Raking Kappa: Describing Potential Impact of Marginal Distributions on Measures of Agreement

Several authors have noted the dependence of kappa measures of inter-rater agreement on the marginal distributions of contingency tables displaying the joint ratings. This paper introduces a smoothed version of kappa computed after raking the table to achieve pre-specified marginal distributions. A comparison of kappa with raked kappa for various margins can indicate the extent of the dependence on the margins, and can indicate how much of the lack of agreement is due to marginal heterogeneity.     

Identification of a 13-kDa protein associated with the polyhydroxyalkanoic acid granules from Acinetobacter spp.

Abstract Transferrin-binding proteins from Neisseria meningitidis vary among different isolates. We have identified and studied a hypervariable region adjacent to the carboxyl-end of the transferrin-binding domain of the Tbp2 molecule. The tbp2 genes from six strains of N. meningitidis were cloned and sequenced in this particular region. Sequence analysis of these regions along with five other sequences available from pathogenic Neisseria showed a common organisation of seven highly variable nucleotide stretches interspersed with six conserved nucleotide stretches. The variable regions correlated with the location of immunoreactive epitopes in polyclonal antisera raised to transferrin-binding proteins identified by peptide pin technology. Sequence analysis suggested a mosaic-like organisation of the tbp2 genes. Taken together, these data suggest that the antigenic variation in this part of the protein may result from a strong host immune pressure.     

The Mitogen-activated Protein (MAP) Kinases p38 and Extracellular Signal-regulated Kinase (ERK) Are Involved in Hepatocyte-mediated Phenotypic Switching in Prostate Cancer Cells

The greatest challenge for the seeding of cancer in metastatic sites is integration into the ectopic microenvironment despite the lack of an orthotopic supportive environment and presence of pro-death signals concomitant with a localized “foreign-body” inflammatory response. In this metastatic location, many carcinoma cells display a reversion of the epithelial-to-mesenchymal transition that marks dissemination in the primary tumor mass. This mesenchymal to epithelial reverting transition (MErT) is thought to help seeding and colonization by protecting against cell death. We have previously shown that hepatocyte coculture induces the re-expression of E-cadherin via abrogation of autocrine EGFR signaling pathway in prostate cancer (PCa) cells and that this confers a survival advantage. Herein, we show that hepatocytes educate PCa to undergo MErT by modulating the activity of p38 and ERK1/2. Hepatocytes inhibited p38 and ERK1/2 activity in prostate cancer cells, which allowed E-cadherin re-expression. Introduction of constitutively active MEK6 and MEK1 to DU145 cells cocultured with hepatocytes abrogated E-cadherin re-expression. At least a partial phenotypic reversion can be achieved by suppression of p38 and ERK1/2 activation in DU145 cells even in the absence of hepatocytes. Interestingly, these mitogen-activated protein kinase activities were also triggered by re-expressed E-cadherin leading to p38 and ERK1/2 activity in PCa cells; these signals provide protection to PCa cells upon challenge with chemotherapy and cell death-inducing cytokines. We propose that distinct p38/ERK pathways are related to E-cadherin levels and function downstream of E-cadherin allowing, respectively, for hepatocyte-mediated MErT and tumor cell survival in the face of death signals.     

The Binaural Masking-Level Difference of Mandarin Tone Detection and the Binaural Intelligibility-Level Difference of Mandarin Tone Recognition in the Presence of Speech-Spectrum Noise

Binaural hearing involves using information relating to the differences between the signals that arrive at the two ears, and it can make it easier to detect and recognize signals in a noisy environment. This phenomenon of binaural hearing is quantified in laboratory studies as the binaural masking-level difference (BMLD). Mandarin is one of the most commonly used languages, but there are no publication values of BMLD or BILD based on Mandarin tones. Therefore, this study investigated the BMLD and BILD of Mandarin tones. The BMLDs of Mandarin tone detection were measured based on the detection threshold differences for the four tones of the voiced vowels /i/ (i.e., /i1/, /i2/, /i3/, and /i4/) and /u/ (i.e., /u1/, /u2/, /u3/, and /u4/) in the presence of speech-spectrum noise when presented interaurally in phase (S₀N₀) and interaurally in antiphase (S_πN₀). The BILDs of Mandarin tone recognition in speech-spectrum noise were determined as the differences in the target-to-masker ratio (TMR) required for 50% correct tone recognitions between the S₀N₀ and S_πN₀ conditions. The detection thresholds for the four tones of /i/ and /u/ differed significantly (p<0.001) between the S₀N₀ and S_πN₀ conditions. The average detection thresholds of Mandarin tones were all lower in the S_πN₀ condition than in the S₀N₀ condition, and the BMLDs ranged from 7.3 to 11.5 dB. The TMR for 50% correct Mandarin tone recognitions differed significantly (p<0.001) between the S₀N₀ and S_πN₀ conditions, at –13.4 and –18.0 dB, respectively, with a mean BILD of 4.6 dB. The study showed that the thresholds of Mandarin tone detection and recognition in the presence of speech-spectrum noise are improved when phase inversion is applied to the target speech. The average BILDs of Mandarin tones are smaller than the average BMLDs of Mandarin tones.     

Simultaneous Quantification of Multiple Urinary Naphthalene Metabolites by Liquid Chromatography Tandem Mass Spectrometry

Naphthalene is an environmental toxicant to which humans are exposed. Naphthalene causes dose-dependent cytotoxicity to murine airway epithelial cells but a link between exposure and human pulmonary disease has not been established. Naphthalene toxicity in rodents depends on P450 metabolism. Subsequent biotransformation results in urinary elimination of several conjugated metabolites. Glucuronide and sulfate conjugates of naphthols have been used as markers of naphthalene exposure but, as the current studies demonstrate, these assays provide a limited view of the range of metabolites generated from the parent hydrocarbon. Here, we present a liquid chromatography tandem mass spectrometry method for measurement of the glucuronide and sulfate conjugates of 1-naphthol as well as the mercapturic acids and N-acetyl glutathione conjugates from naphthalene epoxide. Standard curves were linear over 2 log orders. On column detection limits varied from 0.91 to 3.4 ng; limits of quantitation from 1.8 to 6.4 ng. The accuracy of measurement of spiked urine standards was -13.1 to + 5.2% of target and intra-day and inter-day variability averaged 7.2 (± 4.5) and 6.8 (± 5.0) %, respectively. Application of the method to urine collected from mice exposed to naphthalene at 15 ppm (4 hrs) showed that glutathione-derived metabolites accounted for 60-70% of the total measured metabolites and sulfate and glucuronide conjugates were eliminated in equal amounts. The method is robust and directly measures several major naphthalene metabolites including those derived from glutathione conjugation of naphthalene epoxide. The assays do not require enzymatic deconjugation, extraction or derivatization thus simplifying sample work up.     

Early real-time estimation of the basic reproduction number of emerging or reemerging infectious diseases in a community with heterogeneous contact pattern: Using data from Hong Kong 2009 H1N1 Pandemic Influenza as an illustrative example

Emerging and re-emerging infections such as SARS (2003) and pandemic H1N1 (2009) have caused concern for public health researchers and policy makers due to the increased burden of these diseases on health care systems. This concern has prompted the use of mathematical models to evaluate strategies to control disease spread, making these models invaluable tools to identify optimal intervention strategies. A particularly important quantity in infectious disease epidemiology is the basic reproduction number, R_0. Estimation of this quantity is crucial for effective control responses in the early phase of an epidemic. In our previous study, an approach for estimating the basic reproduction number in real time was developed. This approach uses case notification data and the structure of potential transmission contacts to accurately estimate R₀ from the limited amount of information available at the early stage of an outbreak. Based on this approach, we extend the existing methodology; the most recent method features intra- and inter-age groups contact heterogeneity. Given the number of newly reported cases at the early stage of the outbreak, with parsimony assumptions on removal distribution and infectivity profile of the diseases, experiments to estimate real time R₀ under different levels of intra- and inter-group contact heterogeneity using two age groups are presented. We show that the new method converges more quickly to the actual value of R₀ than the previous one, in particular when there is high-level intra-group and inter-group contact heterogeneity. With the age specific contact patterns, number of newly reported cases, removal distribution, and information about the natural history of the 2009 pandemic influenza in Hong Kong, we also use the extended model to estimate R₀ and age-specific R₀.