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1.  Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens 
Gut  2010;59(1):88-97.
Background and aims
Hepatocellular carcinoma (HCC) frequently results from synergism between chemical and infectious liver carcinogens. Worldwide, the highest incidence of HCC is in regions endemic for the foodborne contaminant aflatoxin B1 (AFB1) and hepatitis B virus (HBV) infection. Recently, gut microbes have been implicated in multisystemic diseases including obesity and diabetes. Here, the hypothesis that specific intestinal bacteria promote liver cancer was tested in chemical and viral transgenic mouse models.
Helicobacter-free C3H/HeN mice were inoculated with AFB1 and/or Helicobacter hepaticus. The incidence, multiplicity and surface area of liver tumours were quantitated at 40 weeks. Molecular pathways involved in tumourigenesis were analysed by microarray, quantitative real-time PCR, liquid chromatography/mass spectrometry, ELISA, western blot and immunohistochemistry. In a separate experiment, C57BL/6 FL-N/35 mice harbouring a full-length hepatitis C virus (HCV) transgene were crossed with C3H/HeN mice and cancer rates compared between offspring with and without H hepaticus.
Intestinal colonisation by H hepaticus was sufficient to promote aflatoxin- and HCV transgene-induced HCC. Neither bacterial translocation to the liver nor induction of hepatitis was necessary. From its preferred niche in the intestinal mucus layer, H hepaticus activated nuclear factor-κB (NF-κB)-regulated networks associated with innate and T helper 1 (Th1)-type adaptive immunity both in the lower bowel and liver. Biomarkers indicative of tumour progression included hepatocyte turnover, Wnt/β-catenin activation and oxidative injury with decreased phagocytic clearance of damaged cells.
Enteric microbiota define HCC risk in mice exposed to carcinogenic chemicals or hepatitis virus transgenes. These results have implications for human liver cancer risk assessment and prevention.
PMCID: PMC3891362  PMID: 19850960
2.  Transcriptomes of the major human pancreatic cell types 
Diabetologia  2011;54(11):10.1007/s00125-011-2283-5.
We sought to determine the mRNA transcriptome of all major human pancreatic endocrine and exocrine cell subtypes, including human alpha, beta, duct and acinar cells. In addition, we identified the cell type-specific distribution of transcription factors, signalling ligands and their receptors.
Islet samples from healthy human donors were enzymatically dispersed to single cells and labelled with cell type-specific surface-reactive antibodies. Live endocrine and exocrine cell subpopulations were isolated by FACS and gene expression analyses were performed using microarray analysis and quantitative RT-PCR. Computational tools were used to evaluate receptor–ligand representation in these populations.
Analysis of the transcriptomes of alpha, beta, large duct, small duct and acinar cells revealed previously unrecognised gene expression patterns in these cell types, including transcriptional regulators HOPX and HDAC9 in the human beta cell population. The abundance of some regulatory proteins was different from that reported in mouse tissue. For example, v-maf musculoaponeurotic fibrosarcoma oncogene homologue B (avian) (MAFB) was detected at equal levels in adult human alpha and beta cells, but is absent from adult mouse beta cells. Analysis of ligand–receptor interactions suggested that EPH receptor–ephrin communication between exocrine and endocrine cells contributes to pancreatic function.
This is the first comprehensive analysis of the transcriptomes of human exocrine and endocrine pancreatic cell types—including beta cells—and provides a useful resource for diabetes research. In addition, paracrine signalling pathways within the pancreas are shown. These results will help guide efforts to specify human beta cell fate by embryonic stem cell or induced pluripotent stem cell differentiation or genetic reprogramming.
PMCID: PMC3880150  PMID: 21882062
Alpha cell; Beta cell; Paracrine signalling; Transcription factor
3.  Mechanism of Action of and Mechanism of Reduced Susceptibility to the Novel Anti-Clostridium difficile Compound LFF571 
LFF571 is a novel semisynthetic thiopeptide and potent inhibitor of Gram-positive bacteria. We report that the antibacterial activity of LFF571 against Clostridium difficile is due to inhibition of translation. Single-step mutants of C. difficile with reduced susceptibility to LFF571 were selected at frequencies of <4.5 × 10−11 to 1.2 × 10−9. Sequencing revealed a G260E substitution in the thiopeptide-binding pocket of elongation factor Tu. Importantly, this mutation did not confer cross-resistance to clinically used antimicrobials. These results support the development of LFF571 as a treatment for C. difficile infection.
PMCID: PMC3421628  PMID: 22644023
4.  Fatality and Injury Severity of Older Adult Motor Vehicle Collisions in Orange County, California, 1998–2007 
Introduction: Injuries and fatalities in adult drivers 18–65 years of age have decreased in recent years due to safer vehicles, enhanced medical policies, and implementation of injury prevention policies. However, adult drivers over 65 years of age are continuing to suffer from motor vehicle collision-related injuries and fatalities at a more constant rate. A number of physiological factors contribute to the deterioration in visual acuity, slower reaction speeds, and decreased awareness in older drivers. The objective of this study was to examine injury severity and fatality rates in older drivers compared to their younger counterparts in Orange County, California.
Methods: This study used the Statewide Integrated Traffic Record System data for Orange County for the years 1998–2007. Drivers were categorized into 4 age groups: 25–64, 65–74, 75–84, and older than 85 years of age. Injury severity was assessed by the investigating officer.
Results: Of the 197,814 drivers involved in motor vehicle collisions, 178,481 (90.2%) were in the 25–64 age group; 11,397 (5.8%) were 65–74; 6,592 (3.3%) were 75–84; and 1,344 drivers (0.7%) were over 85. Those aged 25–64 had the lowest fatality rate per 100,000 people, 2.5, whereas those 75–84 had the highest fatality rate, 4.9. The percent of crashes involving a left turn increased with age, and the percent that were stopped in the road decreases with age. Change in injury collision involvement ratio in the 3 younger age groups decreased by 26% to 32%, but decreased by 18% among drivers aged 85 years and older.
Conclusion: The decrease in collision fatalities was greater in the 25–64-year-old group compared to the older adult population. This disparity highlights the need for further injury prevention efforts for older drivers.
PMCID: PMC3583287  PMID: 23451291
5.  Hypoparathyroidism in the Adult: Epidemiology, Diagnosis, Pathophysiology, Target Organ Involvement, Treatment, and Challenges for Future Research 
Journal of Bone and Mineral Research  2011;26(10):2317-2337.
PMCID: PMC3405491  PMID: 21812031
hypoparathyroidism; calcium; epidemiology; genetics; parathyroid hormone; hypocalcemia
6.  Infection, inflammation and colon carcinogenesis 
Oncotarget  2012;3(8):737-738.
PMCID: PMC3478450  PMID: 22964519
7.  In Vitro and In Vivo Activities of Novel, Semisynthetic Thiopeptide Inhibitors of Bacterial Elongation Factor Tu ▿ 
Antimicrobial Agents and Chemotherapy  2011;55(11):5277-5283.
Recently, we identified aminothiazole derivatives of GE2270 A. These novel semisynthetic congeners, like GE2270 A, target the essential bacterial protein elongation factor Tu (EF-Tu). Medicinal chemistry optimization of lead molecules led to the identification of preclinical development candidates 1 and 2. These cycloalklycarboxylic acid derivatives show activity against difficult to treat Gram-positive pathogens and demonstrate increased aqueous solubility compared to GE2270 A. We describe here the in vitro and in vivo activities of compounds 1 and 2 compared to marketed antibiotics. Compounds 1 and 2 were potent against clinical isolates of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci (MIC90 ≤ 0.25 μg/ml) but weaker against the streptococci (MIC90 ≥ 4 μg/ml). Like GE2270 A, the derivatives inhibited bacterial protein synthesis and selected for spontaneous loss of susceptibility via mutations in the tuf gene, encoding EF-Tu. The mutants were not cross-resistant to other antibiotic classes. In a mouse systemic infection model, compounds 1 and 2 protected mice from lethal S. aureus infections with 50% effective doses (ED50) of 5.2 and 4.3 mg/kg, respectively. Similarly, compounds 1 and 2 protected mice from lethal systemic E. faecalis infections with ED50 of 0.56 and 0.23 mg/kg, respectively. In summary, compounds 1 and 2 are active in vitro and in vivo activity against difficult-to-treat Gram-positive bacterial infections and represent a promising new class of antibacterials for use in human therapy.
PMCID: PMC3195004  PMID: 21825297
8.  Implications and Approach to Incidental Findings in Live Ultrasound Models 
Incidental findings during ultrasound examinations occur frequently with live models in training sessions. Because of the broad scope of training sessions available, the ethics and guidelines of dealing with incidental findings in live models need to be discussed.
We provide a case of an endovaginal ultrasound that had significant unexpected findings.
This report demonstrates an important finding uncovered during an endovaginal modeling session.
Models should be notified beforehand of the possibility of an incidental finding, informed about it, made aware of potential associated costs, referred to another physician for follow-up, and provided a copy of the scans. A secure copy of the ultrasound scan should be stored for future reference.
PMCID: PMC3236140  PMID: 22224140
9.  Comparison of Pressures Applied by Digital Tourniquets in the Emergency Department 
Digital tourniquets used in the emergency department have been scrutinized due to complications associated with their use, including neurovascular injury secondary to excessive tourniquet pressure and digital ischemia caused by a forgotten tourniquet. To minimize these risks, a conspicuous tourniquet that applies the least amount of pressure necessary to maintain hemostasis is recommended.
To evaluate the commonly used tourniquet methods, the Penrose drain, rolled glove, the Tourni-cot and the T-Ring, to determine which applies the lowest pressure while consistently preventing digital perfusion.
We measured the circumference of selected digits of 200 adult males and 200 adult females to determine the adult finger size range. We then measured the pressure applied to four representative finger sizes using a pressure monitor and assessed the ability of each method to prevent digital blood flow with a pulse oximeter.
We selected four representative finger sizes: 45mm, 65mm, 70mm, and 85mm to test the different tourniquet methods. All methods consistently prevented digital perfusion. The highest pressure recorded for the Penrose drain was 727 mmHg, the clamped rolled glove 439, the unclamped rolled glove 267, Tourni-cot 246, while the T-Ring had the lowest at 151 mmHg and least variable pressures of all methods.
All tested methods provided adequate hemostasis. Only the Tourni-cot and T-Ring provided hemostasis at safe pressures across all digit sizes with the T-Ring having a lower overall average pressure.
PMCID: PMC3099617  PMID: 21691536
12.  Helicobacter pullorum Outbreak in C57BL/6NTac and C3H/HeNTac Barrier-Maintained Mice▿  
Journal of Clinical Microbiology  2010;48(5):1908-1910.
Helicobacter pullorum is a bacterial pathogen in humans. By using microaerobic culture techniques, H. pullorum was isolated from the feces of barrier-maintained mice and identified, on the basis of biochemical, restriction fragment length polymorphism, and 16S rRNA gene sequence analyses. This finding presents an opportunity to study H. pullorum pathogenesis in mice.
PMCID: PMC2863944  PMID: 20220161
13.  Electron Transfer Dissociation on Small Intact Proteins in an Ultra High Resolution Quadrupole Time of Flight Mass Spectrometer 
Electron Transfer Dissociation (ETD) has become a powerful technique for characterizing post translational modifications of proteins. Requiring interaction of both, analyte as well as ETD reagent ions, ETD is most commonly implemented in trapping instruments like 2D or 3D ion traps, providing low acquisition speed and mass accuracy. In contrast, Orthogonal Time of Flight (OTOF) instruments feature very high acquisition speed, mass accuracy, and in-spectra dynamic range. We present an instrument merging the trapping technique of ETD with an ultra high resolution quadrupole TOF, providing a resolution of 40,000, a mass accuracy <2ppm and an LC compatible spectra rate. The instrument used for this work is a Bruker ETD-maXis quadrupole TOF. ETD reagent anions were generated in an nCI source and are orthogonally injected between a pair of octapoles; which along with the nCI source were adapted from amaZon ETD ion trap. Reagent and analyte ions were mass selectively transmitted through a mass resolving quad and trapped in a hexapole collision cell. After the ETD reaction, product ions are transferred to a cooling cell where they are stored and extracted to the TOF analyzer. While ions are extracted, the next ETD experiment is ongoing in the collision cell thus maximizing duty cycle. ETD MS/MS data of intact proteins show a very complex mixture of ETD product ions, where the high resolution and mass accuracy capability of the TOF instrument was more than sufficient for protein identification with Mascot data base search of the intact protein. The work thus far shows a novel ultra-high resolution quadrupole TOF that is capable of rapid ETD experiments with sufficient resolving power for ETD MS/MS analysis of small intact proteins. We will present ETD MS/MS of proteins samples (ubiquitin, cytochrome C, beta-casein and carbonic anhydrase) resulting in sequence coverage of up to 90%.
PMCID: PMC2918003
14.  The Mass Spectrometry Core Laboratory of the Biomolecular Research Facility at the University of Virginia Health System 
The W. M. Keck Biomedical Mass Spectrometry Laboratory was established 14.5 years ago. Our expertise and advanced mass spectrometry instrumentation enable us to provide detailed characterization of proteins and proteomes for our researchers at a resonable cost. Equally important, we provide our researchers with consultations at both the experimental design and data analysis levels. The facility, through its large user-base and numerous professional contacts, serves as a focal point for the introduction of new techniques and technology to investigators. In the last year, we added a Thermo LTQ Velos Orbitrap Mass Spectrometer and a Thermo TSQ Quantum Access Max Triple Quadrupole MS as well as new services to meet the growing needs of our research community. These services include separation and characterization of proteins from a variety of biological sources; identification of post-translational modifications (phosphorylation, acetylation, ubiquitination, etc.); de novo (manual) sequence analysis of novel proteins; high resolution/mass accuracy measurements of peptides and small proteins; Binding partner analysis; and quantification of proteins using SRMs with heavy peptides or NSI-LC-MS-MS of chemically labeled peptides (TMT, iTRAQ, SILAC, or 18O).
PMCID: PMC2918018
15.  An Ion Trap with Increased Resolution and Scan Speed for Top-Down Proteomics with ETD/PTR 
Journal of Biomolecular Techniques : JBT  2010;21(3 Suppl):S36-S37.
MS/MS-techniques for top-down proteomics are electron-induced fragmentation processes like ECD or ETD. However, the analysis of ETD data of highly charged proteins is complicated because of multiply charged and overlaid fragment ions. The complexity of the ETD MS/MS-data is reduced when the initial ETD step is followed by proton transfer reaction (PTR) reducing the charge states of the multiple charge fragments. However, even following PTR a resolving power for ETD-fragments of z > 4 is demanded. We investigate the role of the increased resolution of a modified ion trap on top-down sequencing of larger peptides and proteins with ETD/PTR. An ion trap with improved control of the non-linear ejection process and faster scan modes as well as a higher mass resolution was used. ETD/PTR of isolated proteins is performed with reagent anions dedicated for either ETD or PTR. The formation of the different reagent anion is accomplished from only one neutral compound by altering the voltage of the negative chemical ionization source. The resolution of the used traps at a scan speed of 4,600 Th/sec is ideal for the identification of fragment ions with charge states up to 6+. Since with each proton transfer the m/z of an ETD-fragment will be shifted towards higher masses, the used high m/z range up to 3000u is essential for sufficient sequence coverage of intact proteins. We will present the impact of the increased resolution on the sequence analysis of intact proteins with a molecular weight up to 35kDa. With the increased resolution we were able to sequence a purified biomarker protein which has been previously discovered via MALDI imaging of breast cancer tissues.
PMCID: PMC2918044
16.  Bothrops Jararaca Venom: Insights into the Ontogenetic Variation from Pharmacological and Proteomic Approaches 
Previous studies have demonstrated that the pharmacological activities displayed by the venom of the snake Bothrops jararaca undergo a significant ontogenetic shift. Variation in the venom proteome is a well-documented phenomenon, however, variation in the venom peptidome is poorly understood. We report a comparative proteomic and peptidomic analysis of venoms from newborn and adult specimens of B. jararaca and correlate it with the evaluation of important venom features. We demonstrate that newborn and adult venoms have similar hemorrhagic activities, while the adult venom has a slightly higher lethal activity upon mice; however, the newborn venom is extremely more potent to kill chicks. The coagulant activity of newborn venom upon human plasma is ten times higher than that of adult venom. These differences were clearly reflected in their different profiles of 2D-PAGE and spot identification, gelatin zimography, immunostaining using specific antibodies, glycosylation pattern, and concanavalin A-binding proteins. The venom comparison by isobaric tag peptide labeling (iTRAQ) revealed clear differences in toxin levels. Metalloproteinases, serine proteinases and growth factors are among the proteins with higher expression in adult venom. Furthermore, we report the analysis of the peptide fraction of newborn and adult venoms by MALDI-TOF mass spectrometry and LC/MS/MS which revealed different contents of peptides, while the bradykinin potentiating peptides (BPPs) showed rather similar profiles, and were detected in the venoms showing their canonical sequences and also novel sequences corresponding to BPPs processed from their precursor protein at sites so far not described. As a result of these studies, we demonstrate a clear relationship between the ontogenetic shift in diet and animal size, and the venom proteome/peptidome in B. jararaca species.
PMCID: PMC2918092
17.  Experts' Round Table: Core Models and Management 
The landscape in which cores find themselves today is in flux, in part driven by ever changing scientific focus, scientific technology as well as funding streams.The question commonly heard is if the role of shared research resources in support of biomedical research changing and if so what models of core structure, organization and management best meet the needs of the research community. In this panel discussion we hope to outline current models of core structures, discuss various approaches to organization, funding and management and look forward to see whether there are new models to consider which may better meet the needs or the research community.The discussion will open, free flowing with the views, thoughts, and questions of the audience fully addressed.The participants will leave the session with thoughts for reflection on the current core in which they work and developmental concepts for the future directions, structure and operationof their core.
PMCID: PMC2918102
18.  Fast and Highly Accurate QTOF ETD MS/MS for Top-Down Sequencing 
The profiling of plasma proteins is a challenge in proteome analyses due to the dynamic range and the number of analytes. Once the statistic approach discovers a potential biomarker the major objective is the identification and characterization. Most of the biomarkers are too large to obtain substantial sequence information with common techniques like CID. Dedicated MS/MS-techniques for top-down analysis are electron-induced fragmentation processes like ECD or ETD. Presented here is the profiling and top-down identification of plasma proteins by the Bruker maxis UHR-TOF equipped with ETD. The goal of the present protein profiling approach is targeted towards proteins revealing molecular weight below 10 kDa. Plasma proteins with higher mass were depleted with a 10 kDa cutoff filter. Resulting proteins were subjected to a LC-separation using monolithic columns. The eluting and partially separated proteins were split towards the MS and fractionated. Afterwards selected fractions were infused offline into the MS. A scheduled list of protein precursor ions are then mass selectively fragmented by ETD. With the highly accurate TOF-analyzer the resulting ETD-fragments are detected. The method is evaluated with protein standards spiked into plasma. Due to the high resolving power of the TOF analyzer the monoisotopic annotation and the determination of charge states for both precursor and ETD fragment ions is possible. The data is submitted to a database search engine (Mascot) optimized for Top-Down data. Sequence tags and Top-Down related sequence analyses were generated in BioTools using a mixture of automated calculations and interactive sequence assignments.
PMCID: PMC2918179
19.  Helicobacter bilis: bacterial provocateur orchestrates host immune responses to commensal flora in a model of inflammatory bowel disease 
Gut  2007;56(7):898-900.
Helicobacter bilis can elicit heterologous immune responses to lower gut flora
PMCID: PMC1994372  PMID: 17566023
20.  Chronic Hepatitis, Hepatic Dysplasia, Fibrosis, and Biliary Hyperplasia in Hamsters Naturally Infected with a Novel Helicobacter Classified in the H. bilis Cluster▿  
Journal of Clinical Microbiology  2009;47(11):3673-3681.
We recently described helicobacter-associated progressive, proliferative, and dysplastic typhlocolitis in aging (18- to 24-month-old) Syrian hamsters. Other pathogens associated with typhlocolitis in hamsters, Clostridium difficile, Lawsonia intracellularis, and Giardia spp., were not indentified. The presence of Helicobacter genus-specific DNA was noted by PCR in cecal and paraffin-embedded liver samples from aged hamsters by the use of Helicobacter-specific PCR primers. By 16S rRNA analysis, the Helicobacter sp. isolated from the liver tissue was identical to the cecal isolates from hamsters. The six hamster 16S rRNA sequences form a genotypic cluster most closely related to Helicobacter sp. Flexispira taxon 8, part of the Helicobacter bilis/H. cinaedi group. Livers from aged helicobacter-infected hamsters showed various stages of predominantly portocentric and, to a lesser extent, perivenular fibrosis. Within nodules, there was cellular atypia consistent with nodular dysplasia. The livers also exhibited a range of chronic active portal/interface and lobular inflammation, with significant portal hepatitis being present. The inflammation was composed of a mixture of lymphocytes, neutrophils, and macrophages, indicative of its chronic-active nature in these aged hamsters infected with Helicobacter spp. The isolation of novel Helicobacter spp., their identification by PCR from the diseased livers of aged hamsters, and their taxonomic classification as belonging to the Helicobacter bilis cluster strengthen the argument that H. bilis and closely related Helicobacter spp. play an etiological role in hepatobiliary disease in both animals and humans.
PMCID: PMC2772605  PMID: 19759229
21.  Ileocecal Intussusception in the Adult Population: Case Series of Two Patients 
Intussusception is a condition found primarily in the pediatric population. In the adult population, however, intussusception is usually due to a pathological process, with a higher risk of bowel obstruction, vascular compromise, inflammatory changes, ischemia, and necrosis. Radiographic and sonographic evidence can aid in the diagnosis. Surgical intervention involving resection of affected bowel is the standard of care in adult cases of intussusception.
Case Reports:
We present the case of a 21-year-old female who presented to the Emergency Department with diffuse cramping abdominal pain and distention. Workup revealed ileocecal intussusception, with a prior appendectomy scar serving as the lead point discovered during exploratory laparotomy. We also present the case of a 66-year-old male, who presented with one week of intermittent lower abdominal pain associated with several episodes of nausea and vomiting. Workup revealed ileocolic intussusception secondary to adenocarcinoma of the right colon, confirmed upon exploratory laparotomy with subsequent right hemicolectomy.
In the adult population, intussusception is usually caused by a lead point, with subsequent telescoping of one part of the bowel into an adjacent segment. While intussusception can occur in any part of the bowel, it usually occurs between a freely moving segment and either a retroperitoneal or an adhesion-fixed segment. The etiology may be associated with pathological processes such as carcinoma or iatrogenic causes, such as scars or adhesions from prior surgeries. The cases presented here demonstrate important etiologies of abdominal pain in adult patients. Along with gynecological etiologies of lower quadrant abdominal pain in female patients, it is important for the emergency physician to expand the differential diagnosis to include other causes, such as intussusceptions, especially given the symptoms that could be associated with bowel obstruction.
PMCID: PMC2908657  PMID: 20823972
22.  Prevalence of Escherichia coli O157:H7 in Organically and Naturally Raised Beef Cattle ▿ †  
Applied and Environmental Microbiology  2009;75(16):5421-5423.
We determined the prevalence of Escherichia coli O157:H7 in organically and naturally raised beef cattle at slaughter and compared antibiotic susceptibility profiles of the isolates to those of isolates from conventionally raised beef cattle. The prevalences of E. coli O157:H7 were 14.8 and 14.2% for organically and naturally raised cattle, respectively. No major difference in antibiotic susceptibility patterns among the isolates was observed.
PMCID: PMC2725470  PMID: 19542334
23.  Effect of a Medical Student Emergency Ultrasound Clerkship on Number of Emergency Department Ultrasounds 
To determine whether a medical student emergency ultrasound clerkship has an effect on the number of patients undergoing ultrasonography and the number of total scans in the emergency department.
We conducted a prospective, single-blinded study of scanning by emergency medicine residents and attendings with and without medical students. Rotating ultrasound medical students were assigned to work equally on all days of the week. We collected the number of patients scanned and the number of scans, as well as participation of resident and faculty.
In seven months 2,186 scans were done on the 109 days with students and 707 scans on the 72 days without them. Data on 22 days was not recorded. A median of 13 patients per day were scanned with medical students (CI 12–15) versus seven (CI 6–9) when not. In addition, the median number of scans was 18 per day with medical students (CI 16–20) versus eight (CI 6–10) without them.
There were significantly more patients scanned and scans done when ultrasound medical students were present.
PMCID: PMC2850850  PMID: 20411072
24.  A Multivariate Multilevel Approach to the Modeling of Accuracy and Speed of Test Takers 
Psychometrika  2008;74(1):21-48.
Response times on test items are easily collected in modern computerized testing. When collecting both (binary) responses and (continuous) response times on test items, it is possible to measure the accuracy and speed of test takers. To study the relationships between these two constructs, the model is extended with a multivariate multilevel regression structure which allows the incorporation of covariates to explain the variance in speed and accuracy between individuals and groups of test takers. A Bayesian approach with Markov chain Monte Carlo (MCMC) computation enables straightforward estimation of all model parameters. Model-specific implementations of a Bayes factor (BF) and deviance information criterium (DIC) for model selection are proposed which are easily calculated as byproducts of the MCMC computation. Both results from simulation studies and real-data examples are given to illustrate several novel analyses possible with this modeling framework.
PMCID: PMC2792348  PMID: 20037635
speed; accuracy; IRT; response times
25.  Cytolethal Distending Toxin Promotes Helicobacter cinaedi-Associated Typhlocolitis in Interleukin-10-Deficient Mice▿  
Infection and Immunity  2009;77(6):2508-2516.
Helicobacter cinaedi colonizes a wide host range, including rodents, and may be an emerging zoonotic agent. Colonization parameters, pathology, serology, and inflammatory responses to wild-type H. cinaedi (WTHc) were evaluated in B6.129P2-IL-10tm1Cgn (IL-10−/−) mice for 36 weeks postinfection (WPI) and in C57BL/6 (B6) mice for 12 WPI. Because cytolethal distending toxin (CDT) may be a virulence factor, IL-10−/− mice were also infected with the cdtBHc and cdtB-NHc isogenic mutants and evaluated for 12 WPI. Consistent with other murine enterohepatic helicobacters, WTHc did not cause typhlocolitis in B6 mice, but mild to severe lesions developed at the cecocolic junction in IL-10−/− mice, despite similar colonization levels of WTHc in the cecum and colon of both B6 and IL-10−/− mice. WTHc and cdtB mutants also colonized IL-10−/− mice to a similar extent, but infection with either cdtB mutant resulted in attenuated typhlocolitis and hyperplasia compared to infection with WTHc (P < 0.03), and only WTHc infection caused dysplasia and intramucosal carcinoma. WTHc and cdtBHc mutant infection of IL-10−/− mice elevated mRNA expression of tumor necrosis factor alpha, inducible nitric oxide synthase, and gamma interferon in the cecum, as well as elevated Th1-associated serum immunoglobulin G2ab compared to infection of B6 mice (P < 0.05). Although no hepatitis was noted, liver samples were PCR positive at various time points for WTHc or the cdtBHc mutant in approximately 33% of IL-10−/− mice and in 10 to 20% of WTHc-infected B6 mice. These results indicate that WTHc can be used to model inflammatory bowel disease in IL-10−/− mice and that CDT contributes to the virulence of H. cinaedi.
PMCID: PMC2687359  PMID: 19307212

Results 1-25 (249)