Comparing EUS-directed Transgastric ERCP (EDGE) Versus Laparoscopic-Assisted ERCP Versus Enteroscopic ERCP: A Network Meta-analysis.

BACKGROUND: Management of choledocholithiasis in patients with Roux-en-Y gastric bypass surgery is challenging. This study aims to compare technical success rates, adverse events, and procedural time between 3 current approaches: endoscopic ultrasound-directed transgastric Endoscopic retrograde cholangiopancreatography (ERCP) (EDGE), enteroscopy-assisted ERCP (E-ERCP), and laparoscopic-assisted ERCP (LA-ERCP). METHODS: A systematic search of 5 databases was conducted. Direct and network meta-analyses were performed to compare interventions using the random effects model. A significance threshold of P < 0.05 was applied. RESULTS: Sixteen studies were included. On direct meta-analysis, technical success rates were comparable between EDGE and LA-ERCP (odds ratio: 0.768, CI: 0.196-3.006, P = 0.704, I2 = 14.13%). However, EDGE and LA-ERCP showed significantly higher success rates than E-ERCP. No significant differences in adverse events were found between EDGE versus LA-ERCP, EDGE versus E-ERCP, and LA-ERCP versus E-ERCP on direct meta-analysis. In terms of procedural time, EDGE was significantly shorter than E-ERCP [mean difference (MD): -31 minutes, 95% CI: -40.748 to -21.217, P < 0.001, I2 = 19.89%), and E-ERCP was shorter than LA-ERCP (MD: -44.567 minutes, 95% CI: -76.018 to -13.116, P = 0.005, I2 = 0%). EDGE also demonstrated a significant time advantage over LA-ERCP (MD: -78.145 minutes, 95% CI: -104.882 to -51.407, P < 0.001, I2 = 0%). All findings were consistent with network meta-analysis on random effects model. The heterogeneity of the model was low. CONCLUSIONS: EDGE and LA-ERCP showed superior technical success rates compared with E-ERCP. Adverse events did not significantly differ among the three approaches. Furthermore, EDGE demonstrated the shortest procedural duration. We recommend considering EDGE as a first-choice procedure.

Neuromuscular function of the shoulder girdle and upper extremity musculature in individuals with a history of glenohumeral labral repair.

The purpose of this study was to compare neuromuscular function in the upper extremity musculature between individuals with glenohumeral labrum repair and uninjured controls. This cross-sectional study examined 16 individuals with a primary, unilateral glenohumeral labral repair (male/female: 13/3, age: 24.1 ± 5.0 years, time from surgery: 36.7 ± 33.3 months) and 14 uninjured individuals (male/female: 11/3, age: 23.8 ± 2.7 years) matched by age, sex, activity level, and limb dominance participated. Mass-normalized shoulder abduction and wrist flexion maximal voluntary isometric contraction (MVIC) torque, motoneuron pool excitability of the flexor carpi radialis (Hoffmann reflex), and corticospinal excitability of the upper trapezius, middle deltoid, and flexor carpi radialis (active motor threshold [AMT]) were evaluated. Dependent and independent t-tests were used to assess between-limb and between-group comparisons. Cohen's d effect sizes with 95% confidence intervals were used to quantify the magnitude of differences observed. Within the injured group, the involved limb had lesser shoulder abduction MVIC torque (p < 0.001, d = 1.16) and higher AMT for the upper trapezius (p = 0.01, d = 0.81) compared with the contralateral limb. The labral repair group had lesser shoulder abduction MVIC torque (p < 0.001, d = 1.17) and Hoffmann reflex (p = 0.01, d = 0.99), as well as higher AMT for the upper trapezius (p < 0.001, d = 1.23) in their involved limb compared with the control group. Large magnitude neuromuscular impairments are present beyond 6 months from glenohumeral labral repair, suggesting potential origins of impairments to be addressed during post-operative rehabilitation.

Direct Oral Anticoagulants Versus Warfarin in Morbidly Obese Patients With Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-analysis.

BACKGROUND: Direct oral anticoagulants (DOACs) have been increasingly preferred over warfarin; however, The International Society of Thrombosis and Hemostasis recommended avoiding the use of DOACs in morbidly obese patients (body mass index >40 or weight >120 kg) because of limited clinical data. STUDY QUESTION: Are DOACs effective and safe in morbidly obese patients with nonvalvular atrial fibrillation (NVAF). DATA SOURCES: We performed a comprehensive search for published studies indexed in PubMed/MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials that evaluated the efficacy and safety of DOACs in morbidly obese patients with NVAF. STUDY DESIGN: Information on patient characteristics, comorbidities, primary anticoagulation indications, pharmacologic treatment, and outcomes were collected. The primary outcome of interest was stroke or systemic embolism (SSE) rate. The secondary outcome was major bleeding (MB). RESULTS: A total of 10 studies including, 89,494 morbidly obese patients with NVAF on oral anticoagulation therapy (45,427 on DOACs vs. 44,067 on warfarin) were included in the final analysis. The SSE rate was significantly lower in DOACs group compared with warfarin group [odds ratio: 0.71; 95% confidence interval (CI): 0.62-0.81; P < 0.0001; I2 = 0%]. MB rate was also significantly lower in DOACs group compared with the warfarin group (odds ratio: 0.60; 95% CI: 0.46-0.78; P < 0.0001; I2 = 86%). On subgroup analysis, SSE and MB event rates were significantly lower in rivaroxaban and apixaban than warfarin; however, dabigatran showed noninferiority to warfarin in SSE rate but superiority in the safety outcome. CONCLUSIONS: Our meta-analysis demonstrated that DOACs are effective and safe with statistical superiority when compared with warfarin in morbidly obese patients. Large-scale randomized clinical trials are needed to further evaluate the efficacy and safety of DOACs in this cohort of patients.

Outcomes of treatment modalities for ruptured intracranial aneurysms based on age - A meta-analysis.

BACKGROUND: Data comparing the effect of age on outcomes of patients who underwent either endovascular coiling (EVC) or neurosurgical clipping (NSC) for ruptured intracranial aneurysms remains limited. OBJECTIVE: To better elucidate the preferred intervention for ruptured aneurysm management by presenting the results of our systematic review of the literature that evaluated the potential advantages of the two interventions between different age groups. METHODS: Systematic review of PubMed and Embase was performed (2002 - June 10, 2019) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2013 guidelines. Median ages of EVC and NSC cohorts were 54 and 56, respectively. Ages below the median were used in our "younger" cohort; ages above the median were used in our "older" cohort. RESULTS: We reviewed 13 studies on 7,137 patients. In the younger cohort, there were 2840 (EVC: 1412, NSC: 1428) patients. In the older cohort, there were 4297 (EVC: 2552, NSC: 1745) patients. Overall, there was a significant difference in functionality between EVC (77.70%) and NSC (69.23%) (OR=1.69; 95% C.I.: 1.10-2.60, p = 0.0212). In our younger cohort, functionality was significantly different between EVC (77%) and NSC (69%) (OR=1.54; 95% C.I.: 1.29-1.84, p < 0.001). For the older cohort, there was no significant difference in functionality, complications, or efficacy. CONCLUSIONS: We have highlighted the importance of considering age prior to deciding which intervention is most appropriate for ruptured aneurysms, with higher morbidity and mortality with NSC versus EVC in the younger population.

Technical advance in targeted NGS analysis enables identification of lung cancer risk-associated low frequency TP53, PIK3CA, and BRAF mutations in airway epithelial cells.

BACKGROUND: Standardized Nucleic Acid Quantification for SEQuencing (SNAQ-SEQ) is a novel method that utilizes synthetic DNA internal standards spiked into each sample prior to next generation sequencing (NGS) library preparation. This method was applied to analysis of normal appearing airway epithelial cells (AEC) obtained by bronchoscopy in an effort to define a somatic mutation field effect associated with lung cancer risk. There is a need for biomarkers that reliably detect those at highest lung cancer risk, thereby enabling more effective screening by annual low dose CT. The purpose of this study was to test the hypothesis that lung cancer risk is characterized by increased prevalence of low variant allele frequency (VAF) somatic mutations in lung cancer driver genes in AEC. METHODS: Synthetic DNA internal standards (IS) were prepared for 11 lung cancer driver genes and mixed with each AEC genomic (g) DNA specimen prior to competitive multiplex PCR amplicon NGS library preparation. A custom Perl script was developed to separate IS reads and respective specimen gDNA reads from each target into separate files for parallel variant frequency analysis. This approach identified nucleotide-specific sequencing error and enabled reliable detection of specimen mutations with VAF as low as 5 × 10- 4 (0.05%). This method was applied in a retrospective case-control study of AEC specimens collected by bronchoscopic brush biopsy from the normal airways of 19 subjects, including eleven lung cancer cases and eight non-cancer controls, and the association of lung cancer risk with AEC driver gene mutations was tested. RESULTS: TP53 mutations with 0.05-1.0% VAF were more prevalent (p < 0.05) and also enriched for tobacco smoke and age-associated mutation signatures in normal AEC from lung cancer cases compared to non-cancer controls matched for smoking and age. Further, PIK3CA and BRAF mutations in this VAF range were identified in AEC from cases but not controls. CONCLUSIONS: Application of SNAQ-SEQ to measure mutations in the 0.05-1.0% VAF range enabled identification of an AEC somatic mutation field of injury associated with lung cancer risk. A biomarker comprising TP53, PIK3CA, and BRAF somatic mutations may better stratify individuals for optimal lung cancer screening and prevention outcomes.

Ursolic acid facilitates apoptosis in rheumatoid arthritis synovial fibroblasts by inducing SP1-mediated Noxa expression and proteasomal degradation of Mcl-1.

Rheumatoid arthritis (RA) is characterized by hyperplastic pannus formation mediated by activated synovial fibroblasts (RASFs) that cause joint destruction. We have shown earlier that RASFs exhibit resistance to apoptosis, primarily as a result of enhanced expression of myeloid cell leukemia-1 (Mcl-1). In this study, we discovered that ursolic acid (UA), a plant-derived pentacyclic triterpenoid, selectively induces B-cell lymphoma 2 homology 3-only protein Noxa in human RASFs. We observed that UA-induced Noxa expression was followed by a consequent decrease in Mcl-1 expression in a dose-dependent manner. Subsequent evaluation of the signaling pathways showed that UA-induced Noxa is primarily mediated by the JNK pathway in human RASFs. Chromatin immunoprecipitation (IP) studies into the promoter region of Noxa indicated the role of transcription factor specificity protein 1 in JNK-mediated Noxa expression. Furthermore, the results from IP studies and proximity ligation assays indicated that UA-induced Noxa colocalizes and associates with Mcl-1 to prime it for proteasomal degradation through K48-linked ubiquitination by the selective recruitment of Mcl-1 ubiquitin ligase E3, a homologous to E6-associated protein C terminus domain-containing E3 ubiquitin ligase. These findings unveil a novel mechanism of inducing apoptosis in RASFs and a potential adjunct therapeutic strategy of regulating synovial hyperplasia in RA.-Kim, E. Y., Sudini, K., Singh, A. K., Haque, M., Leaman, D., Khuder, S., Ahmed, S. Ursolic acid facilitates apoptosis in rheumatoid arthritis synovial fibroblasts by inducing SP1-mediated Noxa expression and proteasomal degradation of Mcl-1.

Rising Events and Improved Outcomes of Gastrointestinal Bleed With Shock in USA: A 12-year National Analysis.

OBJECTIVE: Limited information is available based on single-center studies on trends of incidence and outcomes in gastrointestinal (GI) bleed with shock. METHODS: We analyzed data from 2002 to 2013 National Inpatient Sample. Using ICD-9 codes we identified 6.4 million hospital discharges of GI bleed from National Inpatient Sample database. Events were analyzed based on type of GI bleed, in-hospital mortality, hemodynamic status, and use of blood products. RESULTS: GI bleed with shock results in higher hospital mortality (20.77% with shock vs. 2.6% without shock). Between 2002 and 2013, there has been an increase in the percentage of upper and lower GI bleed with shock (1.35% to 4.92% and 1.49% to 3.06%) along with a reduction in mortality in both upper GI bleed with shock (26.9% to 13.8%) and lower GI bleed with shock (54.7% to 19.7%). Consistent with the rise in GI bleed with shock was an increase in blood product utilization. Packed red blood cell (pRBC) transfusion was associated with reduction in mortality in both nonvariceal upper GI bleed with shock (18.3% without pRBC vs. 13.9% receiving pRBC) and lower GI bleed with shock (36.05% without pRBC vs. 22.13% receiving pRBC), but did not affect mortality in variceal upper GI bleed with shock (31.79% vs. 32.22%). CONCLUSIONS: GI bleed with shock carries a higher mortality and have been steadily increasing from 2002 to 2013. pRBC transfusion was associated in improved mortality in GI bleed with shock except variceal bleed.

The 6-year clinical outcomes for patients registered in a multiregional United States Kidney Paired Donation program - a retrospective study.

We examined what happened during a 6-year period to 1121 end-stage renal disease patients who registered with their willing/incompatible living donors for kidney exchanges with the Alliance for Paired Donation (APD). Of all patients, 65% were transplanted: 37% in kidney paired donation (APD-KPD, APD-other-KPD); 10% with compatible live donors (APD-LD); and 18% with deceased donors (APD-DD). The remaining patients were withdrawn (sick/died/others; 15%), or were still waiting (20%). For those patients with a cPRA 0-94%, 72% received a transplant. In contrast, only 49% of very highly sensitized (VHS; cPRA 95-100%) were transplanted. Of the VHS patients, 50% were transplanted by KPD/APD-LD while 50% benefited through prioritization of deceased donors in the modified kidney allocation system (KAS introduced in 2014). All APD transplanted groups had similar death-censored 4-year graft survivals as their relevant Organ Procurement and Transplantation Network (OPTN) groups. It is noteworthy that VHS graft and patient survival results were comparable to less sensitized and nonsensitized patients. All patients should be encouraged to search for compatible donors through different options. Expanding the donor pool through KPD and the new KAS of the OPTN increases the likelihood of transplantation for VHS patients.

Radiofrequency ablation combined with biliary stent placement versus stent placement alone for malignant biliary strictures: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Unresectable malignant biliary strictures are generally managed by palliative stent placement for drainage of biliary tree. Recently, radiofrequency ablation (RFA) has been used to improve the patency of biliary stents in these patients. Several studies have evaluated the effectiveness of biliary stent placement with RFA on stent patency and patient survival with variable results. We performed this meta-analysis to evaluate the efficacy and safety of biliary stent placement with RFA compared with stent placement alone in patients with malignant biliary strictures. METHODS: We performed a comprehensive search of electronic databases for all studies comparing RFA with biliary stent placement versus stent placement only. Measured outcomes included patient survival, stent patency, and procedure-related adverse events. An inverse variance method was used to pool data on stent patency into a random-effects model. Cox-regression analysis was used to calculate hazard ratio for survival analysis. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework to interpret our findings. RESULTS: Nine studies (including 2 abstracts) with a total of 505 patients were included in the meta-analysis. The pooled weighted mean difference in stent patency was 50.6 days (95% confidence interval [CI], 32.83-68.48), favoring patients receiving RFA. Pooled survival analysis of the reconstructed Kaplan-Meier data showed improved survival in patients treated with RFA (hazard ratio, 1.395; 95% CI, 1.145-1.7; P < .001). However, RFA was associated with a higher risk of postprocedural abdominal pain (31% vs 20%, P = .003). Our analysis did not show significant difference between the RFA and stent placement-only groups with regard to the risk of cholangitis, acute cholecystitis, pancreatitis, and hemobilia. CONCLUSIONS: In the light of this limited data based on observational studies, RFA was found to be safe and was associated with improved stent patency in patients with malignant biliary strictures. In addition, RFA may be associated with improved survival in these patients.

RNAseq analysis of bronchial epithelial cells to identify COPD-associated genes and SNPs.

BACKGROUND: There is a need for more powerful methods to identify low-effect SNPs that contribute to hereditary COPD pathogenesis. We hypothesized that SNPs contributing to COPD risk through cis-regulatory effects are enriched in genes comprised by bronchial epithelial cell (BEC) expression patterns associated with COPD. METHODS: To test this hypothesis, normal BEC specimens were obtained by bronchoscopy from 60 subjects: 30 subjects with COPD defined by spirometry (FEV1/FVC < 0.7, FEV1% < 80%), and 30 non-COPD controls. Targeted next generation sequencing was used to measure total and allele-specific expression of 35 genes in genome maintenance (GM) genes pathways linked to COPD pathogenesis, including seven TP53 and CEBP transcription factor family members. Shrinkage linear discriminant analysis (SLDA) was used to identify COPD-classification models. COPD GWAS were queried for putative cis-regulatory SNPs in the targeted genes. RESULTS: On a network basis, TP53 and CEBP transcription factor pathway gene pair network connections, including key DNA repair gene ERCC5, were significantly different in COPD subjects (e.g., Wilcoxon rank sum test for closeness, p-value = 5.0E-11). ERCC5 SNP rs4150275 association with chronic bronchitis was identified in a set of Lung Health Study (LHS) COPD GWAS SNPs restricted to those in putative regulatory regions within the targeted genes, and this association was validated in the COPDgene non-hispanic white (NHW) GWAS. ERCC5 SNP rs4150275 is linked (D' = 1) to ERCC5 SNP rs17655 which displayed differential allelic expression (DAE) in BEC and is an expression quantitative trait locus (eQTL) in lung tissue (p = 3.2E-7). SNPs in linkage (D' = 1) with rs17655 were predicted to alter miRNA binding (rs873601). A classifier model that comprised gene features CAT, CEBPG, GPX1, KEAP1, TP73, and XPA had pooled 10-fold cross-validation receiver operator characteristic area under the curve of 75.4% (95% CI: 66.3%-89.3%). The prevalence of DAE was higher than expected (p = 0.0023) in the classifier genes. CONCLUSIONS: GM genes comprised by COPD-associated BEC expression patterns were enriched for SNPs with cis-regulatory function, including a putative cis-rSNP in ERCC5 that was associated with COPD risk. These findings support additional total and allele-specific expression analysis of gene pathways with high prior likelihood for involvement in COPD pathogenesis.

A lung cancer risk classifier comprising genome maintenance genes measured in normal bronchial epithelial cells.

BACKGROUND: Annual low dose CT (LDCT) screening of individuals at high demographic risk reduces lung cancer mortality by more than 20%. However, subjects selected for screening based on demographic criteria typically have less than a 10% lifetime risk for lung cancer. Thus, there is need for a biomarker that better stratifies subjects for LDCT screening. Toward this goal, we previously reported a lung cancer risk test (LCRT) biomarker comprising 14 genome-maintenance (GM) pathway genes measured in normal bronchial epithelial cells (NBEC) that accurately classified cancer (CA) from non-cancer (NC) subjects. The primary goal of the studies reported here was to optimize the LCRT biomarker for high specificity and ease of clinical implementation. METHODS: Targeted competitive multiplex PCR amplicon libraries were prepared for next generation sequencing (NGS) analysis of transcript abundance at 68 sites among 33 GM target genes in NBEC specimens collected from a retrospective cohort of 120 subjects, including 61 CA cases and 59 NC controls. Genes were selected for analysis based on contribution to the previously reported LCRT biomarker and/or prior evidence for association with lung cancer risk. Linear discriminant analysis was used to identify the most accurate classifier suitable to stratify subjects for screening. RESULTS: After cross-validation, a model comprising expression values from 12 genes (CDKN1A, E2F1, ERCC1, ERCC4, ERCC5, GPX1, GSTP1, KEAP1, RB1, TP53, TP63, and XRCC1) and demographic factors age, gender, and pack-years smoking, had Receiver Operator Characteristic area under the curve (ROC AUC) of 0.975 (95% CI: 0.96-0.99). The overall classification accuracy was 93% (95% CI 88%-98%) with sensitivity 93.1%, specificity 92.9%, positive predictive value 93.1% and negative predictive value 93%. The ROC AUC for this classifier was significantly better (p < 0.0001) than the best model comprising demographic features alone. CONCLUSIONS: The LCRT biomarker reported here displayed high accuracy and ease of implementation on a high throughput, quality-controlled targeted NGS platform. As such, it is optimized for clinical validation in specimens from the ongoing LCRT blinded prospective cohort study. Following validation, the biomarker is expected to have clinical utility by better stratifying subjects for annual lung cancer screening compared to current demographic criteria alone.

Clinical outcomes associated with per-operative discontinuation of aspirin in patients with coronary artery disease: A systematic review and meta-analysis.

BACKGROUND: Postoperative state is characterized by increased thrombotic risk by virtue of platelet activation. Whether aspirin ameliorates this risk in patients with established coronary artery disease undergoing cardiac or noncardiac surgery is unknown. We conducted a systematic review and meta-analysis to compare the risk of major adverse cardiac events (MACE) and the risk of bleeding in patients with early (3-5 or more days before surgery) vs. late discontinuation(<3-5 days)/no discontinuation of aspirin. METHODS: Multiple databases were searched from inception of these databases until March 2015 to identify studies that reported discontinuation of aspirin in patients undergoing surgery. The outcomes measured were all cause mortality, nonfatal myocardial infarction and other relevant thrombotic events (MACE) which also may include, fatal and nonfatal MI, stent thrombosis and restenosis, stroke, perioperative cardiovascular complications (heart failure, MI, VTE, acute stroke) and perioperative bleeding during the perioperative period to up to 30 days after surgery. RESULTS: A total of 1,018 titles were screened, after which six observational studies met the inclusion criteria. Our analysis suggests that there is no difference in MACE with planned discontinuation of aspirin (OR = 1.17, 95% CI = 0.76-1.81; P = 0.05; I2 = 55%). Early discontinuation of aspirin showed a decreased risk of peri-operative bleeding (OR 0.82, 95% CI = 0.67-0.99; P = 0.04; I2 = 42%). CONCLUSION: Our analysis suggests that planned short-term discontinuation in the appropriate clinical setting appears to be safe in the correct clinical setting with no increased risk of thrombotic events and with a decreased risk of bleeding. © 2016 Wiley Periodicals, Inc.

Prevalence of autonomic dysfunction in hospitalized patients with Guillain-Barré syndrome.

INTRODUCTION: There is a paucity of data regarding autonomic dysfunction (AD) in Guillain-Barré Syndrome (GBS). Concern exists regarding inpatient mortality risk in GBS. We sought to identify the prevalence of AD in GBS inpatients. METHODS: We used the Health Cost and Utilization Project Nationwide Inpatient Sample (NIS). GBS hospitalizations were identified by International Classification of Diseases, Ninth Revision, Clinical Modification code-357.0. Non-GBS hospitalizations were matched to these cases 4:1 by age and gender. RESULTS: We identified 2,587 GBS patients and a control population of 10,348 patients during 2010-2011. The most common manifestations of AD were: diarrhea/constipation (15.5%), hyponatremia (14.9%), syndrome of inappropriate antidiuretic hormone secretion (SIADH) (4.8%), bradycardia (4.7%), and urinary retention (3.9%). GBS patients had higher rates of reversible cardiomyopathy, syncope, tachycardia, and Horner syndrome (P < 0.0001). CONCLUSIONS: AD most commonly manifests as diarrhea/constipation, SIADH/hyponatremia, and cardiac dysfunction. This report can help increase awareness of AD in GBS and aid in early identification, treatment, and mortality reduction. Muscle Nerve 56: 331-333, 2017.

Haplotype and diplotype analyses of variation in ERCC5 transcription cis-regulation in normal bronchial epithelial cells.

Excision repair cross-complementation group 5 (ERCC5) gene plays an important role in nucleotide excision repair, and dysregulation of ERCC5 is associated with increased lung cancer risk. Haplotype and diplotype analyses were conducted in normal bronchial epithelial cells (NBEC) to better understand mechanisms responsible for interindividual variation in transcript abundance regulation of ERCC5 We determined genotypes at putative ERCC5 cis-regulatory SNPs (cis-rSNP) rs751402 and rs2296147, and marker SNPs rs1047768 and rs17655. ERCC5 allele-specific transcript abundance was assessed by a recently developed targeted sequencing method. Syntenic relationships among alleles at rs751402, rs2296147, and rs1047768 were assessed by allele-specific PCR followed by Sanger sequencing. We then assessed association of ERCC5 allele-specific expression at rs1047768 with haplotype and diplotype structure at cis-rSNPs rs751402 and rs2296147. Genotype analysis revealed significantly (P < 0.005) higher interindividual variation in allelic ratios in cDNA samples relative to matched gDNA samples at both rs1047768 and rs17655. By diplotype analysis, mean expression was higher at the rs1047768 alleles syntenic with rs2296147 T allele compared with rs2296147 C allele. Furthermore, mean expression was lower at rs17655 C allele, which is syntenic with G allele at a linked SNP rs873601 (D' = 0.95). These data support the conclusions that in NBEC, T allele at SNP rs2296147 upregulates ERCC5, variation at rs751402 does not alter ERCC5 regulation, and that C allele at SNP rs17655 downregulates ERCC5 Variation in ERCC5 transcript abundance associated with allelic variation at these SNPs could result in variation in NER function in NBEC and lung cancer risk.

Identification of potential genomic biomarkers for Sjögren's syndrome using data pooling of gene expression microarrays.

Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration and destruction of salivary and lacrimal glands. The diagnosis of SS can be challenging due to lack of a specific test for the disease. The purpose of this study is to examine the accuracy of using gene expression profile for diagnosis of SS. We identified 9 publically available datasets that included gene expression data from saliva and salivary gland biopsy samples of 52 patients with SS and 51 controls. Out of these datasets, we compiled and pooled data from three datasets that included 37 and 29 samples from SS patients and healthy controls, respectively, which were designated as "training set." Then, we performed cross-listing in a group of independent gene expression datasets from patients with SS to identify consensus gene list of differentially expressed genes. We performed Linear Discriminant Analysis (LDA) to quantify the accuracy of discriminating genes to predict SS in both the "training set" and an independent group of datasets that was designated as "test set." We identified 55 genes as potential classifier genes to differentiate SS from healthy controls. An LDA by leave-one-out cross-validation method identified 19 genes (EPSTI1, IFI44, IFI44L, IFIT1, IFIT2, IFIT3, MX1, OAS1, SAMD9L, PSMB9, STAT1, HERC5, EV12B, CD53, SELL, HLA-DQA1, PTPRC, B2M, and TAP2) with highest classification accuracy rate (95.7 %). Moreover, we validated our results by reproducing the same gene expression profile as a discriminatory test in the "test set," which included data from salivary gland samples of 15 patients with SS and 22 controls with 94.6 % accuracy. We propose that gene expression profile in the saliva or salivary glands could represent a promising simple and reproducible diagnostic biomarker for SS.

Factors influencing the diameter of human anterior and posterior intercostal arteries.

At present, there have not been any detailed studies examining the size relationships of the intercostal arteries. This study was carried out to investigate the relationship between the vessel lumenal diameter of ipsilateral, paired anterior and posterior IC arteries, as well as with the length of the IC space supplied by each artery. Samples were collected from the second-sixth anterior and posterior IC arteries near their site of origin, and the lengths of the corresponding IC spaces were measured in 42 cadavers. Lumenal diameters of both the anterior and posterior IC arteries at consecutive IC space closely followed second degree polynomial regression models (R(2) = 0.9655, and R(2) = 0.9741, respectively), and reached maximum size at the fifth IC space, which was found to be the longest of the IC spaces. No direct relationship was observed between diameters of the paired anterior and posterior IC arteries, although there was a trend for the larger anterior IC arteries to be paired with the larger posterior IC arteries. The calculated rate of blood flow at each IC artery was approximately two-fold greater in males than in females. These results suggest that the length of the IC space, and hence the extent of the thoracic wall supplied, is a major factor in determining the diameter of both anterior and posterior IC arteries. Since COPD is such a prevalent disease, this study also examined its influence on the IC arteries, and found that the posterior IC arteries are significantly larger among afflicted subjects.

Cardioprotective role of ischemic postconditioning in acute myocardial infarction: a systematic review and meta-analysis.

BACKGROUND: Evidence suggests that ischemic postconditioning (IPoC) may reduce the extent of reperfusion injury. We performed a meta-analysis of randomized controlled trials, which compared the role of IPoC during primary percutaneous coronary intervention (PCI) to PCI alone (control group) in ST-segment elevation myocardial infarction. METHODS: Several databases were searched, which yielded 19 studies. The outcomes of interest were measures of myocardial damage (serum cardiac enzymes and infarct size by imaging) and left ventricular function (left ventricular ejection fraction and wall motion score index). Mean difference (MD) and standardized mean difference (SMD) were used to assess the treatment effect. An inverse variance method was used to pool data into a random-effects model. RESULTS: Ischemic postconditioning demonstrated a decrease in serum cardiac enzymes (SMD -0.48, 95% CI -0.92 to -0.05, I(2) = 92%), reduction in infarct size by imaging (SMD -0.30, 95% CI -0.58 to -0.01, I(2) = 80%), wall motion score index (MD -0.19, 95% CI -0.29 to -0.09, I(2) = 44%), and showed improvement in left ventricular ejection fraction (IPoC 52 ± 0.4, control 49.7 ± 0.4) (MD 2.78, 95% CI 0.66-4.91, I(2) = 69%). All included studies were limited by high risk of performance and publication bias. CONCLUSIONS: Ischemic postconditioning during PCI in ST-segment elevation myocardial infarction appears to be superior to PCI alone in reduction of both myocardial injury or damage and improvement in global and regional left ventricular function. The effect seems to be more pronounced when a greater myocardial area is at risk. Given the limitations of the current available evidence, additional data from large randomized controlled trials are warranted.

Role of ADAM-17, p38 MAPK, cathepsins, and the proteasome pathway in the synthesis and shedding of fractalkine/CX3 CL1 in rheumatoid arthritis.

OBJECTIVE: To evaluate the mechanism of fractalkine (FKN)/CX3 CL1 synthesis and shedding in rheumatoid arthritis synovial fibroblasts (RASFs) and in rat adjuvant-induced arthritis (AIA). METHODS: The effect of tumor necrosis factor α (TNFα) and/or interferon-γ (IFNγ) on FKN synthesis and shedding in human RASFs was determined over time by immunostaining, quantitative reverse transcription-polymerase chain reaction, and Western blotting. The role of protease enzymes and signaling pathways was evaluated using chemical inhibitors and small interfering RNA (siRNA). The activity of 20S proteasome in the lysates and the DNA binding of NF-κB/p65 in the nuclear fractions were evaluated. The in vivo relevance of these findings was examined in rat AIA. RESULTS: In RASFs, stimulation with the combination of TNFα and IFNγ induced cellular expression of FKN within 24 hours. Activation of ADAM-17, but not ADAM-10, partly mediated the proteolytic shedding and release of soluble FKN (sFKN) following TNFα/IFNγ stimulation for 24-72 hours. Compared with control siRNA, ADAM-17 siRNA markedly inhibited TNFα/IFNγ-induced sFKN production (by ∼33%). TNFα/IFNγ-induced sFKN release was markedly suppressed by inhibitors of ADAM-17, p38 MAPK, proteasome, or cathepsin inhibitor but not by inhibitors of caspase 3 or calpain. TNFα/IFNγ-induced proteasome activity also correlated with rapid degradation of IκBα and p38 MAPK phosphorylation. In vivo findings showed increased FKN expression in the joints of rats with AIA, which correlated with increased expression of ADAM-17 and phospho-p38 MAPK. CONCLUSION: Our results provide new understanding of the role of ADAM-17, p38 MAPK, cathepsins, and the proteasome pathway in FKN expression and shedding. Regulating these pathways may suppress FKN-mediated inflammation and tissue destruction.

Phenotypic analysis of pneumococcal polysaccharide-specific B cells.

The phenotype of B cells responsible for the production of anti-pneumococcal polysaccharide Ab has been unclear. Although individuals that respond poorly to the 23-valent pneumococcal polysaccharide (PPS) vaccine, Pneumovax, such as children <2 y, the asplenic, and a subset of common variable immunodeficiency patients, are profoundly deficient or lack IgM memory cells (CD27(+)IgM(+)), they are also deficient in the switched memory (CD27(+)IgM(-)) compartment. Direct characterization of PPS-specific B cells has not been performed. In this study, we labeled PPS14 and PPS23F with fluorescent markers. Fluorescently labeled PPS were used in FACSAria flow cytometry to characterize the phenotype of PPS-specific B cells obtained from 18 young adults pre- and postimmunization with Pneumovax. The labeled PPS were capable of inhibiting binding of Ab to the native PPS. Similarly, the native PPS were able to inhibit binding of PPS-specific B cells in a flow cytometric assay demonstrating specificity and functionality. Phenotypic analysis of unselected B cells, pre- and postimmunization, demonstrated a predominance of naive CD27(-)IgM(+) cells accounting for 61.5% of B cells. Likewise, the PPS-specific B cells obtained preimmunization consisted primarily of naive, CD27(-) B cells, 55.4-63.8%. In contrast, the PPS-specific B cells obtained postimmunization were predominantly IgM memory cells displaying the CD27(+)IgM(+), 54.2% for PPS14 and 66% for PPS23F, significantly higher than both unselected B cells and PPS-specific B cells. There was no significant difference in switched memory B cell populations (CD27(+)IgM(-)) between groups. These results suggest a dominant role of IgM memory cells in the immune response to pneumococcal polysaccharides.