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1.  Unplanned Reoperation within 30 Days of Fusion Surgery for Spinal Deformity 
PLoS ONE  2014;9(3):e87172.
No recent studies have analyzed the rates of or reasons for unanticipated revision surgery within 30 days of primary surgery in spinal deformity patients. Our aim was to examine the incidence, characteristics, reasons, and risk factors for unplanned revision surgery in spinal deformity patients treated at one institution. All patients with a diagnosis of spinal deformity presenting for primary instrumented spinal fusion at a single institution from 1998 to 2012 were reviewed. All unplanned reoperations performed within 30 days after primary surgery were analyzed in terms of demographics, surgical data, and complications. Statistical analyses were performed to obtain correlations and risk factors for anticipated revision. Of 2758 patients [aged 16.07 years (range, 2–71), 69.8% female] who underwent spinal fusion surgery, 59 (2.1%) required reoperation within 30 days after primary surgery. The length of follow up for each patient was more than 30 days. Of those that required reoperation, 87.0% had posterior surgery only, 5.7% had anterior surgery, and 7.3% underwent an anteroposterior approach. The reasons for reoperation included implant failure (n = 20), wound infection (n = 12), neurologic deficit (n = 9), pulmonary complications (n = 17), and coronal plane imbalance (n = 1). The risk factors for reoperation were age, diagnosis, and surgical procedure with osteotomy.
doi:10.1371/journal.pone.0087172
PMCID: PMC3942308  PMID: 24595145
2.  Estimating Tree Height-Diameter Models with the Bayesian Method 
The Scientific World Journal  2014;2014:683691.
Six candidate height-diameter models were used to analyze the height-diameter relationships. The common methods for estimating the height-diameter models have taken the classical (frequentist) approach based on the frequency interpretation of probability, for example, the nonlinear least squares method (NLS) and the maximum likelihood method (ML). The Bayesian method has an exclusive advantage compared with classical method that the parameters to be estimated are regarded as random variables. In this study, the classical and Bayesian methods were used to estimate six height-diameter models, respectively. Both the classical method and Bayesian method showed that the Weibull model was the “best” model using data1. In addition, based on the Weibull model, data2 was used for comparing Bayesian method with informative priors with uninformative priors and classical method. The results showed that the improvement in prediction accuracy with Bayesian method led to narrower confidence bands of predicted value in comparison to that for the classical method, and the credible bands of parameters with informative priors were also narrower than uninformative priors and classical method. The estimated posterior distributions for parameters can be set as new priors in estimating the parameters using data2.
doi:10.1155/2014/683691
PMCID: PMC3953559
3.  Posterior hemivertebra resection with bisegmental fusion for congenital scoliosis: more than 3 year outcomes and analysis of unanticipated surgeries 
European Spine Journal  2012;22(2):387-393.
Purpose
Until now there have been many reports on hemivertebra resection. But there were no large series on the posterior hemivertebra resection with bisegmental fusion. This is a retrospective study to evaluate the surgical outcomes of posterior hemivertebra resection only with bisegmental fusion for congenital scoliosis caused by fully segmented non-incarcerated hemivertebra.
Methods
In our study, 36 consecutive cases (19 males, 17 females) diagnosed with congenital scoliosis, resulting from fully segmented non-incarcerated hemivertebra, treated by posterior hemivertebra resection with bisegmental fusion were investigated retrospectively, with at least a 3 year follow-up period (36–106 months).
Results
The total number of resected hemivertebra was 36. Mean operation time was 188.6 min with average blood loss of 364.2 ml. The segmental scoliosis was corrected from 36.6° to 5.1° with a correction rate of 86.1 %, and segmental kyphosis(difference to normal segmental alignment) from 21.2° to 5.8° at the latest follow-up. The correction rate of the compensatory cranial and caudal curve is 76.4 and 75.1 %. Unanticipated surgeries were performed on eight patients, including one delayed wound healing, two pedicle fractures, one progressive deformity and four implants removals.
Conclusions
Posterior hemivertebra resection with bisegmental fusion allows for early intervention in very young children. Excellent correction can be obtained while the growth potential of the unaffected spine could be preserved well. However, it is not indicated for the hemivertebra between L5 and S1. The most common complication of this procedure is implant failure. Furthermore, in the very young children we noted that although solid fusion could be observed in the fusion level, implants migration may still happen during the time of adolescence, when the height of the body developed rapidly. So a close follow-up is necessary.
doi:10.1007/s00586-012-2577-4
PMCID: PMC3555607  PMID: 23179979
Posterior instrumentation; Bisegmetal fusion; Hemivertebra
4.  Cohort Profile: The Fangshan Cohort Study of Cardiovascular Epidemiology in Beijing, China 
Journal of Epidemiology  2014;24(1):84-93.
Background
Urbanizing rural areas in China face a rapidly growing cardiovascular disease burden. Epidemiologic studies and effective preventive strategies are urgently needed.
Methods
The Fangshan Cohort Study is a prospective study that began in 2008 and targets local residents aged 40 years or older living in 3 towns in the Fangshan district of Beijing. The baseline examination included a questionnaire on medical history, health knowledge, and behaviors related to cardiovascular disease, as well as physical and blood biochemical examinations. The questionnaire survey will be readministered every 2 years. A system for surveillance of mortality and morbidity of cardiovascular disease is under development.
Results
A total of 20 115 adults (6710 men and 13 405 women) were investigated at baseline (participation rate = 84.5%). The data indicate that overweight/obesity is a serious public health issue in Fangshan: average body mass index was 25.4 kg/m2 among men and 26.5 kg/m2 among women, and the prevalences of overweight and obesity were 43.6% and 10.3% among men and 47.0% and 17.7% among women.
Conclusions
The Fangshan Cohort Study will provide data on cardiovascular risk factors and disease profile, which will assist in developing appropriate prevention and control strategies for cardiovascular disease in rural Chinese communities.
doi:10.2188/jea.JE20120230
PMCID: PMC3872529  PMID: 24162310
risk factors; cardiovascular disease; rural population; cohort study; China
5.  Research on chemical characteristics of soil salt crusts with saline groundwater drip-irrigation in the Tarim Desert Highway Shelterbelt 
SpringerPlus  2013;2(Suppl 1):S5.
Soil salt crusts are special layers at soil surface which are widely distributed in the Trim Desert Highway Shelterbelt under drip-irrigation with high salinity groundwater. In order to reveal annual variation of their chemical characteristics, soil salt crusts in shelterbelt of different ages in hinterland of the Taklimakan Desert were sampled. SOM, total salt, inions and pH were analyzed. Following results were obtained. SOM of salt crusts increased with the shelterbelt ages, but increasing trend became lower gradually. Total salt, ions, and pH of salt crusts reduced gradually with the shelterbelt ages. Total salt of salt crusts in shelterbelt of different ages was much higher than shifting sandy land. Ions were higher than shifting sandy land, Cl-, Na+, and SO42- increased more obvious, then Mg2+, K+, Ca2+ and HCO3-, CO32- was little and nearly had no change. pH was all alkaline, pH of salt crusts in shelterbelt of 11 years was even lower than shifting sandy land. We can include that the quality of shallow soil (0~30 cm) in the Trim Desert Highway Shelterbelt becomes better gradually.
doi:10.1186/2193-1801-2-S1-S5
PMCID: PMC3973407
Chemical characteristics; Soil salt crusts; Saline groundwater drip-irrigation; Trim Desert Highway Shelterbelt
6.  Identification of CHIP as a Novel Causative Gene for Autosomal Recessive Cerebellar Ataxia 
PLoS ONE  2013;8(12):e81884.
Autosomal recessive cerebellar ataxias are a group of neurodegenerative disorders that are characterized by complex clinical and genetic heterogeneity. Although more than 20 disease-causing genes have been identified, many patients are still currently without a molecular diagnosis. In a two-generation autosomal recessive cerebellar ataxia family, we mapped a linkage to a minimal candidate region on chromosome 16p13.3 flanked by single-nucleotide polymorphism markers rs11248850 and rs1218762. By combining the defined linkage region with the whole-exome sequencing results, we identified a homozygous mutation (c.493CT) in CHIP (NM_005861) in this family. Using Sanger sequencing, we also identified two compound heterozygous mutations (c.389AT/c.441GT; c.621C>G/c.707GC) in CHIP gene in two additional kindreds. These mutations co-segregated exactly with the disease in these families and were not observed in 500 control subjects with matched ancestry. CHIP colocalized with NR2A, a subunit of the N-methyl-D-aspartate receptor, in the cerebellum, pons, medulla oblongata, hippocampus and cerebral cortex. Wild-type, but not disease-associated mutant CHIPs promoted the degradation of NR2A, which may underlie the pathogenesis of ataxia. In conclusion, using a combination of whole-exome sequencing and linkage analysis, we identified CHIP, encoding a U-box containing ubiquitin E3 ligase, as a novel causative gene for autosomal recessive cerebellar ataxia.
doi:10.1371/journal.pone.0081884
PMCID: PMC3846781  PMID: 24312598
7.  Tree Biomass Estimation of Chinese fir (Cunninghamia lanceolata) Based on Bayesian Method 
PLoS ONE  2013;8(11):e79868.
Chinese fir (Cunninghamia lanceolata (Lamb.) Hook.) is the most important conifer species for timber production with huge distribution area in southern China. Accurate estimation of biomass is required for accounting and monitoring Chinese forest carbon stocking. In the study, allometric equation was used to analyze tree biomass of Chinese fir. The common methods for estimating allometric model have taken the classical approach based on the frequency interpretation of probability. However, many different biotic and abiotic factors introduce variability in Chinese fir biomass model, suggesting that parameters of biomass model are better represented by probability distributions rather than fixed values as classical method. To deal with the problem, Bayesian method was used for estimating Chinese fir biomass model. In the Bayesian framework, two priors were introduced: non-informative priors and informative priors. For informative priors, 32 biomass equations of Chinese fir were collected from published literature in the paper. The parameter distributions from published literature were regarded as prior distributions in Bayesian model for estimating Chinese fir biomass. Therefore, the Bayesian method with informative priors was better than non-informative priors and classical method, which provides a reasonable method for estimating Chinese fir biomass.
doi:10.1371/journal.pone.0079868
PMCID: PMC3835933  PMID: 24278198
8.  High-Frequency Stimulation of Nucleus Accumbens Changes in Dopaminergic Reward Circuit 
PLoS ONE  2013;8(11):e79318.
Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is a potential remedial therapy for drug craving and relapse, but the mechanism is poorly understood. We investigated changes in neurotransmitter levels during high frequency stimulation (HFS) of the unilateral NAc on morphine-induced rats. Sixty adult Wistar rats were randomized into five groups: the control group (administration of saline), the morphine-only group (systematic administration of morphine without electrode implantation), the morphine-sham-stimulation group (systematic administration of morphine with electrode implantation but not given stimulation), the morphine-stimulation group (systematic administration of morphine with electrode implantation and stimulation) and the saline-stimulation group (administration of saline with electrode implantation and stimulation). The stimulation electrode was stereotaxically implanted into the core of unilateral NAc and microdialysis probes were unilaterally lowered into the ipsilateral ventral tegmental area (VTA), NAc, and ventral pallidum (VP). Samples from microdialysis probes in the ipsilateral VTA, NAc, and VP were analyzed for glutamate (Glu) and γ-aminobutyric acid (GABA) by high-performance liquid chromatography (HPLC). The levels of Glu were increased in the ipsilateral NAc and VP of morphine-only group versus control group, whereas Glu levels were not significantly changed in the ipsilateral VTA. Furthermore, the levels of GABA decreased significantly in the ipsilateral NAc, VP, and VTA of morphine-only group when compared with control group. The profiles of increased Glu and reduced GABA in morphine-induced rats suggest that the presence of increased excitatory neurotransmission in these brain regions. The concentrations of the Glu significantly decreased while the levels of GABA increased in ipsilateral VTA, NAc, and VP in the morphine-stimulation group compared with the morphine-only group. No significant changes were seen in the morphine-sham stimulation group compared with the morphine-only group. These findings indicated that unilateral NAc stimulation inhibits the morphine-induced rats associated hyperactivation of excitatory neurotransmission in the mesocorticolimbic reward circuit.
doi:10.1371/journal.pone.0079318
PMCID: PMC3828386  PMID: 24244479
9.  Significantly increased expression of OCT4 and ABCG2 in spheroid body-forming cells of the human gastric cancer MKN-45 cell line 
Oncology Letters  2013;6(4):891-896.
The cancer stem cell (CSC) theory hypothesizes that CSCs are the cause of tumor formation, recurrence and metastasis. Key to the study of CSCs is their isolation and identification. The present study investigated whether spheroid body-forming cells in the human gastric cancer (GC) MKN-45 cell line are enriched for CSC properties, and also assessed the expression of the candidate CSC markers, octamer-binding transcription factor-4 (OCT4) and adenosine triphosphate-binding cassette transporter G2 (ABCG2) in the MKN-45 spheroid body cells. The MKN-45 cells were plated in a stem cell-conditioned culture system to allow for spheroid body formation. The expression levels of OCT4 and ABCG2 in the spheroid body cells were assessed by qPCR, western blot analysis and immunofluorescence staining, while the tumorigenicity of the spheroid body-forming cells was assessed by in vivo xenograft studies in nude mice. The MKN-45 cells were able to form spheroid bodies when cultured in stem cell-conditioned medium. The spheroid body-forming cells showed a significantly higher (P<0.01) expression of OCT4 and ABCG2 compared with the parental cells. These data suggest that the spheroid body cells from the MKN-45 GC cell line cultured in stem cell-conditioned medium possessed gastric CSC properties. The co-expression of OCT4 and ABCG2 by these cells may represent the presence of a subpopulation of gastric CSCs.
doi:10.3892/ol.2013.1506
PMCID: PMC3796425  PMID: 24137432
human gastric cancer; cancer stem cell; OCT4; ABCG2
10.  Exome Sequencing and Linkage Analysis Identified Tenascin-C (TNC) as a Novel Causative Gene in Nonsyndromic Hearing Loss 
PLoS ONE  2013;8(7):e69549.
In this study, a five-generation Chinese family (family F013) with progressive autosomal dominant hearing loss was mapped to a critical region spanning 28.54 Mb on chromosome 9q31.3-q34.3 by linkage analysis, which was a novel DFNA locus, assigned as DFNA56. In this interval, there were 398 annotated genes. Then, whole exome sequencing was applied in three patients and one normal individual from this family. Six single nucleotide variants and two indels were found co-segregated with the phenotypes. Then using mass spectrum (Sequenom, Inc.) to rank the eight sites, we found only the TNC gene be co-segregated with hearing loss in 53 subjects of F013. And this missense mutation (c.5317G>A, p.V1773M ) of TNC located exactly in the critical linked interval. Further screening to the coding region of this gene in 587 subjects with nonsyndromic hearing loss (NSHL) found a second missense mutation, c.5368A>T (p. T1796S), co-segregating with phenotype in the other family. These two mutations located in the conserved region of TNC and were absent in the 387 normal hearing individuals of matched geographical ancestry. Functional effects of the two mutations were predicted using SIFT and both mutations were deleterious. All these results supported that TNC may be the causal gene for the hearing loss inherited in these families. TNC encodes tenascin-C, a member of the extracellular matrix (ECM), is present in the basilar membrane (BM), and the osseous spiral lamina of the cochlea. It plays an important role in cochlear development. The up-regulated expression of TNC gene in tissue repair and neural regeneration was seen in human and zebrafish, and in sensory receptor recovery in the vestibular organ after ototoxic injury in birds. Then the absence of normal tenascin-C was supposed to cause irreversible injuries in cochlea and caused hearing loss.
doi:10.1371/journal.pone.0069549
PMCID: PMC3728356  PMID: 23936043
11.  Exome Sequencing of 47 Chinese Families with Cone-Rod Dystrophy: Mutations in 25 Known Causative Genes 
PLoS ONE  2013;8(6):e65546.
Objective
The goal of this study was to identify mutations in 25 known causative genes in 47 unrelated Chinese families with cone-rod dystrophy (CORD).
Methods
Forty-seven probands from unrelated families with CORD were recruited. Genomic DNA prepared from leukocytes was analyzed by whole exome sequencing. Variants in the 25 genes were selected and then validated by Sanger sequencing.
Results
Fourteen potential pathogenic mutations, including nine novel and five known, were identified in 10 of the 47 families (21.28%). Homozygous, compound heterozygous, and hemizygous mutations were detected in three, four, or three families, respectively. The 14 mutations in the 10 families were distributed among CNGB3 (three families), PDE6C (two families), ABCA4 (one family), RPGRIP1 (one family), RPGR (two families), and CACNA1F (one family).
Conclusions
This study provides a brief view on mutation spectrum of the 25 genes in a Chinese cohort with CORD. Identification of novel mutations enriched our understanding of variations in these genes and their associated phenotypes. To our knowledge, this is the first systemic exome-sequencing analysis of all of the 25 CORD-associated genes.
doi:10.1371/journal.pone.0065546
PMCID: PMC3679152  PMID: 23776498
12.  Automatic Segmentation of Ground-Glass Opacities in Lung CT Images by Using Markov Random Field-Based Algorithms 
Journal of Digital Imaging  2011;25(3):409-422.
Chest radiologists rely on the segmentation and quantificational analysis of ground-glass opacities (GGO) to perform imaging diagnoses that evaluate the disease severity or recovery stages of diffuse parenchymal lung diseases. However, it is computationally difficult to segment and analyze patterns of GGO while compared with other lung diseases, since GGO usually do not have clear boundaries. In this paper, we present a new approach which automatically segments GGO in lung computed tomography (CT) images using algorithms derived from Markov random field theory. Further, we systematically evaluate the performance of the algorithms in segmenting GGO in lung CT images under different situations. CT image studies from 41 patients with diffuse lung diseases were enrolled in this research. The local distributions were modeled with both simple and adaptive (AMAP) models of maximum a posteriori (MAP). For best segmentation, we used the simulated annealing algorithm with a Gibbs sampler to solve the combinatorial optimization problem of MAP estimators, and we applied a knowledge-guided strategy to reduce false positive regions. We achieved AMAP-based GGO segmentation results of 86.94%, 94.33%, and 94.06% in average sensitivity, specificity, and accuracy, respectively, and we evaluated the performance using radiologists’ subjective evaluation and quantificational analysis and diagnosis. We also compared the results of AMAP-based GGO segmentation with those of support vector machine-based methods, and we discuss the reliability and other issues of AMAP-based GGO segmentation. Our research results demonstrate the acceptability and usefulness of AMAP-based GGO segmentation for assisting radiologists in detecting GGO in high-resolution CT diagnostic procedures.
doi:10.1007/s10278-011-9435-5
PMCID: PMC3348983  PMID: 22089834
Image segmentation; Lung diseases; Markov chains; Tomography; X-ray computed
13.  Olmsted syndrome: exploration of the immunological phenotype 
Background
Olmsted syndrome is a rare congenital skin disorder presenting with periorifical hyperkeratotic lesions and mutilating palmoplantar keratoderma, which is often associated with infections of the keratotic area. A recent study identified de novo mutations causing constitutive activation of TRPV3 as a cause of the keratotic manifestations of Olmsted syndrome.
Methods
Genetic, clinical and immunological profiling was performed on a case study patient with the clinical diagnosis of Olmsted syndrome.
Results
The patient was found to harbour a previously undescribed 1718G-C transversion in TRPV3, causing a G573A point mutation. In depth clinical and immunological analysis found multiple indicators of immune dysregulation, including frequent dermal infections, inflammatory infiltrate in the affected skin, hyper IgE production and elevated follicular T cells and eosinophils in the peripheral blood.
Conclusions
These results provide the first comprehensive assessment of the immunological features of Olmsted syndrome. The systemic phenotype of hyper IgE and persistent eosinophilia suggest a primary or secondary role of immunological processes in the pathogenesis of Olmsted syndrome, and have important clinical consequences with regard to the treatment of Olmsted syndrome patients.
doi:10.1186/1750-1172-8-79
PMCID: PMC3662572  PMID: 23692804
Olmsted syndrome; TRPV3; IgE; Eosinophil; Follicular T cell
14.  Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant 
Background
We studied a family including two half-siblings, sharing the same mother, affected by slowly progressive, adult-onset neurological syndromes. In spite of the diversity of the clinical features, characterized by a mild movement disorder with cognitive impairment in the elder patient, and severe motor-neuron disease (MND) in her half-brother, the brain Magnetic Resonance Imaging (MRI) features were compatible with adult-onset Alexander’s disease (AOAD), suggesting different expression of the same, genetically determined, condition.
Methods
Since mutations in the alpha isoform of glial fibrillary acidic protein, GFAP-α, the only cause so far known of AOAD, were excluded, we applied exome Next Generation Sequencing (NGS) to identify gene variants, which were then functionally validated by molecular characterization of recombinant and patient-derived cells.
Results
Exome-NGS revealed a mutation in a previously neglected GFAP isoform, GFAP-ϵ, which disrupts the GFAP-associated filamentous cytoskeletal meshwork of astrocytoma cells. To shed light on the different clinical features in the two patients, we sought for variants in other genes. The male patient had a mutation, absent in his half-sister, in X-linked histone deacetylase 6, a candidate MND susceptibility gene.
Conclusions
Exome-NGS is an unbiased approach that not only helps identify new disease genes, but may also contribute to elucidate phenotypic expression.
doi:10.1186/1750-1172-8-66
PMCID: PMC3654953  PMID: 23634874
15.  Effects of EHD2 interference on migration of esophageal squamous cell carcinoma 
C-Terminal EH domain-containing protein 2 (EHD2) of the EHD family is associated with plasma membrane. We investigated the expression of EHD2 in human esophageal squamous cell carcinoma (ESCC) and the EHD2 expression to study the therapeutic effect of chemotherapy drugs. Western blot and immunohistochemistry were used to measure the expression of EHD2 protein in ESCC and adjacent normal tissue in 98 patients. EHD2 protein level was reduced in ESCC tissues in comparison with adjacent normal tissues. Under-expression of EHD2 increased the motility property of ESCC cell TE1 in vitro by wound-healing assays and transwell migration assays, and it was concurrent with the decreased expression of epithelial marker E-cadherin. Under-expression of EHD2 in TE1 can cause resistance to cisplatin. Our results suggested that EHD2 low expression is involved in the pathogenesis of ESCC, and it might be a favorable independent poor prognostic parameter for ESCC.
doi:10.1007/s12032-012-0396-4
PMCID: PMC3586404  PMID: 23354948
EHD2; Esophageal squamous cell carcinoma; Migration; Prognosis
16.  Association of enrolment in primary care networks with diabetes care and outcomes among First Nations and low-income Albertans 
Open Medicine  2012;6(4):e155-e165.
Background
The prevalence of diabetes mellitus and its complications is higher among First Nations people and people with low socio-economic status (SES). Previous studies in Alberta have shown that provision of care through Primary Care Networks (PCNs) is associated with better quality of care and better outcomes for people with diabetes, possibly because of greater utilization of chronic disease management programs. However, it is unknown whether First Nations individuals and those in lower SES groups experience these benefits.
Methods
We used administrative and laboratory data for a population-based cohort analysis of Alberta residents under 65 years of age with diabetes. The primary outcome, assessed over a 1-year period, was admission to hospital or emergency department visit for a diabetes-specific ambulatory care sensitive condition (ACSC). Secondary outcomes were 2 quality-of-care indicators (likelihood of measurement of glycated hemoglobin [HbA1c] and or retinal screening) and 2 measures of health care utilization (visits to specialist and primary care physicians). We used negative binomial regression to determine the association between care within a PCN and hospital admission or emergency department visit for diabetes-specific ACSCs. We also assessed outcomes in 3 populations of interest (individuals receiving a health care subsidy [household income less than $39 250 and not eligible for Income Support], those receiving Income Support, and First Nations individuals) relative to the remainder of the population, controlling for whether care was provided in a PCN and adjusting for several baseline characteristics.
Results
We identified a total of 106 653 patients with diabetes eligible for our study, of whom 43 327 (41%) received care in a PCN. Receiving care through a PCN was associated with lower rates of ACSC-related hospital admission or emergency department visits for all groups of interest, which suggests that PCNs had similar effects across each group. However, regardless of where care was provided, First Nations and low-SES patients had more than twice the adjusted rates of hospital admission or emergency department visits for diabetes-specific ACSCs than the general population and were less likely to receive guideline-recommended care, including measurement of HbA1c and retinal screening.
Interpretation
Care in a PCN was associated with lower risks of hospital admission or emergency department visits for diabetes-specific ACSCs, even within vulnerable groups such as First Nations people and those of low SES. However, differences in outcomes and quality-of-care indicators persisted for First Nations individuals and those of low SES, relative to the general population, irrespective of where care was provided.
PMCID: PMC3654512  PMID: 23687531
17.  Spheroid body-forming cells in the human gastric cancer cell line MKN-45 possess cancer stem cell properties 
International Journal of Oncology  2012;42(2):453-459.
The cancer stem cell theory hypothesizes that cancer stem cells (CSCs), which possess self-renewal and other stem cell properties, are regarded as the cause of tumor formation, recurrence and metastasis. The isolation and identification of CSCs could help to develop novel therapeutic strategies specifically targeting CSCs. In this study, we enriched gastric cancer stem cells through spheroid body formation by cultivating the human gastric cancer cell line MKN-45 in defined serum-free medium. The stemness characteristics of spheroid body-forming cells, including self-renewal, proliferation, chemoresistance, tumorigenicity of the MKN-45 spheroid body-forming cells were evaluated, and the expression levels of stemness genes and related proteins in the MKN-45 spheroid body-forming cells were assessed. Furthermore, immunofluorescence staining for the stem cell markers on spheroid body-forming cells was examined to evaluate the association between stemness factors (Oct4, Sox2, Nanog) and the proposed CSC marker CD44. Our data demonstrated that non-adherent spheroid body-forming cells from the gastric cancer cell line MKN-45 cultured in stem cell-conditioned medium possessed gastric CSC properties, such as persistent self-renewal, extensive proliferation, drug resistance, high tumorigenic capacity and overexpression of CSC-related genes and proteins (Oct4, Sox2, Nanog and CD44), compared with the parental cells. More importantly, CD44-positive cells co-expressing the pluripotency genes Oct4, Sox2 and Nanog may represent gastric CSCs. Further experiments using more refined selection criteria such as a combination of two or multiple markers would be useful to specifically identify and purify CSCs.
doi:10.3892/ijo.2012.1720
PMCID: PMC3583623  PMID: 23229446
gastric cancer; cancer stem cell; CD44; Oct4; Sox2; Nanog
18.  A novel homozygous mutation in SUCLA2 gene identified by exome sequencing 
Molecular Genetics and Metabolism  2012;107(3):403-408.
Mitochondrial disorders with multiple mitochondrial respiratory chain (MRC) enzyme deficiency and depletion of mitochondrial DNA (mtDNA) are autosomal recessive conditions due to mutations in several nuclear genes necessary for proper mtDNA maintenance.
In this report, we describe two Italian siblings presenting with encephalomyopathy and mtDNA depletion in muscle. By whole exome-sequencing and prioritization of candidate genes, we identified a novel homozygous missense mutation in the SUCLA2 gene in a highly conserved aminoacid residue. Although a recurrent mutation in the SUCLA2 gene is relatively frequent in the Faroe Islands, mutations in other populations are extremely rare. In contrast with what has been reported in other patients, methyl-malonic aciduria, a biomarker for this genetic defect, was absent in our proband and very mildly elevated in her affected sister.
This report demonstrates that next-generation technologies, particularly exome-sequencing, are user friendly, powerful means for the identification of disease genes in genetically and clinically heterogeneous inherited conditions, such as mitochondrial disorders.
Highlights
► We report a novel homozygous mutation in the SUCLA2, identified by exome sequencing. ► Methyl-malonic aciduria can be absent in patients with SUCLA2 mutations. ► Exome sequencing is useful for the diagnosis of genetically heterogeneous diseases.
doi:10.1016/j.ymgme.2012.08.020
PMCID: PMC3490101  PMID: 23010432
MDS, mtDNA depletion syndrome; MMA, methylmalonic acid; MRC, mitochondrial respiratory chain; mtDNA, mitochondrial DNA; NGS, next-generation sequencing; OXPHOS, oxidative phosphorylation; Mitochondrial disorder; Encephalomyopathy; Mitochondrial DNA depletion; SUCLA2; Exome-sequencing
20.  The efficacy and complications of posterior hemivertebra resection 
European Spine Journal  2011;20(10):1692-1702.
There have been several reports on hemivertebra resection via a posterior-only procedure. However, the number of reported cases is small, and various types of instrumentation have been used. In our study, we retrospectively investigated 56 consecutive cases of congenital scoliosis that were treated by posterior hemivertebra resection with transpedicular instrumentation. Radiographs were reviewed to determine the type and location of the hemivertebra, the coronal curve magnitude and the sagittal alignment pre-operatively, post-operatively and at the latest follow-up. Radiographs were also used to assess implant failure and inter-body fusion. Surgical reports and patient charts were reviewed to record any peri-operative complications. Fifty-eight posterior hemivertebrae resections from 56 patients aged 1.5–17 years with fully segmented non-incarcerated hemivertebra were evaluated. The average age at surgery was 9.9 years (1.5–17 years). The average follow-up was 32.9 months (24–58 months). The mean fusion level was 5.0 segments (2–11 segments). There was a mean improvement of 72.9% in the segmental scoliosis, from 42.4° before surgery to 12.3° at the time of the latest follow-up, and there was a mean improvement of 70% in segmental kyphosis from 42.0° to 14.5° over the same time period. The thoracic kyphosis (T5–T12) averaged 10.8° before surgery and 23.9° at the latest follow-up. The lumbar lordosis (L1–S1) averaged −52.8° before surgery and −51.6° at the latest follow-up. Two cases with neurological claudications had complete recovery immediately after the surgery. There was one case of delayed wound healing, two fractures of the pedicle at the instrumented level, two rod breakages and one proximal junction kyphosis that required revision. There were no neurological complications. Radiolucent gaps were found in the residual space after resection on the lateral view in five cases, without any sign of implant failure or correction loss. Our results show that one-stage posterior hemivertebra resection with transpedicular instrumentation can achieve excellent correction, 360° decompression and short fusion without neurological complications. Pedicle cutting still remains a challenge in younger children when using bisegmental instrumentation. In addition, the radiolucent gaps in the residual space require further investigation.
doi:10.1007/s00586-011-1710-0
PMCID: PMC3175869  PMID: 21318279
Congenital scoliosis; Hemivertebra; Resection; Posterior surgery
21.  Numbl inhibits glioma cell migration and invasion by suppressing TRAF5-mediated NF-κB activation 
Molecular Biology of the Cell  2012;23(14):2635-2644.
Numblike, a negative regulator in glioma cell migration and invasion, was found to mediate nuclear factor kappa B activation by suppressing tumor necrosis factor receptor–associated factor 5.
The Notch signaling regulator Numblike (Numbl) is expressed in the brain, but little is known regarding its role in the pathophysiology of glial cells. In this paper, we report that Numbl expression was down-regulated in high-grade human glioma tissue samples and glioblastoma cell lines. To investigate the role of Numbl in glioma migration and invasion, we generated human glioma cell lines in which Numbl was either overexpressed or depleted. Overexpression of Numbl suppressed, while elimination of Numbl promoted, the migration and invasion of glioma cells. Numbl inhibited glioma migration and invasion by dampening NF-κB activity. Furthermore, Numbl interacted directly with tumor necrosis factor receptor–associated factor 5 (TRAF5), which signals upstream and is required for the activation of NF-κB, and committed it to proteasomal degradation by promoting K48-linked polyubiquitination of TRAF5. In conclusion, our data suggest that Numbl negative regulates glioma cell migration and invasion by abrogating TRAF5-induced activation of NF-κB.
doi:10.1091/mbc.E11-09-0805
PMCID: PMC3395653  PMID: 22593207
22.  Genome-wide and molecular evolution analysis of the Poplar KT/HAK/KUP potassium transporter gene family 
Ecology and Evolution  2012;2(8):1996-2004.
As the largest K+ transport gene family, KT/HAK/KUP family plays an important role in plant growth, development, and stress adaptation. However, there is limited information about this family in woody plant species. In this study, with genome-wide in-depth investigation, 31 Poplar KT/HAK/KUP transporter genes including six pairs of tandem duplicated and eight pairs of segmental duplicated paralogs have been identified, suggesting segmental and tandem duplication events contributed to the expansion of this family in Poplar. The combination of phylogenetic, exon structure and splice site, and paragon analysis revealed 11 pairs of Poplar KT/HAK/KUP duplicates. For these 11 pairs, all pairs are subject to purify selection, and asymmetric evolutionary rates have been found to occur in three pairs. This study might provide more insights into the underlying evolution mechanisms of trees acclimating to their natural habitat.
doi:10.1002/ece3.299
PMCID: PMC3434002  PMID: 22957200
Asymmetric evolutionary rates; KT/HAK/KUP family; segmental duplication; tandem duplication.
23.  Enrolment in primary care networks: impact on outcomes and processes of care for patients with diabetes 
Background:
Primary care networks are a newer model of primary care that focuses on improved access to care and the use of multidisciplinary teams for patients with chronic disease. We sought to determine the association between enrolment in primary care networks and the care and outcomes of patients with diabetes.
Methods:
We used administrative health care data to study the care and outcomes of patients with incident and prevalent diabetes separately. For patients with prevalent diabetes, we compared those whose care was managed by physicians who were or were not in a primary care network using propensity score matching. For patients with incident diabetes, we studied a cohort before and after primary care networks were established. Each cohort was further divided based on whether or not patients were cared for by physicians enrolled in a network. Our primary outcome was admissions to hospital or visits to emergency departments for ambulatory care sensitive conditions specific to diabetes.
Results:
Compared with patients whose prevalent diabetes is managed outside of primary care networks, patients in primary care networks had a lower rate of diabetes-specific ambulatory care sensitive conditions (adjusted incidence rate ratio 0.81, 95% confidence interval [CI] 0.75 to 0.87), were more likely to see an ophthalmologist or optometrist (risk ratio 1.19, 95% CI 1.17 to 1.21) and had better glycemic control (adjusted mean difference −0.067, 95% CI −0.081 to −0.052).
Interpretation:
Patients whose diabetes was managed in primary care networks received better care and had better clinical outcomes than patients whose condition was not managed in a network, although the differences were very small.
doi:10.1503/cmaj.110755
PMCID: PMC3273535  PMID: 22143232
24.  Prevalence of cardiovascular disease and risk factors in a rural district of Beijing, China: a population-based survey of 58,308 residents 
BMC Public Health  2012;12:34.
Background
Cardiovascular disease (CVD) is the leading cause of global disease burden. Although stroke was thought to be more prevalent than coronary heart disease (CHD) in Chinese, the epidemic pattern might have been changed in some rural areas nowadays. This study was to estimate up-to-date prevalence of CVD and its risk factors in rural communities of Fangshan District, Beijing, China.
Methods
A cross-sectional population survey was carried out by stratified cluster sampling. A total of 58,308 rural residents aged over 40 years were surveyed by face-to-face interview and physical examination during 2008 and 2010. The standardized prevalence was calculated according to adult sample data of China's 5th Population Census in 2000, and the adjusted prevalence odds ratio (POR) was calculated for the association of CHD/stroke with its cardiovascular risk factors in multivariate logistic regression models.
Results
Age- and sex-standardized prevalence was 5.6% for CHD (5.2% in males and 5.9% in females), higher than the counterpart of 3.7% (4.7% in males and 2.6% in females) for stroke. Compared with previous studies, higher prevalence of 7.7%, 47.2%, 53.3% in males and 8.2%, 44.8%, 60.7% in females for diabetes, hypertension and overweight/obesity were presented accordingly. Moreover, adjusted POR (95% confidence interval) of diabetes, obesity, stage 1 and stage 2 hypertension for CHD as 2.51 (2.29 to 2.75), 1.53 (1.38 to 1.70), 1.13 (1.02 to 1.26) and 1.35 (1.20 to 1.52), and for stroke as 2.24 (1.98 to 2.52), 1.25 (1.09 to 1.44), 1.44 (1.25 to 1.66) and 1.70 (1.46 to 1.98) were shown respectively in the multivariate logistic regression models.
Conclusions
High prevalence of CVD and probably changed epidemic pattern in rural communities of Beijing, together with the prevalent cardiovascular risk factors and population aging, might cause public health challenges in rural Chinese population.
doi:10.1186/1471-2458-12-34
PMCID: PMC3292979  PMID: 22248490
25.  Evaluation of an electronic warfarin nomogram for anticoagulation of hemodialysis patients 
BMC Nephrology  2011;12:46.
Background
Warfarin nomograms to guide dosing have been shown to improve control of the international normalized ratio (INR) in the general outpatient setting. However, the effectiveness of these nomograms in hemodialysis patients is unknown. We evaluated the effectiveness of anticoagulation using an electronic warfarin nomogram administered by nurses in outpatient hemodialysis patients, compared to physician directed therapy.
Methods
Hemodialysis patients at any of the six outpatient clinics in Calgary, Alberta, treated with warfarin anticoagulation were included. Two five-month time periods were compared: prior to and post implementation of the nomogram. The primary endpoint was adequacy of anticoagulation (proportion of INR measurements within range ± 0.5 units).
Results
Overall, 67 patients were included in the pre- and 55 in the post-period (with 40 patients in both periods). Using generalized linear mixed models, the adequacy of INR control was similar in both periods for all range INR levels: in detail, range INR 1.5 to 2.5 (pre 93.6% (95% CI: 88.6% - 96.5%); post 95.6% (95% CI: 89.4% - 98.3%); p = 0.95); INR 2.0 to 3.0 (pre 82.2% (95% CI: 77.9% - 85.8%); post 77.4% (95% CI: 72.0% - 82.0%); p = 0.20); and, INR 2.5 to 3.5 (pre 84.3% (95% CI: 59.4% - 95.1%); post 66.8% (95% CI: 39.9% - 86.0%); p = 0.29). The mean number of INR measurements per patient decreased significantly between the pre- (30.5, 95% CI: 27.0 - 34.0) and post- (22.3, 95% CI: 18.4 - 26.1) (p = 0.003) period. There were 3 bleeding events in each of the periods.
Conclusions
An electronic warfarin anticoagulation nomogram administered by nurses achieved INR control similar to that of physician directed therapy among hemodialysis patients in an outpatient setting, with a significant reduction in frequency of testing. Future controlled trials are required to confirm the efficacy of this nomogram.
doi:10.1186/1471-2369-12-46
PMCID: PMC3189863  PMID: 21943221
Anticoagulation; Hemodialysis; Warfarin nomogram

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