Exploring the Unique Contrast Properties of Aptamer-Gadolinium Conjugates in Magnetic Resonance Imaging for Targeted Imaging of Thrombi.

Objective: An important clinical question in the determination of the extent of thrombosis-related vascular conditions is the identification of blood clot location. Fibrin is a major molecular constituent of blood clots and can, therefore, be utilized in molecular imaging. In this proof-of-concept study, we sought to prepare a fibrin-targeting magnetic resonance imaging contrast agent, using a Gd(III)-loaded fibrinogen aptamer (FA) chelate conjugate (Gd(III)-NOTA-FA) (NOTA = 1,4,7-triazacyclononane-1,4,7-triacetic acid), to endow the ability to specifically accumulate at the location of blood clots, thereby enhancing contrast capabilities. Methods: The binding affinity of FA for fibrin was confirmed by fluorescence microscopy and microscale thermophoresis. The preparation and effective loading of the chelate-aptamer conjugates were confirmed by mass spectrometry and a xylenol orange colorimetric test. Longitudinal and transverse relaxivities and the effects of target binding were assessed using T1- and T2-map sequences at 7 T. T1- and T2-weighted images were acquired after blood clots were treated with Gd(III)-NOTA-FA. Collagen was used as the protein control, while an unrelated aptamer sequence, FB139, was used as the aptamer control. Results: FA demonstrated a high affinity and selectivity toward the polymeric protein, with a Kd of 16.6 nM, confirming an avidity over fibrinogen. The longitudinal (r1) and transverse (r2) relaxivities of Gd(III)-NOTA-FA demonstrated that conjugation to the long aptamer strand shortened T1 relaxation times and increased T2 relaxation times (3.04 and 38.7 mM-1 s-1, respectively). These effects were amplified by binding to the fibrin target (1.73 and 46.5 mM-1 s-1, respectively). In vitro studies with thrombin-polymerized human blood (clots) in whole blood showed an unexpected enhancement of signal intensity (hyperintense) produced exclusively at the location of the clot during the T2-weighted scan, while the presence of fibrinogen within a whole blood pool resulted in T1 signal intensity enhancement throughout the pool. This is advantageous, as simply reversing the type of a scan from a typical T1-weighted to a T2-weighted would allow to selectively highlight the location of blood clots. Conclusions: Gd(III)-NOTA-FA can be used for molecular imaging of thrombi, through fibrin-targeted delivery of contrast to the location of blood clots in T2-weighted scans.

A Guide to Extract Spinal Cord for Translational Stem Cell Biology Research: Comparative Analysis of Adult Human, Porcine, and Rodent Spinal Cord Stem Cells.

Improving the clinical translation of animal-based neural stem/progenitor cell (NSPC) therapies to humans requires an understanding of intrinsic human and animal cell characteristics. We report a novel in vitro method to assess spinal cord NSPCs from a small (rodent) and large (porcine) animal model in comparison to human NSPCs. To extract live adult human, porcine, and rodent spinal cord tissue, we illustrate a strategy using an anterior or posterior approach that was simulated in a porcine model. The initial expansion of primary NSPCs is carried out using the neurosphere assay followed by a pharmacological treatment phase during which NSPCs derived from humans, porcines, and rodents are assessed in parallel using the same defined parameters. Using this model, NSPCs from all species demonstrated multi-lineage differentiation and self-renewal. Importantly, these methods provide conditions to enable the direct comparison of species-dependent cell behavior in response to specific exogenous signals.

Management of cervical spine epidural abscess: a systematic review.

BACKGROUND: Cervical spinal epidural abscess (CSEA) is a localized infection between the thecal sac and cervical spinal column which may result in neurological deficit and death if inadequately treated. Two treatment options exist: medical management and surgical intervention. Our objective was to analyze CSEA patient outcomes in order to determine the optimal method of treatment. METHODS: An electronic literature search for relevant case series and retrospective reviews was conducted through June 2016. Data abstraction and study quality assessment were performed by two independent reviewers. A lack of available data led to a post hoc decision not to perform meta-analysis of the results; study findings were synthesized qualitatively. RESULTS: 927 studies were identified, of which 11 were included. Four studies were ranked as good quality, and seven ranked as fair quality. In total, data from 173 patients were included. Mean age was 55 years; 61.3% were male. Intravenous drug use was the most common risk factor for CSEA development. Staphylococcus aureus was the most commonly cultured pathogen. 140 patients underwent initial surgery, an additional 18 patients were surgically treated upon failure of medical management, and 15 patients were treated with antibiotics alone. CONCLUSION: The rates of medical management failure described in our review were much higher than those reported in the literature for thoracolumbar spinal epidural abscess patients, suggesting that CSEA patients may be at a greater risk for poor outcomes following nonoperative treatment. Thus, early surgery appears most viable for optimizing CSEA patient outcomes. Further research is needed in order to corroborate these recommendations.

Association Between the Estrogen Receptor Beta (ESR2) Rs1256120 Single Nucleotide Polymorphism and Adolescent Idiopathic Scoliosis: A Systematic Review and Meta-Analysis.

STUDY DESIGN: A systematic review and meta-analysis. OBJECTIVE: The aim of this study was to assess and synthesize the current evidence on the association between the rs1256120 single nucleotide polymorphism (SNP) of the estrogen receptor beta gene (ESR2) and adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Hormonal disturbance has been postulated as a potential etiological factor in the development of AIS. As estrogen receptors are important mediators of estrogen response, mutations in these genes, including rs1256120 of ESR2, have been chosen as susceptibility candidates for AIS predisposition. The association of rs1256120 with AIS has been investigated in several recent studies, but showed conflicting evidence. We conducted a systematic review to evaluate the strength of this body of evidence and quantitative synthesis to examine sources of heterogeneity. METHODS: This study conformed to PRISMA guidelines. Using a sensitive search strategy, PubMed (MEDLINE), EMBASE, and HuGE Literature Finder databases were searched to identify relevant studies for inclusion in the systematic review and meta-analysis. Risk of bias was assessed using a modified Newcastle-Ottawa Scale. The inverse variance model was used to calculate summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the allelic (C vs. T) and genotypic comparisons. Planned subgroup and sensitivity analyses were performed. RESULTS: Three studies were included for systematic review and meta-analysis (n = 1264 AIS cases and n=1020 controls). A null relationship was found between rs1256120 and AIS (allelic OR = 1.20, 95% CI: 0.81-1.78, P = 0.36, I = 84.9%), with the first reported association likely to be false-positive and contributing substantially to heterogeneity. CONCLUSION: Findings from the systematic review and meta-analysis suggest that rs1256120 of ESR2 is unlikely to be a predisposing or disease-modifying genetic risk factor for AIS. LEVEL OF EVIDENCE: 2.

Effect of Perioperative Vitamin C Supplementation on Postoperative Pain and the Incidence of Chronic Regional Pain Syndrome: A Systematic Review and Meta-Analysis.

OBJECTIVES: Postoperative pain can contribute to increased risk for complications and lengthened hospital stays. The objective was to analyze the effects of perioperative vitamin C supplementation on postoperative pain and the development of complex regional pain syndrome I (CRPS I) in patients undergoing surgical procedures. MATERIALS AND METHODS: A systematic review of published literature was performed through April 2014. References from relevant studies were scanned for additional studies. Results were screened for relevance independently, and full-text studies were assessed for eligibility. Reporting quality was assessed using a modified Newcastle-Ottawa Scale. RESULTS: The search strategy yielded 710 studies, of which 13 were included: 7 on postoperative pain and 6 on CRPS I. In the final analysis, 1 relevant study found a reduction in postoperative morphine utilization after preoperative vitamin C consumption, whereas another showed no difference in postoperative pain outcomes between the vitamin C and control groups. A meta-analysis of 3 applicable CRPS I studies showed a decrease in postoperative CRPS I after perioperative vitamin C supplementation (relative risk=2.25; τ²=0). DISCUSSION: There is moderate-level evidence supporting the use of a 2 g preoperative dose of vitamin C as an adjunct for reducing postoperative morphine consumption, and high-level evidence supporting perioperative vitamin C supplementation of 1 g/d for 50 days for CRPS I prevention after extremity surgery. Additional studies are necessary to increase the level of evidence to determine the overall effectiveness and optimum dosage of vitamin C.

Association between the ESR1 -351A>G single nucleotide polymorphism (rs9340799) and adolescent idiopathic scoliosis: a systematic review and meta-analysis.

PURPOSE: A single nucleotide polymorphism in the promoter region of the estrogen receptor alpha gene (ESR1), rs9340799, has been linked with adolescent idiopathic scoliosis (AIS) in several association studies with limited sample size and inconsistent findings. A systematic review can provide a comprehensive appraisal of literature evidence and a meta-analysis can obtain a more precise estimate of any association. The purpose of the present study was to assess and synthesize the currently available evidence on the association between rs9340799 and AIS by conducting a systematic review and meta-analysis. METHODS: This review followed the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. PubMed (MEDLINE), EMBASE, Scopus and HuGE Literature Finder databases were systematically searched to identify relevant studies following a sensitive strategy. Summary odds ratios and corresponding 95% confidence intervals (95 % CI) were estimated using the fixed-effect inverse variance model for allelic (G vs. A) and genotypic comparisons. RESULTS: Meta-analysis of four studies (n = 1,827 AIS cases and n = 1,253 controls) found a non-significant association between rs9340799 and AIS (allelic odds ratio 1.09, 95 % CI 0.96-1.23, p = 0.17). CONCLUSIONS: When examined in isolation, the rs9340799 polymorphism does not appear to be a likely susceptibility variant for AIS predisposition. However, rs9340799 may be associated with AIS severity, progression and treatment; further investigation is necessary to confirm these potential associations.

Association of rs11190870 near LBX1 with adolescent idiopathic scoliosis in East Asians: a systematic review and meta-analysis.

BACKGROUND CONTEXT: The rs11190870 single nucleotide polymorphism in the 3'-flanking region of the LBX1 gene has been implicated in the etiology of adolescent idiopathic scoliosis (AIS). A thorough appraisal of the evidence supporting this association has not been previously attempted. PURPOSE: To provide a comprehensive assessment and synthesis of the currently available evidence on the association between rs11190870 and AIS. STUDY DESIGN: A systematic review and meta-analysis. METHODS: This review followed the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. PubMed (MEDLINE), EMBASE, Scopus, and HuGE Literature Finder databases were systematically searched through November 2013 to identify relevant studies following a sensitive strategy. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using the fixed-effect inverse variance model for allelic (T vs. C) and genotypic comparisons. RESULTS: Meta-analysis of four studies conducted in East Asian populations (n=3,215 AIS cases and n=15,347 controls) found a highly statistically significant and robust association between rs11190870 and AIS. Comparison of summary ORs indicated a codominant model effect of the T allele. Carriers of the TC and TT genotypes were 69% (OR=1.69, 95% CI: 1.48-1.94, p<.001) and 162% (OR=2.62, 95% CI: 2.28-3.02, p<.001), respectively, more likely to have AIS compared with carriers of the CC genotype. CONCLUSIONS: Based on a comprehensive analysis of the currently available evidence, rs11190870 is likely a susceptibility variant for AIS in East Asians. Further investigation of this association is necessary in other populations.

Association between the IL10 -1082A>G (rs1800896) single-nucleotide polymorphism and atopic dermatitis: a systematic review and meta-analysis.

BACKGROUND: The potentially functionally relevant IL10 -1082A>G (rs1800896) promoter region single-nucleotide polymorphism has been implicated in the pathogenesis of atopic dermatitis (AD). Although this relationship has been studied extensively, these association studies were limited by small sample size. OBJECTIVE: To increase statistical power and obtain a more precise estimate of the association, literature evidence on IL10 -1082A>G and AD was assessed by conducting a systematic review and meta-analysis. METHODS: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed (MEDLINE), EMBASE, Scopus, and HuGE Literature Finder literature databases were systematically searched for relevant studies. Summary odds ratios and corresponding 95% confidence intervals were estimated using the fixed-effect inverse variance analysis method for allelic (G vs A) and genotypic comparisons. RESULTS: Meta-analysis of 7 studies (n = 849 cases and 1195 controls) found a nonsignificant association between the IL10 -1082A>G polymorphism and AD (allelic odds ratio, 1.02; 95% confidence interval, 0.88-1.19; P = 0.77). CONCLUSIONS: This study was unable to find a direct association between IL10 -1082A>G and AD. Further studies are needed to reveal the contributions of haplotype and gene-gene and gene-environment interaction effects involving this single-nucleotide polymorphism to AD.

Association between the SERPINE1 (PAI-1) 4G/5G insertion/deletion promoter polymorphism (rs1799889) and pre-eclampsia: a systematic review and meta-analysis.

The SERPINE1 -675 4G/5G promoter region insertion/deletion polymorphism (rs1799889) has been implicated in the pathogenesis of pre-eclampsia (PE), but the genetic association has been inconsistently replicated. To derive a more precise estimate of the association, a systematic review and meta-analysis was conducted. This study conformed to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed (MEDLINE), Scopus and HuGE Literature Finder literature databases were systematically searched for relevant studies. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for the allelic comparison (4G versus 5G) and genotypic comparisons following the co-dominant (4G/4G versus 5G/5G and 4G/5G versus 5G/5G), dominant (4G/4G+4G/5G versus 5G/5G) and recessive (4G/4G versus 4G/5G+5G/5G) genetic models. Between-study heterogeneity was quantified by I(2) statistics and publication bias was appraised with funnel plots. Sensitivity analysis was conducted to evaluate the robustness of meta-analysis findings. Meta-analysis of 11 studies involving 1297 PE cases and 1791 controls found a significant association between the SERPINE1 -675 4G/5G polymorphism and PE for the recessive genetic model (OR = 1.36, 95% CI: 1.13-1.64, P = 0.001), a robust finding according to sensitivity analysis. A low level of between-study heterogeneity was detected (I(2) = 20%) in this comparison, which may be explained by ethnic differences. Funnel plot inspection did not reveal evidence of publication bias. In conclusion, this study provides a comprehensive examination of the available literature on the association between SERPINE1 -675 4G/5G and PE. Meta-analysis results support this polymorphism as a likely susceptibility variant for PE.

Association between the TLR4 +896A>G (Asp299Gly) polymorphism and asthma: a systematic review and meta-analysis.

OBJECTIVE: To determine whether there is an association between the toll-like receptor 4 (TLR4) +896A>G single nucleotide polymorphism and asthma by conducting a systematic review and meta-analysis. METHODS: The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search for relevant studies was performed using PubMed (MEDLINE), Scopus, and HuGE Literature Finder databases with additional consultation of the reference lists of included studies. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated for the allelic comparison (G vs. A) and the genotypic comparison assuming a dominant genetic model (AG + GG vs. AA). I² statistics were calculated to assess the presence of between-study heterogeneity and funnel plots were inspected for indication of publication bias. Sensitivity analysis was performed to evaluate the influence of individual studies on the overall effect estimates. RESULTS: Meta-analysis of nine studies consisting of 1838 asthma cases and 1764 controls did not find a significant association between TLR4 +896A>G and asthma (genotypic OR = 1.12, 95% CI: 0.91-1.39, p = .27). Between-study heterogeneity was not detected (I² = 0%) and publication bias was not evident. Sensitivity analysis demonstrated the stability of the null association. CONCLUSIONS: The meta-analysis findings suggest a lack of direct association between the TLR4 +896A>G polymorphism and asthma, but gene-environment and gene-gene interaction effects and other considerations involving this polymorphism may exist. Therefore, further study is necessary to fully elucidate the role of TLR4 +896A>G in asthma.