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1.  Cardiovascular events prior to or early after diagnosis of systemic lupus erythematosus in the systemic lupus international collaborating clinics cohort 
Lupus Science & Medicine  2016;3(1):e000143.
Objective
To describe the frequency of myocardial infarction (MI) prior to the diagnosis of systemic lupus erythematosus (SLE) and within the first 2 years of follow-up.
Methods
The systemic lupus international collaborating clinics (SLICC) atherosclerosis inception cohort enters patients within 15 months of SLE diagnosis. MIs were reported and attributed on a specialised vascular event form. MIs were confirmed by one or more of the following: abnormal ECG, typical or atypical symptoms with ECG abnormalities and elevated enzymes (≥2 times upper limit of normal), or abnormal stress test, echocardiogram, nuclear scan or angiogram. Descriptive statistics were used.
Results
31 of 1848 patients who entered the cohort had an MI. Of those, 23 patients had an MI prior to SLE diagnosis or within the first 2 years of disease. Of the 23 patients studied, 60.9% were female, 78.3% were Caucasian, 8.7% black, 8.7% Hispanic and 4.3% other. The mean age at SLE diagnosis was 52.5±15.0 years. Of the 23 MIs that occurred, 16 MIs occurred at a mean of 6.1±7.0 years prior to diagnosis and 7 occurred within the first 2 years of follow-up. Risk factors associated with early MI in univariate analysis are male sex, Caucasian, older age at diagnosis, hypertension, hypercholesterolaemia, family history of MI and smoking. In multivariate analysis only age (OR=1.06 95% CI 1.03 to 1.09), hypertension (OR=5.01, 95% CI 1.38 to 18.23), hypercholesterolaemia (OR=4.43, 95% CI 1.51 to 12.99) and smoking (OR=7.50, 95% CI 2.38 to 23.57) remained significant risk factors.
Conclusions
In some patients with lupus, MI may develop even before the diagnosis of SLE or shortly thereafter, suggesting that there may be a link between autoimmune inflammation and atherosclerosis.
doi:10.1136/lupus-2015-000143
PMCID: PMC4836282  PMID: 27099765
Systemic Lupus Erythematosus; Cardiovascular Disease; Inflammation
2.  Osterix Regulates Tooth Root Formation in a Site-specific Manner 
Journal of Dental Research  2015;94(3):430-438.
Bone and dentin share similar biochemical compositions and physiological properties. Dentin, a major tooth component, is formed by odontoblasts; in contrast, bone is produced by osteoblasts. Osterix (Osx), a zinc finger-containing transcription factor, has been identified as an essential regulator of osteoblast differentiation and bone formation. However, it has been difficult to establish whether Osx functions in odontoblast differentiation and dentin formation. To understand the role of Osx in dentin formation, we analyzed mice in which Osx was subjected to tissue-specific ablation under the control of either the Col1a1 or the OC promoter. Two independent Osx conditional knockout mice exhibited similar molar abnormalities. Although no phenotype was found in the crowns of these teeth, both mutant lines exhibited short molar roots due to impaired root elongation. Furthermore, the interradicular dentin in these mice showed severe hypoplastic features, which were likely caused by disruptions in odontoblast differentiation and dentin formation. These phenotypes were closely related to the temporospatial expression pattern of Osx during tooth development. These findings indicate that Osx is required for root formation by regulating odontoblast differentiation, maturation, and root elongation. Cumulatively, our data strongly indicate that Osx is a site-specific regulator in tooth root formation.
doi:10.1177/0022034514565647
PMCID: PMC4814021  PMID: 25568170
Osx; tooth development; odontoblasts; tooth roots; dentinogenesis; mice
3.  Wntless Regulates Dentin Apposition and Root Elongation in the Mandibular Molar 
Journal of Dental Research  2015;94(3):439-445.
Wnt signaling plays an essential role in the dental epithelium and mesenchyme during tooth morphogenesis. However, it remains unclear if Wnt ligands, produced from dental mesenchyme, are necessary for odontoblast differentiation and dentin formation. Here, we show that odontoblast-specific disruption of Wntless (Wls), a chaperon protein that regulates Wnt sorting and secretion, leads to severe defects in dentin formation and root elongation. Dentin thickness decreased remarkably and pulp chambers enlarged in the mandibular molars of OC-Cre;WlsCO/CO mice. Although the initial odontoblast differentiation was normal in the mutant crown, odontoblasts became cuboidal and dentin thickness was reduced. In immunohistochemistry, Wnt10a, β-catenin, type I collagen, and dentin sialoprotein were significantly down-regulated in the odontoblasts of mutant crown. In addition, roots were short and root canals were widened. Cell proliferation was reduced in the developing root apex of mutant molars. Furthermore, Wnt10a and Axin2 expression was remarkably decreased in the odontoblasts of mutant roots. Deletion of the Wls gene in odontoblasts appears to reduce canonical Wnt activity, leading to inhibition of odontoblast maturation and root elongation.
doi:10.1177/0022034514567198
PMCID: PMC4814015  PMID: 25595365
odontoblasts; mice; tooth development; Wnt signaling pathway; tooth roots; dentinogenesis
4.  How do K-RAS-activated cells evade cellular defense mechanisms? 
Oncogene  2015;35(7):827-832.
Lung adenocarcinomas, like other cancers, develop through the accumulation of epigenetic and genetic alterations. Numerous studies have shown that K-RAS mutation is among the most important early events in carcinogenesis of the lung. However, it is also well established that growth-stimulating signals feed back into growth-suppressing pathways, and any imbalance in these signaling networks will cause the cell to exit the cell cycle, thereby preventing uncontrolled cell growth. How, then, do K-RAS-activated cells evade cellular defense mechanisms? To answer this question, it is necessary to identify the molecular event(s) responsible for the development of early dysplastic lesions that are unable to defend against aberrant oncogene activation. Lineage-determining transcriptional regulators govern differentiation status during normal lung development, as well as in lung adenocarcinoma. Among the genes involved in K-RAS-induced lung tumorigenesis, RUNX3 is unique: inactivation of Runx3 in mouse lung induces lung adenoma and abrogates the ARF–p53 pathway. This observation raises the possibility of intimate cross-talk between the differentiation program and oncogene surveillance. In this review, we summarized evidences suggesting that K-RAS-activated cells do not evade cellular defense mechanisms per se; instead, cells with K-RAS mutations are selected only if they occur in cells in which defense mechanism is abrogated.
doi:10.1038/onc.2015.153
PMCID: PMC4761642  PMID: 25961920
5.  Autoantibodies as Biomarkers for the Prediction of Neuropsychiatric Events in Systemic Lupus Erythematosus 
Annals of the rheumatic diseases  2011;70(10):1726-1732.
Objective
Neuropsychiatric (NP) events occur unpredictably in systemic lupus erythematosus (SLE) and most biomarker associations remain to be prospectively validated. We examined a disease inception cohort of 1047 SLE patients to determine which autoantibodies at enrollment predicted subsequent NP events.
Methods
Patients with recent SLE diagnosis were assessed prospectively for up to 10 years for NP events using ACR case definitions. Decision rules of graded stringency determined whether NP events were attributable to SLE. Associations between the first NP event and baseline autoantibodies (lupus anticoagulant, anticardiolipin, anti-β2 glycoprotein-I, anti-ribosomal P and anti-NR2 glutamate receptor) were tested by Cox proportional hazards regression.
Results
Disease duration at enrollment was 5.4±4.2 months, followup was 3.6±2.6 years. Patients were 89.1% female with mean (±SD) age 35.2±13.7 years. 495/1047 (47.3%) developed ≥1 NP event (total 917 events). NP events attributed to SLE were 15.4% (model A) and 28.2% (model B). At enrollment 21.9% of patients had lupus anticoagulant, 13.4% anticardiolipin, 15.1% anti-β2 glycoprotein-I, 9.2% anti-ribosomal P and 13.7% anti-NR2 antibodies. Lupus anticoagulant at baseline was associated with subsequent intracranial thrombosis (total n=22) attributed to SLE (model B) (Hazard ratio, HR 2.54 (95% CI: 1.08–5.94). Anti-ribosomal P antibody was associated with subsequent psychosis (total n=14) attributed to SLE (model B) (HR: 3.92 (95% CI:1.23–12.5); p=0.02). Other autoantibodies did not predict NP events.
Conclusion
In a prospective study of 1047 recently diagnosed SLE patients, lupus anticoagulant and anti-ribosomal P antibodies are associated with an increased future risk for intracranial thrombosis and lupus psychosis respectively
doi:10.1136/ard.2010.148502
PMCID: PMC4664555  PMID: 21893582 CAMSID: cams5141
Systemic lupus erythematosus; Neuropsychiatric; Inception cohort; Autoanibodies; Biomarkers
6.  Short-Term Outcome of Neuropsychiatric Events in Systemic Lupus Erythematosus upon Enrollment into an International Inception Cohort Study 
Arthritis and rheumatism  2008;59(5):721-729.
Objective
To determine the short-term outcome of neuropsychiatric (NP) events upon enrollment into an international, inception cohort of SLE patients.
Methods
The study was performed by the Systemic Lupus International Collaborating Clinics. Patients were enrolled within 15 months of diagnosis of SLE and NP events were characterized using the ACR case definitions. Decision rules were derived to identify NP events attributable to SLE. Physician outcome scores of NP events and patient derived mental (MCS) and physical (PCS) component summary scores of the SF-36 were recorded.
Results
There were 890 patients (88.7% female) with a mean (± SD) age of 33.8 ± 13.4 years and mean disease duration of 5.3 ± 4.2 months. Within the enrollment window 271/890 (33. 5%) patients had at least 1 NP event encompassing 15 NP syndromes. NP events attributed to SLE varied from 16.5% – 33.9% using alternate attribution models and occurred in 6.0% – 11.5% of patients. Outcome scores for NP events attributed to SLE were significantly better than for NP events due to non-SLE causes. Higher global disease activity was associated with worse outcomes. MCS scores were lower in patients with NP events, regardless of attribution, and were also lower in patients with diffuse and central NP events. There was a significant association between physician outcome scores and patient MCS scores only for NP events attributed to SLE.
Conclusion
In SLE patients the short-term outcome of NP events is determined by both the characteristics and attribution of the events.
doi:10.1002/art.23566
PMCID: PMC4656032  PMID: 18438902 CAMSID: cams5140
Systemic lupus erythematosus; Neuropsychiatric; Inception cohort; Attribution; Outcome
7.  Autoantibodies and Neuropsychiatric events at diagnosis of SLE 
Arthritis and rheumatism  2008;58(3):843-853.
Objective
To examine the association between neuropsychiatric (NP) events with antiphospholipid antibodies (lupus anticoagulant, anticardiolipin), anti-β2 glycoprotein-I, anti-ribosomal P and anti-NR2 glutamate receptor antibodies in an international inception cohort.
Methods
NP events were identified using the ACR case definitions and clustered into central/peripheral and diffuse/focal events. Attribution of NP events was determined using decision rules of different stringency (model A and model B). Autoantibodies were measured without knowledge of NP events or their attribution.
Results
412 patients (87.3% female; mean (± SD) age of 34.9 ± 13.5 years; mean disease duration 5.0 ± 4.2 months) were studied. There were 214 NP events in 133 (32.3%) patients. NP events attributed to SLE varied from 15% (model A) to 36% (model B). There was no association between autoantibodies and NP events from all causes. However the frequency of anti-ribosomal P antibodies in patients with NP events due to SLE (model A) was 4/24 (16.6%) compared to 3/109 (2.8%) for all other NP events and 24/279 (8.6%) with no NP events (P=0.07). Furthermore anti-ribosomal P antibodies in patients with central NP events attributed to SLE (model A) was 4/20 (20%) vs. 3/107 (2.8%) for other NP events and 24/279 (8.6%) with no NP events (P = 0.04). For diffuse NP events the antibody frequencies were 3/11 (27%) compared to 4/111 (3.6%) and 24/279 (8.6%) respectively (P=0.02).
Conclusion
NP events at onset of SLE were associated with anti-ribosomal P antibodies, suggesting a pathogenetic role for this autoantibody. There was no association with other autoantibodies.
doi:10.1002/art.23218
PMCID: PMC4656035  PMID: 18311802 CAMSID: cams5142
Systemic lupus erythematosus; Neuropsychiatric; Autoantibodies; Inception cohort; Attribution
8.  RUNX family members are covalently modified and regulated by PIAS1-mediated sumoylation 
Oncogenesis  2014;3(4):e101-.
Transcription factors of the RUNX family (RUNXs), which play pivotal roles in normal development and neoplasia, are regulated by various post-translational modifications. To understand the molecular mechanisms underlying the regulation of RUNXs, we performed a large-scale functional genetic screen of a fly mutant library. The screen identified dPias (the fly ortholog of mammalian PIASs), an E3 ligase for the SUMO (small ubiquitin-like modifier) modification, as a novel genetic modifier of lz (the fly ortholog of mammalian RUNX3). Molecular biological analysis revealed that lz/RUNXs are sumoylated by dPias/PIAS1 at an evolutionarily conserved lysine residue (K372 of lz, K144 of RUNX1, K181 of RUNX2 and K148 of RUNX3). PIAS1-mediated sumoylation inhibited RUNX3 transactivation activity, and this modification was promoted by the AKT1 kinase. Importantly, PIAS1 failed to sumoylate some RUNX1 mutants associated with breast cancer. In nude mice, tumorigenicity was promoted by RUNX3 bearing a mutation in the sumoylation site, but suppressed by wild-type RUNX3. Our results suggest that RUNXs are sumoylated by PIAS1, and that this modification could play a critical role in the regulation of the tumor-suppressive activity of these proteins.
doi:10.1038/oncsis.2014.15
PMCID: PMC4007197  PMID: 24777122
RUNX3; PIAS1; AKT1; sumoylation; tumor suppressor
9.  Breast Cancer in Systemic Lupus Erythematosus 
Oncology  2013;85(2):117-121.
Objective
Evidence points to a decreased breast cancer risk in systemic lupus erythematosus (SLE). We analyzed data from a large multisite SLE cohort, linked to cancer registries.
Methods
Information on age, SLE duration, cancer date, and histology was available. We analyzed information on histological type and performed multivariate logistic regression analyses of histological types according to age, SLE duration, and calendar year.
Results
We studied 180 breast cancers in the SLE cohort. Of the 155 cases with histology information, 11 were referred to simply as ‘carcinoma not otherwise specified’. In the remaining 144 breast cancers, the most common histological type was ductal carcinoma (n = 95; 66%) followed by lobular adenocarcinoma (n = 11; 8%), 15 cancers were of mixed histology, and the remaining ones were special types. In our regression analyses, the independent risk factors for lobular versus ductal carcinoma was age [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.01–1.14] and for the ‘special’ subtypes it was age (OR 1.06, 95% CI 1.01–1.10) and SLE duration (OR 1.05, 95% CI 1.00–1.11).
Conclusions
Generally, up to 80% of breast cancers are ductal carcinomas. Though our results are not definitive, in the breast cancers that occur in SLE, there may be a slight decrease in the ductal histological type. In our analyses, age and SLE duration were independent predictors of histological status.
doi:10.1159/000353138
PMCID: PMC3934367  PMID: 23887245
Breast cancer; Systemic lupus erythematosus; Histopathology; Epidemiology
10.  SF-36 summary and subscale scores are reliable outcomes of neuropsychiatric events in systemic lupus erythematosus 
Annals of the rheumatic diseases  2011;70(6):961-967.
Objective
To examine change in health-related quality of life (HRQoL) in association with clinical outcomes of neuropsychiatric (NP) events in SLE.
Methods
An international study evaluated newly diagnosed SLE patients for NP events attributed to SLE and non-SLE causes. Outcome of events was determined by physician-completed 7-point scale and compared to patient-completed SF-36 questionnaires. Statistical analysis used linear mixed-effects regression models with patient specific random effects.
Results
274 patients (92% female; 68% Caucasian), from a cohort of 1400, had ≥ 1 NP event where the interval between assessments was 12.3 ± 2 months. The overall difference in change between visits in mental component summary (MCS) scores of the SF-36 was significant (p<0.0001) following adjustments for gender, ethnicity, center and previous score. A consistent improvement in NP status (N=295) was associated with an increase in the mean(SD) adjusted MCS score of 3.66(0.89) in SF-36 scores. Between paired visits where NP status consistently deteriorated (N=30), the adjusted MCS score decreased by 4.00(1.96). For the physical component summary (PCS) scores the corresponding changes were +1.73(0.71) and −0.62(1.58) (p<0.05) respectively. Changes in SF-36 subscales were in the same direction (p<0.05; with the exception of role physical). Sensitivity analyses confirmed these findings. Adjustment for age, education, medications, SLE disease activity, organ damage, disease duration, attribution and characteristics of NP events did not substantially alter the results.
Conclusion
Changes in SF-36 summary and subscale scores, in particular those related to mental health, are strongly associated with the clinical outcome of NP events in SLE patients.
doi:10.1136/ard.2010.138792
PMCID: PMC3795436  PMID: 21342917
Systemic lupus erythematosus; Neuropsychiatric; Inception cohort; Health related quality of life; SF-36
13.  Identification of new SLE-associated genes with a two-step Bayesian study design 
Genes and immunity  2009;10(5):446-456.
In our previous study, we utilized a Bayesian design to probe the association of ~1,000 genes (~10,000 SNPs) with SLE on a moderate number of trios of parents and children with SLE. Two genes associated with SLE with a multitest corrected False Discovery Rate (FDR) of <0.05. were identified, and a number of noteworthy genes with FDR of <0.8 were also found, pointing out a future direction for the study. In the present report, using a large population of controls and adult- or -childhood onset SLE cases, we have extended the previous investigation to explore the SLE association of ten of these noteworthy genes (109 SNPs). We have found that seven of these genes exhibit significant (FDR < 0.05) association with SLE, both confirming some genes that have previously been found to be associated with SLE (PTPN22 and IRF5) and novel findings of genes (KLRG1, IL-16, PTPRT, TLR8 and CASP10) which have not been previously reported. The results signify that the two-step candidate pathway design is an efficient way to study the genetic foundations of complex diseases. Furthermore, the novel genes identified in this study point to new directions in both the diagnosis and the eventual treatment of this debilitating disease.
doi:10.1038/gene.2009.38
PMCID: PMC3434884  PMID: 19440200
Autoimmune disease; Genetic Association; KLRG1; IL-16; PTPRT; TLR8; CASP10; SNP
14.  Atherosclerotic Vascular Events in a Multinational Inception Cohort of Systemic Lupus Erythematosus (SLE) 
Arthritis care & research  2010;62(6):881-887.
Objective
To describe vascular events during an 8 year follow-up in a multicentre SLE inception cohort and their attribution to atherosclerosis.
Methods
Clinical data including co-morbidities are recorded yearly. Vascular events are recorded and attributed to atherosclerosis or not. All events met standard clinical criteria. Factors associated with atherosclerotic vascular events were analysed using descriptive statistics, t-tests and χ2. Stepwise multivariate logistic regression was used to assess the association of factors with vascular events attributed to atherosclerosis.
Results
Since 2000, 1249 patients have been entered into the cohort. There have been 97 vascular events in 72 patients. These include: myocardial infarction (13), angina (15), congestive heart failure (24), peripheral vascular disease (8), transient ischemic attack (13), stroke (23), pacemaker insertion (1). Fifty of the events were attributed to active lupus, 31events in 22 patients were attributed to atherosclerosis, and 16 to other causes. Time from diagnosis to first atherosclerotic event was 2.0 ± 1.5 years. Compared to patients followed for 2 years without atherosclerosis events (615), at enrolment patients with AVE were more frequently Caucasian, male, older at diagnosis of SLE, obese, smokers, hypertensive and had a family history of coronary artery disease. On multivariate analysis only male gender and older age at diagnosis were associated factors.
Conclusion
In an inception cohort with SLE followed for up to 8 years there were 97 vascular events but only 31 were attributable to atherosclerosis. Patients with atherosclerotic events were more likely to be male and to be older at diagnosis of SLE.
doi:10.1002/acr.20122
PMCID: PMC2989413  PMID: 20535799
15.  Prospective Analysis Of Neuropsychiatric Events In An International Disease Inception Cohort of SLE Patients 
Annals of the rheumatic diseases  2009;69(3):529-535.
Objectives
To determine the frequency, accrual, attribution and outcome of neuropsychiatric (NP) events and impact on quality of life over 3 years in a large inception cohort of SLE patients.
Methods
The study was conducted by the Systemic Lupus International Collaborating Clinics. Patients were enrolled within 15 months of SLE diagnosis. NP events were identified using the ACR case definitions and decision rules were derived to determine the proportion of NP disease attributable to SLE. The outcome of NP events was recorded and patient perceived impact determined by the SF-36.
Results
There were 1206 patients (89.6% female) with a mean (±SD) age of 34.5±13.2 years. The mean disease duration at enrollment was 5.4±4.2 months. Over a mean follow-up of 1.9±1.2 years 486/1206 (40.3%) patients had ≥1 NP events which were attributed to SLE in 13.0%–23.6% of patients using two a priori decision rules. The frequency of individual NP events varied from 47.1% (headache) to 0% (myasthenia gravis). The outcome was significantly better for those NP events attributed to SLE especially if they occurred within 1.5 years of the diagnosis of SLE. Patients with NP events, regardless of attribution, had significantly lower summary scores for both mental and physical health over the study.
Conclusions
NP events in SLE patients are variable in frequency, most commonly present early in the disease course and adversely impact patients’ quality of life over time. Events attributed to non-SLE causes are more common than those due to SLE, although the latter have a more favourable outcome.
doi:10.1136/ard.2008.106351
PMCID: PMC2929162  PMID: 19359262
Lupus; Neuropsychiatric; Prospective; Inception cohort
16.  Palindromic rheumatism: different genetic background implies a distinct disease entity 
Annals of the Rheumatic Diseases  2006;65(11):1539-1540.
doi:10.1136/ard.2006.052928
PMCID: PMC1798353  PMID: 17038462
17.  Genetic variation of Hoplolaimus columbus populations in the United States using PCR-RFLP analysis of nuclear rDNA ITS regions1 
Journal of Nematology  2009;41(3):187-193.
Hoplolaimus columbus is an important nematode pest which causes economic loss of crops including corn, cotton, and soybean in the Southeastern United States. DNA sequences of the ITS1-5.8S-ITS2 region of ribosomal DNA from H. columbus were aligned and analyzed to characterize intraspecific genetic variation between eleven populations collected from Georgia, Louisiana, North Carolina, and South Carolina. In comparative sequence analysis with clones from either one or two individuals obtained from the eleven populations, we found variability existed among clones from an individual and that clonal diversity observed from within individuals was verified by PCR-RFLP. PCR-RFLP analysis with Rsa I and Msp I restriction enzymes yielded several fragments on 3.0% agarose gel that corresponded to different haplotypes in all populations and the sum of digested products exceeded the length of undigested PCR products, which revealed that ITS heterogeneity existed in a genome of H. columbus. This indicates that heterogeneity may play a role in the evolution of this parthenogenetic species.
PMCID: PMC3380495  PMID: 22736813
ITS region; PCR-RFLP; haplotypes; Hoplolaimus columbus; lance; nematode
18.  Phylogenetic Analysis of the Hoplolaiminae Inferred from Combined D2 and D3 Expansion Segments of 28S rDNA1 
Journal of Nematology  2009;41(1):28-34.
DNA sequences of the D2-D3 expansion segments of the 28S gene of ribosomal DNA from 23 taxa of the subfamily Hoplolaiminae were obtained and aligned to infer phylogenetic relationships. The D2 and D3 expansion regions are G-C rich (59.2%), with up to 20.7% genetic divergence between Scutellonema brachyurum and Hoplolaimus concaudajuvencus. Molecular phylogenetic analysis using maximum likelihood and maximum parsimony was conducted using the D2-D3 sequence data. Of 558 characters, 254 characters (45.5%) were variable and 198 characters (35.4%) were parsimony informative. All phylogenetic methods produced a similar topology with two distinct clades: One clade consists of all Hoplolaimus species while the other clade consists of the rest of the studied Hoplolaiminae genera. This result suggests that Hoplolaimus is monophyletic. Another clade consisted of Aorolaimus, Helicotylenchus, Rotylenchus, and Scutellonema species. Phylogenetic analysis using the outgroup species Globodera rostocheinsis suggests that Hoplolaiminae is paraphyletic. In this study, the D2-D3 region had levels of DNA sequence divergence sufficient for phylogenetic analysis and delimiting species of Hoplolaiminae.
PMCID: PMC3365300  PMID: 22661775
28S; analysis; Aorolaimus; clade; D2-D3; Helicotylenchus; Hoplolaiminae; Hoplolaimus; lance; nematode; phylogenetic; Rotylenchus; species; spiral; Scutellonema; taxonomy
19.  Golimumab, a human antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study 
Annals of the Rheumatic Diseases  2008;68(6):789-796.
Objective:
The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate therapy.
Methods:
Patients were randomly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules (group 1, n  =  133), golimumab 100 mg injections plus placebo capsules (group 2, n  =  133), golimumab 50 mg injections plus methotrexate capsules (group 3, n  =  89), or golimumab 100 mg injections plus methotrexate capsules (group 4, n  =  89). Injections were administered subcutaneously every 4 weeks. The co-primary endpoints were the proportion of patients with 20% or greater improvement in the American College of Rheumatology criteria (ACR20) at week 14 and the change from baseline in the health assessment questionnaire-disability index (HAQ-DI) score at week 24.
Results:
The proportion of patients who achieved an ACR20 response at week 14 was 33.1% in the placebo plus methotrexate group, 44.4% (p = 0.059) in the golimumab 100 mg plus placebo group, 55.1% (p = 0.001) in the golimumab 50 mg plus methotrexate group and 56.2% (p<0.001) in the golimumab 100 mg plus methotrexate group. At week 24, median improvements from baseline in HAQ-DI scores were 0.13, 0.13 (p = 0.240), 0.38 (p<0.001) and 0.50 (p<0.001), respectively. During the placebo-controlled portion of the study (to week 16), serious adverse events occurred in 2.3%, 3.8%, 5.6% and 9.0% of patients and serious infections occurred in 0.8%, 0.8%, 2.2% and 5.6%, respectively.
Conclusion:
The addition of golimumab to methotrexate in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function.
doi:10.1136/ard.2008.099010
PMCID: PMC2674549  PMID: 19066176
20.  In vitro inhibition of biophysical surface properties and change in ultrastructures of exogenous pulmonary surfactant by albumin or fibrinogen. 
Journal of Korean Medical Science  1998;13(2):123-130.
In order to observe the effects of serum albumin and fibrinogen on biophysical surface properties and the morphology of pulmonary surfactant in vitro, we measured the surface adsorption rate, dynamic minimum and maximum surface tension (min-, max-ST) by Pulsating Bubble Surfactometer, and demonstrated ultrastructures on a series of mixtures with varying concentrations of albumin or fibrinogen and Surfactant-TA. The albumin and fibrinogen significantly inhibited the adsorption rate and ST-lowering properties of surfactant through increasing STs of adsorption rate, min-ST, and max-ST. The characteristic morphology of the Surfactant-TA changed from lamellar rod-like structure with open ends into spherical structures with loss of their open ends by mixing with albumin or fibrinogen. These inhibitory effects of albumin and fibrinogen on surface properties of surfactant were dependent upon the increasing concentration of albumin or fibrinogen. We concluded that albumin and fibrinogen significantly altered surfactant function and its ultrastructural morphology in vitro. These findings support the concept that albumin and fibrinogen-induced surfactant dysfunction may play an important role in the pathophysiology of adult respiratory distress syndrome, and this adverse effect of albumin and fibrinogen on surfactant might be overcome by administration of large doses of exogenous surfactant.
PMCID: PMC3054486  PMID: 9610611
21.  Alterations in the carnitine metabolism in epileptic children treated with valproic acid. 
Journal of Korean Medical Science  1997;12(6):553-558.
Serum concentrations of total carnitine, free carnitine and acylcarnitine were measured in forty-one epileptic patients treated with valproic acid (VPA). Among them, 14 patients were on VPA monotherapy and 27 were on VPA polytherapy. Forty-one age and sex matched healthy normal controls were also evaluated for carnitine metabolism. The mean total and free carnitine were significantly lower in both the VPA monotherapy and polytherapy groups compared with the controls. However, there were no significant differences in concentrations of carnitine between the VPA polytherapy and VPA monotherapy groups. Patients treated with VPA polytherapy had lower carnitine than those treated with VPA monotherapy. An inverse correlation was found between serum concentrations of carnitine and duration of treatment in patients treated with VPA. However, there was no significant correlations between serum concentrations of carnitine and those of VPA. Also, correlation between serum concentrations of carnitine and the activities of serum GOT and GPT was not significant. After L-carnitine supplementation in eleven patients with hypocarnitinemia, the concentrations of carnitine were significantly increased.
PMCID: PMC3054317  PMID: 9443096
22.  A novel transcript encoding an N-terminally truncated AML1/PEBP2 alphaB protein interferes with transactivation and blocks granulocytic differentiation of 32Dcl3 myeloid cells. 
Molecular and Cellular Biology  1997;17(7):4133-4145.
The gene AML1/PEBP2 alphaB encodes the alpha subunit of transcription factor PEBP2/CBF and is essential for the establishment of fetal liver hematopoiesis. Rearrangements of AML1 are frequently associated with several types of human leukemia. Three types of AML1 cDNA isoforms have been described to date; they have been designated AML1a, AML1b, and AML1c. All of these isoforms encode the conserved-Runt domain, which harbors the DNA binding and heterodimerization activities. We have identified a new isoform of the AML1 transcript, termed AML1 deltaN, in which exon 1 is directly connected to exon 4 by alternative splicing. The AML1 deltaN transcript was detected in various hematopoietic cell lines of lymphoid to myeloid cell origin, as revealed by RNase protection and reverse transcriptase PCR analyses. The protein product of AML1 deltaN lacks the N-terminal region of AML1, including half of the Runt domain, and neither binds to DNA nor heterodimerizes with the beta subunit. However, AML1 deltaN was found to interfere with the transactivation activity of PEBP2, and the molecular region responsible for this activity was identified. Stable expression of AML1 deltaN in 32Dcl3 myeloid cells blocked granulocytic differentiation in response to granulocyte colony-stimulating factor. These results suggest that AML1 deltaN acts as a modulator of AML1 function and serves as a useful tool to dissect the functional domains in the C-terminal region of AML1.
PMCID: PMC232267  PMID: 9199349
23.  Cardiac tamponade as an initial manifestation of systemic lupus erythematosus--single case report. 
We describe a case of pericardial tamponade as an initial manifestation of systemic lupus erythematosus (SLE). Although pericarditis or pericardial effusion is the common cardiac complication of SLE, tamponade is unusual. Treatment consists of pericardiocentesis, administration of high dose glucocorticoid an antimalarial drug.
PMCID: PMC3054272  PMID: 9142666
24.  In vitro effect of meconium on the physical surface properties and morphology of exogenous pulmonary surfactant. 
Journal of Korean Medical Science  1996;11(5):429-436.
The pathophysiology of meconium aspiration syndrome(MAS) is related to mechanical obstruction of the airways and to chemical pneumonitis. Meconium is also suggested to cause functional deterioration of pulmonary surfactant. Recent studies have reported that meconium inhibits the physical surface properties of pulmonary surfactant, and that administration of exogenous surfactant may provide therapeutic benefits in animal models or infants with respiratory distress due to MAS. To assess the effects of meconium on physical surface properties, especially the changes on the air-liquid interface and hypophase of pulmonary surfactant in vitro, we studied the following findings; a) the surface spreading rate(SSR) and the surface adsorption rate(SAR), b) the viscosity, c) the electron microscopic changes, on a series of mixtures with various concentrations of lyophilized human meconium and Surfactant-TA(SurfactenTM). The human meconium has significantly increased the surface tension of SSR and the viscosity of pulmonary surfactant, but had decreased the surface pressure of SAR of surfactant, and changed the electron microscopic findings of surfactant. We have concluded that these findings support the concept that meconium-induced surfactant dysfunction may play a role in the pathophysiology of MAS.
PMCID: PMC3054187  PMID: 8934399
25.  Exogenous pulmonary surfactant replacement therapy in a neonate with pulmonary hypoplasia accompanying congenital diaphragmatic hernia--a case report. 
Journal of Korean Medical Science  1996;11(3):265-270.
Pulmonary hypoplasia(PH) commonly occurs in association with oligohydramnios and other congenital anomalies, especially congenital diaphragmatic hernia (CDH). Pulmonary hypoplasia is an important factor, as persistent pulmonary hypertension, in the prognosis of CDH. In some reports, there is a decrement of pulmonary surfactant in PH accompanying CDH. Recently, there are some reports that exogenous pulmonary surfactant therapy is effective in experimental animal model and neonatal respiratory distress with PH. We report a case of a 5 day-old male neonate, who had shown dyspnea and diagnosed as left pulmonary hypoplasia accompanying CDH. The CDH was surgically treated and the ipsilateral PH, with intratracheal administration of exogenous pulmonary surfactant postoperatively. After exogenous pulmonary surfactant application, the left lung volume was increased on chest roentgenogram and lung perfusion scan findings, and there was an improvement in oxygenation and clinical manifestations. We suggest that postoperative exogenous pulmonary surfactant replacement therapy is effective in the case of PH and further trials are needed to clarify the optimal dose and timing of supplementation of surfactant for treatment of infants with PH accompanying CDH.
PMCID: PMC3054049  PMID: 8843010

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