice and studied the developmental potential of TESCs. We demonstrated that TESCs possessed essential pluripotency and differentiation potency to form teratomas, which differentiated into the three germ layers, including diploid embryonic stem cells. TESCs also contributed to the inner cell masses in aggregated chimeric blastocysts, despite the observation that tetraploid embryos fail in normal development soon after implantation in mice. In TESCs, stability after several passages, colony morphology, and alkaline phosphatase activity were similar to those of diploid ESCs. TESCs also exhibited sufficient expression and localization of pluripotent markers and retained the normal epigenetic status of relevant reprogramming factors. TESCs proliferated at a slower rate than ESCs, indicating that the difference in genomic dosage was responsible for the different growth rates. Thus, our findings suggested that mouse ESCs maintained intrinsic pluripotency and differentiation potential despite tetraploidization, providing insights into our understanding of developmental elimination in polyploid mammals.
doi:10.1371/journal.pone.0130585
PMCID: PMC4474668  PMID: 26091100
11.  Particle Simulation of Oxidation Induced Band 3 Clustering in Human Erythrocytes 
PLoS Computational Biology  2015;11(6):e1004210.
Oxidative stress mediated clustering of membrane protein band 3 plays an essential role in the clearance of damaged and aged red blood cells (RBCs) from the circulation. While a number of previous experimental studies have observed changes in band 3 distribution after oxidative treatment, the details of how these clusters are formed and how their properties change under different conditions have remained poorly understood. To address these issues, a framework that enables the simultaneous monitoring of the temporal and spatial changes following oxidation is needed. In this study, we established a novel simulation strategy that incorporates deterministic and stochastic reactions with particle reaction-diffusion processes, to model band 3 cluster formation at single molecule resolution. By integrating a kinetic model of RBC antioxidant metabolism with a model of band 3 diffusion, we developed a model that reproduces the time-dependent changes of glutathione and clustered band 3 levels, as well as band 3 distribution during oxidative treatment, observed in prior studies. We predicted that cluster formation is largely dependent on fast reverse reaction rates, strong affinity between clustering molecules, and irreversible hemichrome binding. We further predicted that under repeated oxidative perturbations, clusters tended to progressively grow and shift towards an irreversible state. Application of our model to simulate oxidation in RBCs with cytoskeletal deficiency also suggested that oxidation leads to more enhanced clustering compared to healthy RBCs. Taken together, our model enables the prediction of band 3 spatio-temporal profiles under various situations, thus providing valuable insights to potentially aid understanding mechanisms for removing senescent and premature RBCs.
Author Summary
In order to maintain a steady internal environment, our bodies must be able to specifically recognize old and damaged red blood cells (RBCs), and remove them from the circulation in a timely manner. Clusters of membrane protein band 3, which form in response to elevated oxidative damage, serve as essential molecular markers that initiate this cell removal process. However, little is known about the details of how these clusters are formed and how their properties change under different conditions. To understand these mechanisms in detail, we developed a computational model that enables the prediction of the time course profiles of metabolic intermediates, as well as the visualization of the resulting band 3 distribution during oxidative treatment. Our model predictions were in good agreement with previous published experimental data, and provided predictive insights on the key factors of cluster formation. Furthermore, simulation experiments of the effects of multiple oxidative pulses and cytoskeletal defect using the model also suggested that clustering is enhanced under such conditions. Analyses using our model can provide hypotheses and suggest experiments to aid the understanding of the physiology of anemia-associated RBC disorders, and optimization of quality control of RBCs in stored blood.
doi:10.1371/journal.pcbi.1004210
PMCID: PMC4457884  PMID: 26046580
12.  Tyrosine levels are associated with insulin resistance in patients with nonalcoholic fatty liver disease 
Objective
Amino acid imbalance is often found in patients with cirrhosis, and this imbalance is associated with insulin resistance. However, the mechanism underlying the relationship between amino acid imbalance and insulin resistance remains unclear. We evaluated serum amino acid concentrations in patients with nonalcoholic fatty liver disease to determine if any of the levels of amino acids were associated with the biochemical markers and fibrosis stage of nonalcoholic steatohepatitis (NASH).
Methods
In 137 patients with nonalcoholic fatty liver disease who underwent liver biopsy, plasma levels of branched-chain amino acid (BCAA), tyrosine (Tyr), and the BCAA-to-Tyr ratio values were determined using mass spectroscopy. These values were then assessed for associations with fibrosis stage, anthropometric markers (age, sex, and body mass index), biochemical markers (alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase, albumin, platelet count, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and glycosylated hemoglobin), and relevant disease-specific biomarkers (homeostasis model assessment of insulin resistance [HOMA-IR], serum iron, ferritin, leptin, adiponectin, high-sensitivity C-reactive protein, and hyaluronic acid).
Results
Serum albumin levels, plasma BCAA levels, and BCAA-to-Tyr ratio values were negatively associated with the fibrosis stage. In contrast, Tyr levels increased with increasing fibrotic staging. Tyr levels were also correlated with HOMA-IR results.
Conclusion
Plasma BCAA levels in patients with NASH decreased with increasing liver fibrosis, while Tyr levels increased with increasing fibrotic stage. These results suggest that amino acid imbalance and insulin resistance are intimately involved in a complex pathogenic mechanism for NASH.
doi:10.2147/HMER.S79100
PMCID: PMC4461125  PMID: 26082668
nonalcoholic steatohepatitis; amino acid imbalance; branched-chain amino acids; branched-chain amino acid-to-tyrosine ratio (BTR)
13.  Clinical significance of the muscle-retracting sign during colorectal endoscopic submucosal dissection 
Endoscopy International Open  2015;3(3):E246-E251.
Background and study aims: During colorectal endoscopic submucosal dissection (ESD), the feature of a muscle layer being pulled toward a neoplastic tumor is sometimes detected. We call this feature the muscle-retracting sign (MR sign). The aim of this study was to evaluate whether the MR sign is associated with particular types of neoplastic lesions and whether it has any clinical significance for ESD sessions.
Patients and methods: A total of 329 patients underwent ESD for 357 colorectal neoplasms. The frequency of positivity for the MR sign was evaluated in different morphologic and histopathologic types of neoplasm. The success rate of complete resection and the incidence of complications were also evaluated according to whether lesions were positive or negative for the MR sign.
Results: The rates of positivity for the MR sign in the various lesion types were as follows: laterally spreading tumor – granular nodular mixed type (LST-G-M), 9.6 %; laterally spreading tumor – granular homogeneous type (LST-G-H) and laterally spreading tumor – nongranular type (LST-NG), 0 %; sessile type, 41.2 %. The resection rate was 100 % (329 /329) in lesions negative for the MR sign; however, it was 64.3 % (18 /28) in lesions positive for the MR sign, which was significantly lower (P < 0.001).
Conclusions: The MR sign was present only in some protruding lesions, and more importantly, it was associated with a high risk of incomplete tumor removal by ESD. Our data indicate that lesions positive for the MR sign lesions should be dissected with great caution; alternatively, based on the features of the individual case, a switch to surgery should be considered for the benefit of the patient.
doi:10.1055/s-0034-1391665
PMCID: PMC4486035  PMID: 26171438
14.  Thymic measurements in pathologically proven normal thymus and thymic hyperplasia: Intra- and interobserver variability 
Academic radiology  2014;21(6):733-742.
Objective:
Determine the intra- and interobserver variability of thymic measurements on computed tomography (CT) in patients with pathological diagnosis of thymic hyperplasia or normal thymus.
Materials and Methods:
Thirty-three patients with pathological diagnosis of thymic hyperplasia (n=25) or normal thymus (n=8) who had identifiable thymus gland on CT were retrospectively studied. Two radiologists independently measured thymic size and CT attenuation. Concordance correlation coefficients (CCCs) and Bland-Altman plots were used to assess intra- and interobserver agreements.
Results:
The intra- and interobserver agreements of thymic diameters and the lobe length were moderate, with CCCs ranging 0.73-0.89 and 0.72-0.81, respectively. Higher agreement was noted among patients whose measurements were performed on the same CT image in two independent measurements, with intraobserver CCC ≥0.95 for diameters and length. After providing readers with an instruction for consistent selection of CT image for measurements, the intra- and interobserver agreement improved, resulting in CCCs ranging 0.81-0.92 and 0.77-0.85 for diameters and length, respectively. Thymic lobe thickness had the least agreement. CT attenuation measurements were highly reproducible, with CCCs ranging 0.88-0.97. In patients with thymic CT attenuation >30HU, the attenuation measurements were more reproducible with narrower 95% limits of agreement.
Conclusion:
Thymic size measurements had moderate to high intra- and interobserver agreement, when the instruction for consistent selection of images were provided to the readers. CT attenuation was highly reproducible, with higher reproducibility for thymic glands with >30HU. Awareness of thymic measurement variability is necessary when interpreting measured values of normal thymus and thymic pathology on CT.
doi:10.1016/j.acra.2014.02.006
PMCID: PMC4022310  PMID: 24809315
Thymus; computed tomography; measurement; intraobserver variability; interobserver variability
15.  Pancreatectomy and splenectomy for a splenic aneurysm associated with segmental arterial mediolysis 
Segmental arterial mediolysis (SAM) is characterized by intra-abdominal, retroperitoneal bleeding or bowel ischemia, and the etiology is unknown. A 44-year-old man complaining of abdominal pain was admitted to our hospital. He had been admitted for a left renal infarction three days earlier and had a past medical history of cerebral aneurysm with spontaneous remission. The ruptured site of the splenic arterial aneurysm was clear via a celiac angiography, and we treated it using trans-arterial embolization. Unfortunately, the aneurysm reruptured after two weeks, and we successfully treated it with distal pancreatomy and splenectomy. We recommended a close follow-up and prompt radiological or surgical intervention because SAM can enlarge rapidly and rupture.
doi:10.4240/wjgs.v7.i5.78
PMCID: PMC4438451  PMID: 26015853
Re-rupture; Segmental arterial mediolysis; Trans-arterial embolization; Spontaneous remission; Splenic artery aneurysm
16.  Inflammatory myopathy with anti-signal recognition particle antibodies: case series of 100 patients 
Background
Anti-signal recognition particle (SRP) antibodies are used as serological markers of necrotizing myopathy, which is characterized by many necrotic and regenerative muscle fibers without or with minimal inflammatory cell infiltration. The clinical spectrum associated with anti-SRP antibodies seems to be broad.
Objective
To describe the clinical characteristics, autoantibodies status, and neurological outcome associated with anti-SRP antibody.
Methods
We studied clinical and laboratory findings of 100 patients with inflammatory myopathy and anti-SRP antibodies. Anti-SRP antibodies in serum were detected by the presence of 7S RNA using RNA immunoprecipitation. In addition, enzyme-linked immunosorbent assays (ELISAs) using a 54-kD protein of SRP (SRP54) and 3-hydroxyl-3-methylglutatyl-coenzyme A reductase (HMGCR) were also conducted.
Results
The mean onset age of the 61 female and 39 male patients was 51 years (range 4–82 years); duration ≥ 12 months before diagnosis was seen in 23 cases. All patients presented limbs weakness; 63 had severe weakness, 70 neck weakness, 41 dysphagia, and 66 muscle atrophy. Extramuscular symptoms and associated disorders were infrequent. Creatine kinase levels were mostly more than 1000 IU/L. Histological diagnosis showed 84 patients had necrotizing myopathy, and apparent cell infiltration was observed in 16 patients. Anti-SRP54 antibodies were undetectable in 18 serum samples with autoantibodies to 7S RNA. Anti-HMGCR antibodies were positive in 3 patients without the statin treatment, however, were negative in 5 patients with statin-exposure at disease onset. All but 3 patients were treated by corticosteroids and 62 (77 %) of these 81 patients required additional immunotherapy. After 2-years treatment, 22 (27 %) of these 81 patients had poor neurological outcomes with modified Rankin scale scores of 3–5. Multivariate analysis revealed that pediatric disease onset was associated with the poor outcomes.
Conclusion
Anti-SRP antibodies are associated with different clinical courses and histological presentations.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-015-0277-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-015-0277-y
PMCID: PMC4440264  PMID: 25963141
Signal recognition particle; Autoantibodies; Necrotizing myopathy; RNA immunoprecipitation; ELISA; Outcome
17.  Pneumothorax triggered by the combination of gefitinib and amrubicin and treated with endobronchial silicone spigots 
Pneumothorax is a rare complication in cancer chemotherapy. We report a case in which a male patient with advanced non-small cell lung cancer (NSCLC) developed repetitive pneumothorax after receiving a combination of the chemotherapeutic drugs gefitinib and amrubicin (GEF + AMR). Both episodes of pneumothorax occurred on the 3rd day of GEF + AMR administration. Tube thoracostomy was performed, but pulmonary air leaks persisted in the second pneumothorax. Whereas surgical intervention was not applicable because of poor respiratory reserve, the chest tube was successfully removed by endoscopic occlusion of bronchopleural fistula with endobronchial Watanabe spigots (EWSs), a type of silicone bronchial blocker.
doi:10.1016/j.rmcr.2015.02.007
PMCID: PMC4501458
Pneumothorax; Gefitinib; Amrubicin; Endoscopic bronchial occlusion; EWS
18.  10% Tumor Diameter Shrinkage on the First Follow-Up Computed Tomography Predicts Clinical Outcome in Patients With Advanced Renal Cell Carcinoma Treated With Angiogenesis Inhibitors: A Follow-Up Validation Study 
The Oncologist  2014;19(5):507-514.
Ten percent tumor shrinkage is validated as a reliable early predictor of outcome in metastatic renal cell carcinoma patients receiving vascular endothelial growth factor-targeted therapies. Given the utility of this response indicator in multiple reports, 10% tumor shrinkage may provide a simple and practical aid for therapeutic decision making if used in clinical trials and practice with a prospective evaluation.
Background.
Vascular endothelial growth factor (VEGF)-targeted agents are standard therapies for metastatic renal cell carcinoma (mRCC), associated with variable tumor shrinkage. Response Evaluation Criteria in Solid Tumors (RECIST) is of limited utility in this setting, and other imaging changes are sought to reliably predict outcome early. We aim to validate 10% tumor shrinkage as the best early indicator of outcome.
Methods.
In this institutional review board-approved, Health Insurance Portability and Accountability Act-compliant study, 66 mRCC patients with 165 lesions on clinical trials of VEGF-targeted agents underwent thoracic and abdominal computed tomography at baseline and at first follow-up after therapy. Measurements were performed according to RECIST and tumor shrinkage of ≥10% decrease in sum of the longest diameter (−10%SLD). Correlation with time-to-treatment failure (TTF) and overall survival (OS) were compared and stratified by response to the radiologic criteria. Receiver-operating characteristics (ROC) analysis yielded the optimal threshold change in SLD, defining patients with prolonged survival.
Results.
More than −10%SLD significantly differentiated responders from nonresponders (median TTF 8.4 vs. 4.1 months, p = .001), whereas partial response by RECIST did not (median TTF 6.9 vs. 5.5 months in responders vs. nonresponders, p = .34). −10%SLD was also significantly predictive of OS (median OS 35.1 vs. 15.0 months in responders vs. nonresponders, p = .003). ROC curve analysis yielded −9.3% in SLD as the optimal threshold for response/no response.
Conclusion.
Ten percent tumor shrinkage is validated as a reliable early predictor of outcome in mRCC patients receiving VEGF-targeted therapies and may provide a practical measure to guide therapeutic decisions.
doi:10.1634/theoncologist.2013-0391
PMCID: PMC4012965  PMID: 24755461
Renal cell carcinoma; VEGF-targeted therapy; RECIST 1.0; Choi; Tumor shrinkage
19.  GNE myopathy: new name and new mutation nomenclature 
Neuromuscular disorders : NMD  2014;24(5):387-389.
doi:10.1016/j.nmd.2014.03.004
PMCID: PMC4015343  PMID: 24685570
Distal myopathy with rimmed vacuoles DMRV); hereditary inclusion body myopathy (HIBM); Inclusion Body Myopathy 2 (IBM2); Nonaka myopathy; sialic acid; UDP-GlcNAc 2-epimersa/ManNAc kinase
20.  GNE Myopathy: current update and future therapy 
GNE myopathy is an autosomal recessive muscle disease due to biallelic mutations in GNE, a gene encoding for a single protein with key enzymatic activities in sialic acid biosynthetic pathway. The diagnosis should be considered primarily in patients presenting with distal weakness (foot drop) in early adulthood (other onset symptoms are possible too). The disease slowly progresses to involve other lower and upper extremities’ muscles, with marked sparing of the quadriceps. Characteristic findings found in biopsies of affected muscles include “rimmed” (autophagic) vacuoles, aggregation of various proteins, and fiber size variation. The diagnosis is confirmed by sequencing of the GNE gene. Note that we use a new mutation nomenclature based upon the longest transcript (GenBank: NM_001128227), which encodes a 31-amino-acid longer protein than the originally described one (GenBank: NM_005476), which has been used previously in most papers. Given the pathophysiology of the disease, recent clinical trials have evaluated the use of sialic acid or ManNAc (a precursor of sialic acid) in patients with GNE myopathy as well as early gene therapy trials. Now that therapies are under investigation, it is critical that a timely and accurate diagnosis is made in patients with GNE myopathy.
doi:10.1136/jnnp-2013-307051
PMCID: PMC4394625  PMID: 25002140
GNE myopathy; hereditary inclusion body myopathy; distal myopathy with rimmed vacuoles; sialic acid; N-acetylmannosamine (ManNAc)
21.  Functional chimeras of flagellar stator proteins between E. coli MotB and Vibrio PomB at the periplasmic region in Vibrio or E. coli 
MicrobiologyOpen  2015;4(2):323-331.
The bacterial flagellar motor has a stator and a rotor. The stator is composed of two membrane proteins, MotA and MotB in Escherichia coli and PomA and PomB in Vibrio alginolyticus. The Vibrio motor has a unique structure, the T ring, which is composed of MotX and MotY. Based on the structural information of PomB and MotB, we constructed three chimeric proteins between PomB and MotB, named PotB91, PotB129, and PotB138, with various chimeric junctions. When those chimeric proteins were produced with PomA in a ΔmotAB strain of E. coli or in ΔpomAB and ΔpomAB ΔmotX strains of Vibrio, all chimeras were functional in E. coli or Vibrio, either with or without the T ring, although the motilities were very weak in E. coli. Furthermore, we could isolate some suppressors in E. coli and identified the mutation sites on PomA or the chimeric B subunit. The weak function of chimeric PotBs in E. coli is derived mainly from the defect in the rotational switching of the flagellar motor. In addition, comparing the motilities of chimera strains in ΔpomAB, PotB138 had the highest motility. The difference between the origin of the α1 and α2 helices, E. coli MotB or Vibro PomB, seems to be important for motility in E. coli and especially in Vibrio.
doi:10.1002/mbo3.240
PMCID: PMC4398512  PMID: 25630862
Basal body; flagellar motor; T ring; V. alginolyticus
22.  Staging systems for hepatocellular carcinoma: Current status and future perspectives 
World Journal of Hepatology  2015;7(3):406-424.
Hepatocellular carcinoma (HCC) is a major health concern worldwide and the third cause of cancer-related death. Despite advances in treatment as well as careful surveillance programs, the mortality rates in most countries are very high. In contrast to other cancers, the prognosis and treatment of HCC depend on the tumor burden in addition to patient’s underlying liver disease and liver functional reserve. Moreover, there is considerable geographic and institutional variation in both risk factors attributable to the underlying liver diseases and the management of HCC. Therefore, although many staging and/or scoring systems have been proposed, there is currently no globally accepted system for HCC due to the extreme heterogeneity of the disease. The aim of this review is to focus on currently available staging systems as well as those newly reported in the literatures since 2012. Moreover, we describe problems with currently available staging systems and attempts to modify and/or add variables to existing staging systems.
doi:10.4254/wjh.v7.i3.406
PMCID: PMC4381166  PMID: 25848467
Hepatocellular carcinoma; Staging system; Scoring system; Prognosis
23.  Imaging Characteristics of Pathologically Proven Thymic Hyperplasia: Identifying Features That Can Differentiate True From Lymphoid Hyperplasia 
OBJECTIVE
The purpose of this article is to investigate the imaging characteristics of pathologically proven thymic hyperplasia and to identify features that can differentiate true hyperplasia from lymphoid hyperplasia.
MATERIALS AND METHODS
Thirty-one patients (nine men and 22 women; age range, 20–68 years) with pathologically confirmed thymic hyperplasia (18 true and 13 lymphoid) who underwent preoperative CT (n = 27), PET/CT (n = 5), or MRI (n = 6) were studied. The length and thickness of each thymic lobe and the transverse and anterior-posterior diameters and attenuation of the thymus were measured on CT. Thymic morphologic features and heterogeneity on CT and chemical shift on MRI were evaluated. Maximum standardized uptake values were measured on PET. Imaging features between true and lymphoid hyperplasia were compared.
RESULTS
No significant differences were observed between true and lymphoid hyperplasia in terms of thymic length, thickness, diameters, morphologic features, and other qualitative features (p > 0.16). The length, thickness, and diameters of thymic hyperplasia were significantly larger than the mean values of normal glands in the corresponding age group (p < 0.001). CT attenuation of lymphoid hyperplasia was significantly higher than that of true hyperplasia among 15 patients with contrast-enhanced CT (median, 47.9 vs 31.4 HU; Wilcoxon p = 0.03). The receiver operating characteristic analysis yielded greater than 41.2 HU as the optimal threshold for differentiating lymphoid hyperplasia from true hyperplasia, with 83% sensitivity and 89% specificity. A decrease of signal intensity on opposed-phase images was present in all four cases with in- and opposed-phase imaging. The mean maximum standardized uptake value was 2.66.
CONCLUSION
CT attenuation of the thymus was significantly higher in lymphoid hyperplasia than in true hyperplasia, with an optimal threshold of greater than 41.2 HU in this cohort of patients with pathologically confirmed thymic hyperplasia.
doi:10.2214/AJR.13.11210
PMCID: PMC4020512  PMID: 24555583
CT; CT attenuation; lymphoid hyperplasia; thymic hyperplasia; thymus
24.  Intra- and Interobserver Variability in CT Size and Attenuation Measurements in Renal Cell Carcinoma Patients on Anti-Angiogenic Therapy: Implications for Alternative Response Criteria 
Cancer  2013;120(5):711-721.
Background
Alternative response criteria have been proposed in patients with metastatic Renal Cell Carcinoma (mRCC) on Vascular Endothelial Growth Factor (VEGF)-targeted therapy, including 10% tumor shrinkage as an indicator of response/outcome. However, intraobserver and interobserver measurement variability have not been defined in this setting. We aim to determine intra- and interobserver agreement of Computed Tomography (CT) size and attenuation measurements, to establish reproducible response indicators.
Methods
Seventy-one mRCC patients with 179 target lesions were enrolled in Phase II and III trials of VEGF-targeted therapies and retrospectively studied with institutional review board approval. Two radiologists independently measured long axis diameter and mean attenuation of targets on baseline and follow-up CT. Concordance correlation coefficients (CCCs) and Bland-Altman plots were used to assess intra- and interobserver agreement.
Results
High CCCs (0.8602–0.9984) were observed in all types of measurements. The 95% limits of agreement for percent change of the sum longest diameter was (−7.30%, 7.86%) for intraobserver variability, indicating 10% tumor shrinkage represents true change in tumor size when measured by one observer. The 95% limits of interobserver variability were (−16.3%, 15.4%). In multivariate analysis, liver location significantly contributed to interobserver variability (p=0.048). The 95% limits of intraobserver agreement for percent change in CT attenuation were (−18.34%, 16.7%).
Conclusion
In mRCC patients treated with VEGF-inhibitors, 10% tumor shrinkage is a reproducible radiologic response indicator when baseline and follow-up studies are measured by a single radiologist. Lesion location contributes significantly to measurement variability and should be considered when selecting target lesions.
doi:10.1002/cncr.28493
PMCID: PMC4031652  PMID: 24264883
Renal Cell Carcinoma; Computed Tomography; RECIST; Tumor Shrinkage; CT Attenuation; Intraobserver Variability; Interobserver Variability
25.  Sensitive and Specific PCR Systems for Detection of Both Chinese and Japanese Severe Fever with Thrombocytopenia Syndrome Virus Strains and Prediction of Patient Survival Based on Viral Load 
Journal of Clinical Microbiology  2014;52(9):3325-3333.
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with a high case fatality risk and is caused by the SFTS virus (SFTSV). A retrospective study conducted after the first identification of an SFTS patient in Japan revealed that SFTS is endemic to the region, and the virus exists indigenously in Japan. Since the nucleotide sequence of Japanese SFTSV strains contains considerable differences compared with that of Chinese strains, there is an urgent need to establish a sensitive and specific method capable of detecting the Chinese and Japanese strains of SFTSV. A conventional one-step reverse transcription-PCR (RT-PCR) (cvPCR) method and a quantitative one-step RT-PCR (qPCR) method were developed to detect the SFTSV genome. Both cvPCR and qPCR detected a Chinese SFTSV strain. Forty-one of 108 Japanese patients suspected of having SFTS showed a positive reaction by cvPCR. The results from the samples of 108 Japanese patients determined by the qPCR method were in almost complete agreement with those determined by cvPCR. The analyses of the viral copy number level in the patient blood samples at the acute phase determined by qPCR in association with the patient outcome confirmed that the SFTSV RNA load in the blood of the nonsurviving patients was significantly higher than that of the surviving patients. Therefore, the cvPCR and qPCR methods developed in this study can provide a powerful means for diagnosing SFTS. In addition, the detection of the SFTSV genome level by qPCR in the blood of the patients at the acute phase may serve as an indicator to predict the outcome of SFTS.
doi:10.1128/JCM.00742-14
PMCID: PMC4313158  PMID: 24989600

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