John W. Emerson

Macrophages Directly Contribute to the Exaggerated Inflammatory Response in Cystic Fibrosis Transmembrane Conductance Regulator−/− Mice

Pulmonary infection with an exaggerated inflammatory response is the major cause of morbidity and mortality in cystic fibrosis (CF). The objective of this study was to determine whether differences in the innate immune system underlie the exaggerated immune response in CF. We established a model that recapitulates the exaggerated immune response in a CF mouse model by exposure to Pseudomonas aeruginosa LPS and assessed the pulmonary cellular and cytokine responses of wild-type (WT) and CF mice. Compared with WT mice, CF mice had increased numbers of neutrophils and increased proinflammatory cytokines in their bronchoalveolar lavage fluid after LPS exposure. Based on the increased levels of IL-1alpha, IL-6, granulocyte colony-stimulating factor (G-CSF), and keratinocyte chemoattractant, all of which are known to be produced by macrophages, we tested whether two populations of macrophages, bone marrow-derived macrophages and alveolar macrophages, directly contribute to the elevated cytokine response of CF mice to LPS. After in vitro stimulation of bone marrow-derived macrophages and alveolar macrophages with LPS, IL-1alpha, IL-6, G-CSF, and monocyte chemoattractant protein-1 were higher in CF compared with WT cell supernatants. Quantitative analyses for IL-6 and keratinocyte chemoattractant revealed that LPS-stimulated CF macrophages have higher mRNA and intracellular protein levels compared with WT macrophages. Our data support the hypothesis that macrophages play a role in the exuberant cytokine production and secretion that characterizes CF, suggesting that the macrophage response may be an important therapeutic target for decreasing the morbidity of CF lung disease.

Do More Expensive Wines Taste Better? Evidence from a Large Sample of Blind Tastings

Individuals who are unaware of the price do not derive more enjoyment from more expensive wine. In a sample of more than 6,000 blind tastings, we find that the correlation between price and overall rating is small and negative, suggesting that individuals on average enjoy more expensive wines slightly less. For individuals with wine training, however, we find indications of a positive relationship between price and enjoyment. Our results are robust to the inclusion of individual fixed effects, and are not driven by outliers: when omitting the top and bottom deciles of the price distribution, our qualitative results are strengthened, and the statistical significance is improved further. Our results indicate that both the prices of wines and wine recommendations by experts may be poor guides for non-expert wine consumers.

A fast Bayesian change point analysis for the segmentation of microarray data

MOTIVATION The ability to detect regions of genetic alteration is of great importance in cancer research. These alterations can take the form of large chromosomal gains and losses as well as smaller amplifications and deletions. The detection of such regions allows researchers to identify genes involved in cancer progression, and to fully understand differences between cancer and non-cancer tissue. The Bayesian method proposed by Barry and Hartigan is well suited for the analysis of such change point problems. In our previous article we introduced the R package bcp (Bayesian change point), an MCMC implementation of Barry and Hartigans method. In a simulation study and real data examples, bcp is shown to both accurately detect change points and estimate segment means. Earlier versions of bcp (prior to 2.0) are O(n(2)) in speed and O(n) in memory (where n is the number of observations), and run in approximately 45 min for a sequence of length 10 000. With the high resolution of newer microarrays, the number of computations in the O(n(2)) algorithm is prohibitively time-intensive. RESULTS We present a new implementation of the Bayesian change point method that is O(n) in both speed and memory; bcp 2.1 runs in approximately 45 s on a single processor with a sequence of length 10,000--a tremendous speed gain. Further speed improvements are possible using parallel computing, supported in bcp via NetWorkSpaces. In simulated and real microarray data from the literature, bcp is shown to quickly and accurately detect aberrations of varying width and magnitude. AVAILABILITY The R package bcp is available on CRAN (R Development Core Team, 2008). The O(n) version is available in version 2.0 or higher, with support for NetWorkSpaces in versions 2.1 and higher.

Quantifying the Effects of Age, Gender, Degeneration, and Adjacent Level Degeneration on Cervical Spine Range of Motion Using Multivariate Analyses

Study Design. Retrospective review and multivariate analysis. Objective. Assess cervical spine segmental range of motion (ROM) with flexion/extension (F/E) radiographs and determine the relation to clinical variables. Summary of Background Data. Previous studies investigated the roles of age and degeneration on cervical ROM with univariate analyses. Multivariate analyses are required to account for multiple factors that may affect ROM and quantify their relative effects. Methods. Radiographs of 195 patients were analyzed, including 133 females and 62 males with ages ranging from 15 to 93 years. Segmental ROM and Kellgren score (KS) of degeneration were assessed for C2–C7. Patient’s age and gender were documented. Multivariate analyses were performed for each level. Independent variables evaluated were: (1) KS at the level of interest, (2) KS at the level above, (3) KS at the level below, (4) age, and (5) gender. Significance was defined as P < 0.05. Results. Interobserver reliabilities for assessing KS (intraclass correlation coefficient 0.81) and segmental ROM (intraclass correlation coefficient 0.72) were good to excellent. Age had a significant negative association with ROM at C2–C3, C3–C4, C4–C5, and C5–C6. KS at the level of interest had a significant negative association with ROM at C2–C3, C3–C4, C4–C5, C5–C6, and C6–C7. KS at the inferior segment had a significant positive association with ROM at C2–C3, C3–C4, and C4–C5. Gender had a significant association with ROM only at C2–C3. Conclusion. Age was associated with declining ROM independent of degeneration, amounting to a 5° decrease in subaxial cervical ROM every 10 years. Degeneration was also associated with ROM. For every point increase in KS at a given level, there was an associated 1.2° decrease in ROM at that level, and a 0.8° increase in ROM at the level above. These results provide a framework with which to counsel patients about cervical ROM and a benchmark from which procedure specific changes can be compared.

Lumbar total disc arthroplasty utilizing the prodisc prosthesis in smokers Versus nonsmokers : A prospective study with 2-year minimum follow-up

Study Design. Prospective nonrandomized clinical series. Objectives. To evaluate the efficacy of ProDisc lumbar artificial disc replacement (ADR) in smokers versus nonsmokers. Summary of Background Data. Smoking is a negative predictor in fusion surgery. To date, a prospective study of the treatment of incapacitating discogenic low back pain using ADR in smokers versus nonsmokers has not been described. Methods. A prospective analysis was performed on 104 patients with disabling discogenic low back pain treated with single-level lumbar ProDisc total disc arthroplasty. Smokers and nonsmokers were assessed before surgery and after surgery using patient satisfaction, Oswestry, and Visual Analog Scores. Additionally, preoperative and postoperative neurologic, radiographic, and pain medication assessments were performed at similar postoperative intervals. Results. Oswestry, Visual Analog Scores, and patient satisfaction scores revealed statistical improvement beginning 3 months after surgery and were maintained at minimum 2-year follow-up. Patient satisfaction scores were higher in smokers (94%) than in nonsmokers (87%) at 2-year follow-up (P = 0.07). Radiographic analysis revealed an affected disc height increase from 4 mm to 13 mm (P < 0.05) and an affected disc motion from 3° to 7° (P < 0.05). No cases of loosening, dislodgment, mechanical failure, infection, or fusion of the affected segment occurred. Conclusions. The results of our study indicate that smokers do equally well compared with nonsmokers when ProDisc ADR is used in the treatment of debilitating lumbar spondylosis. Patient outcome and radiographic scores showed significant improvement compared with preoperative levels. Although not evident in our series, additional surveillance for intraoperative and postoperative vascular spasm and occlusion may be warranted in smokers.

Towards rational molecular design: derivation of property guidelines for reduced acute aquatic toxicity

One of the most elusive yet significant goals of green chemistry is the routine design of commercially useful chemicals with reduced toxicological hazard. The main objective of this study was to derive property guidelines for the design of chemicals with reduced acute aquatic toxicity to multiple species. The properties explored included chemical solubilities, size, shape and molecular orbital energies. Physicochemical properties were predicted using Schrodingers QikProp, while frontier orbital energies (HOMO, LUMO and HOMO–LUMO gap) were determined based on AM1 and DFT calculations using Gaussian03. Experimental toxicity data included acute toxicity thresholds (LC50) for the fathead minnow (Pimephales promelas; 570 compounds), the Japanese medaka (Oryzias latipes; 285 compounds), a cladoceran (Daphnia magna; 363 compounds) and green algae (Pseudokirchneriella subcapitata, 300 compounds). Mechanistically-driven qualitative and quantitative analyses between the in-silico predicted molecular properties and in vivo toxicity data were explored in order to propose property limits associated with higher probabilities of acutely safe chemicals. The analysis indicates that 70–80% of the compounds that have low or no acute aquatic toxicity concern by EPA guidelines to the four species have a defined range of values for octanol-water partition coefficient (logPo/w) and ΔE (LUMO–HOMO gap). Compounds with logPo/w values less than 2 and ΔE (AM1) greater than 9 eV are significantly more likely to have low acute aquatic toxicity compared to compounds that do not meet these criteria. These results are mechanistically rationalized. Our work proposes design guidelines that can be used to significantly increase the probability that a chemical will have low acute toxicity to the four species studied, and potentially other aquatic species.

The Generalized Pairs Plot

This article develops a generalization of the scatterplot matrix based on the recognition that most datasets include both categorical and quantitative information. Traditional grids of scatterplots often obscure important features of the data when one or more variables are categorical but coded as numerical. The generalized pairs plot offers a range of displays of paired combinations of categorical and quantitative variables. A mosaic plot, fluctuation diagram, or faceted bar chart may be used to display two categorical variables. A side-by-side boxplot, stripplot, faceted histogram, or density plot helps visualize a categorical and a quantitative variable. A traditional scatterplot is suitable for displaying a pair of numerical variables, but options also support density contours or annotating summary statistics such as the correlation and number of missing values, for example. By combining these, the generalized pairs plot may help to reveal structure in multivariate data that otherwise might go unnoticed in the process of exploratory data analysis. Two different R packages provide implementations of the generalized pairs plot, gpairs and GGally. Supplementary materials for this article are available online on the journal web site.

Evaluation of a modified protocol for selective laser trabeculoplasty.

PurposeTo compare the intraocular pressure (IOP) response to a modified protocol for selective laser trabeculoplasty (SLT) to standard protocols for SLT and argon laser trabeculoplasty (ALT). Materials and MethodsA retrospective study of 318 eyes of 284 patients diagnosed with either primary open angle, pigmentary or pseudoexfoliation glaucoma who underwent laser trabeculoplasty from September 1997 to September 2005. One hundred and two patients, who underwent a modified SLT protocol with 100 overlapping laser spots over 180 degrees of trabecular meshwork were compared with 89 patients who received SLT with 100 nonoverlapping spots over 360 degrees and another 127 patients who received ALT with 50 spots over 180 degrees. IOPs were measured at baseline and postoperatively at 1 hour, 6 weeks, 4 months, and 14 months. Regression models, based on the observed data, were used to predict the fall in IOP in the 3 groups, controlling for differences in baseline pressure. ResultsThe IOP response to overlapping SLT was significantly worse than to nonoverlapping SLT or ALT, both of which had similar responses. Baseline IOP was the only preoperative factor that predicted response to ALT (P<0.0001) and nonoverlapping SLT (P=0.0019) at all follow-up times. There were no statistically significant predictive factors for IOP reduction in the overlapping SLT group. ConclusionsOverlapping application of SLT results in a poorer IOP response compared with ALT and nonoverlapping SLT.

Accelerated Solvent Extraction of Lignin from Aleurites moluccana (Candlenut) Nutshells

Lignin from candlenut shells was isolated using an ethanol-water accelerated solvent extraction method. Yields (based on Klason lignin) increased from about 14 to 33% as temperature increased from 100 to 195 °C and were also influenced by the amount of aqueous acid used to precipitate lignin from the extraction liquor. These yields were higher than could be obtained using a conventional dioxane-water acidolysis method. The resulting lignin was characterized by IR, 31P NMR, and 1H-13C HMQC NMR spectroscopic techniques. The lignin contained predominantly guaiacyl units, and both the total hydroxyl group content and phenolic hydroxyl group content were high.

Quantifying the effects of degeneration and other patient factors on lumbar segmental range of motion using multivariate analysis.

Study Design. Retrospective review and multivariate analysis. Objectives. Assess lumbar spine segmental range of motion (ROM) with flexion/extension (F/E) radiographs and determine the relation to clinical variables. Summary of Background Data. Prior studies have investigated the roles of age and degeneration on lumbar segmental ROM only using univariate analyses. Multivariate analyses are also required to differentiate the multiple factors that may affect ROM and quantify their relative effects. Methods. Radiographs of 258 patients were analyzed, including 137 females and 121 males with ages ranging from 18 to 92 years. Segmental ROM and Kellgren score (KS) of degeneration were assessed for L1–S1. Multivariate regression analyses were performed for each level. Predicting variables evaluated were: (1) KS at the level of interest, (2) KS at the level above, (3) KS at the level below, (4) age, (5) gender, (6) weight, (7) height, (8) body mass index (BMI), and (9) smoking. Significance was defined as P < 0.05. Results. Interobserver reliabilities for assessing KS (ICC 0.70) and segmental ROM (ICC 0.80) were good to excellent. In the multivariate analyses, age had a significant negative association with ROM at L1–L2, L2–L3, L3–L4, and L4–L5. BMI had a significant negative association with ROM at L2–L3, L3–L4, and L4–L5. KS at the level of interest had significant negative association with ROM only at L5–S1. KS at adjacent levels, gender, weight, height, and smoking did not have a significant association with ROM at any level. Conclusion. The results of this study provide the clinician with insight into factors that influence segmental lumbar ROM. Age was the strongest statistical predictor of ROM and was associated with declining ROM, amounting to an approximate 3° decrease in total sagittal lumbar ROM in the superior 4 segments every 10 years. BMI was another factor associated with lumbar ROM. Degeneration was a significant predictor of ROM only at L5–S1.