bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating Compliance with the 15-Second Rule for Driver-Interface Usability and Safety
Authors: Green Paul
Published: January 2012

This paper describes SAE J2365 (Recommended Practice for Calculating the Time to Complete In-Vehicle Navigation and Route Guidance Tasks), a draft procedure to estimate if the requirements of SAE J2364 (Navigation Function Access) are met. Application of these practices will enhance the safety, ease of use, and customer convenience of driver interfaces. SAE J2364 specifies that drivers should not be allowed to perform navigation-system tasks in a moving vehicle that take more than 15 seconds to complete when measured staticly. Tasks are defined to start when the driver's hands begin to move from the steering wheel and end when feedback from the final-switch actuation is processed.

The 11-step calculation procedure of J2365 involves determining exactly how each task (e.g., destination entry) is carried out, developing a pseudo-code description of the goals and methods used, determining the associated elemental tasks, and adding up the task times. Elemental times [reaching for a device, keying (cursor, letter, space, enter), mental activity, searching, etc.] were derived from the Keystroke-Level Model (Card, Moran, and Newell, 1983) in the human-computer interaction literature, specific automotive studies of navigation data entry (Manes, Green, and Hunter, 1998), and MTM-1 (Barnes, 1968).
An Examination and Comparison of Workload and Subjective Measures Collected from Railroad Dispatchers
Authors: Popkin Stephen M.
Published: January 2012

This study addresses whether subjective workload, stress and fatigue vary as a function of reported workload, time of day, and time on task for railroad dispatchers. Workload and subjective rating data were collected for two weeks at both a freight and a passenger dispatching facility. Results indicate that subjective fatigue is an amalgamation of time-on-task and time-of-day functions, though there appears to be a “rush hour” effect. Subjective stress and workload were mainly affected by reported workload and time-on-task. Number of trains handled was the more influential of the two reported workload measures.
The Effectiveness of Usability Evaluation Methods: Determining the Appropriate Criteria
Authors: Andre Terence S. , Williges Robert C. , Hartson H. Rex
Published: January 2012

Because there are various measures for comparing methods, researchers in human-computer interaction generally find it difficult to make solid conclusions about a particular method. We consider some candidate measures (e.g., thoroughness, validity, reliability) of effectiveness and then provide a summary of studies that have compared usability evaluation methods (UEMs) using one or more of these measures. We find that studies do not always provide the appropriate descriptive statistics to make solid conclusions, especially in terms of validity. In addition, studies do not always compare UEMs to a standard yardstick such as end-user testing to establish an appropriate validity score. Finally, we provide some possible ways to address criterion deficiency and criterion contamination; two important considerations for researchers attempting to optimize the balance between ultimate and actual criteria.
Signal Detection Performance with a Haptic Device
Authors: Dow Steven , Thomas Geb , Johnson Lynn
Published: January 2012

Haptic interfaces are becoming more widely used in virtual reality simulations because of their enhancement to performance in training and simulation. Unintended vibration degrades the effectiveness of a haptic device and can reduce the user's ability to detect small details in the surface of simulated hard objects. Two important design factors for controlling haptic device vibrations are servo update rate and resistive force magnitude. This work employs a signal detection and receiver operator characteristic methodology to evaluate the interaction of these two factors on a user's ability to perceive small details in a hard surface. In a two-factor, full factorial experiment, six male research participants rated their confidence in detecting a 5mm upward step along a simulated hard surface. The independent variables were resistive force magnitude (1.63N or 4.88N) and update rate (468Hz or 1630Hz). The results indicate a significant interaction of the two variables. Participants demonstrated a 69% success rate with the strong force, slow update rate compared with a 86% success rate in the other 3 conditions. The participants may have employed a strategy of detecting the lack of oscillations when entering the surface and then noted their kinesthetic motion while moving back to the oscillating state experience when sliding along the surface of the simulated edge. Either increasing the update rate or reducing the resistive force magnitude can mitigate the effects of vibration when using a haptic device.
Long-Term Retention of Spatial Knowledge Acquired in Virtual Reality
Authors: Miller Michael S. , Clawson Deborah M. , Sebrechts Marc M.
Published: January 2012

Retention of spatial knowledge was compared after acquisition using virtual reality (VR), a map, and a real building. Participants were trained to navigate a route and to note the locations of landmarks. Two weeks later they were tested on their ability to navigate the route and to point to the landmarks they had learned. They were tested in either an aligned or contra-aligned orientation. The orientation specificity for VR observed immediately after training in our previous experiment (Clawson, Miller, Knott, & Sebrechts, 1998) was magnified after retention. On the route test, the VR group performed better than the map group, but only when tested in the aligned orientation. On the survey test, the VR group was less accurate than the map or real building groups, especially in the contra-aligned condition. Potential cognitive and perceptual causes of this orientation specificity are discussed.
Searching for the Presence and Absence of Features in Vigilance: The Decrement Persists
Authors: Catanzaro Jean M. , Scerbo Mark W.
Published: January 2012

The present study was designed to reexamine the ability of individuals to look for the presence or absence of stimulus features in a vigilance setting. Forty individuals participated in a 40-min vigil where they were asked to monitor a display comprised of either two or five circles. Half of the participants were asked to respond when a 4 mm line was present in one of the circles, and the other half responded when the line was absent from one of the circles. The participants were given ample time to search the display and make their responses. The results showed that response times were longer for the larger displays and for the feature-absent search conditions. Also, response times increased over the course of the vigil irrespective of search condition. In addition, participants reported higher levels of subjective workload after the vigil, but there were no differences among conditions. These results are discussed with respect to the feature-integration theory and its applicability to vigilance.
Culture, Control, and Illusory Pattern Perception
Authors: Wang Cynthia S. , Whitson Jennifer A. , Menon Tanya
Published: January 2012

Lacking control causes illusory pattern perception, but does culture influence the patterns people perceive? Different cultural contexts invite distinct types of control, with people from Western cultures emphasizing primary control methods (i.e., personal agency) and people from East Asian cultures emphasizing secondary control methods (i.e., adjustment to surroundings). Four experiments suggest that cultural differences in primary versus secondary control orientation shape the patterns people perceive within horoscopes. When lacking (vs. possessing) control, Westerners are relatively more likely to rely on horoscopes that help them understand themselves, whereas East Asians are relatively more likely to rely on horoscopes that help them understand others. The authors isolate underlying mechanisms, demonstrating that, following loss of control, people high on primary control rely on self-focused horoscopes and people high on secondary control rely on horoscopes about friends. Thus, cultural differences in primary versus secondary control create unique signatures in pattern perception.
Sequencing and comparative genomic analysis of 1227 Felis catus cDNA sequences enriched for developmental, clinical and nutritional phenotypes
Authors: Irizarry Kristopher J , Malladi Sukhaswami B , Gao Xiangming , Mitsouras Katherine , Melendez Lynda , Burris Patricia A , Brockman Jeffrey A , Al-Murrani Samer W
Published: January 2012

Background

The feline genome is valuable to the veterinary and model organism genomics communities because the cat is an obligate carnivore and a model for endangered felids. The initial public release of the Felis catus genome assembly provided a framework for investigating the genomic basis of feline biology. However, the entire set of protein coding genes has not been elucidated.

Results

We identified and characterized 1227 protein coding feline sequences, of which 913 map to public sequences and 314 are novel. These sequences have been deposited into NCBI's genbank database and complement public genomic resources by providing additional protein coding sequences that fill in some of the gaps in the feline genome assembly. Through functional and comparative genomic analyses, we gained an understanding of the role of these sequences in feline development, nutrition and health. Specifically, we identified 104 orthologs of human genes associated with Mendelian disorders. We detected negative selection within sequences with gene ontology annotations associated with intracellular trafficking, cytoskeleton and muscle functions. We detected relatively less negative selection on protein sequences encoding extracellular networks, apoptotic pathways and mitochondrial gene ontology annotations. Additionally, we characterized feline cDNA sequences that have mouse orthologs associated with clinical, nutritional and developmental phenotypes. Together, this analysis provides an overview of the value of our cDNA sequences and enhances our understanding of how the feline genome is similar to, and different from other mammalian genomes.

Conclusions

The cDNA sequences reported here expand existing feline genomic resources by providing high-quality sequences annotated with comparative genomic information providing functional, clinical, nutritional and orthologous gene information.
A mixture framework for inferring ancestral gene orders
Authors: Zhang Yiwei , Hu Fei , Tang Jijun
Published: January 2012

Background

Inferring gene orders of ancestral genomes has the potential to provide detailed information about the recent evolution of species descended from them. Current popular tools to infer ancestral genome data (such as GRAPPA and MGR) are all parsimony-based direct optimization methods with the aim to minimize the number of evolutionary events. Recently a new method based on the approach of maximum likelihood is proposed. The current implementation of these direct optimization methods are all based on solving the median problems and achieve more accurate results than the maximum likelihood method. However, both GRAPPA and MGR are extremely time consuming under high rearrangement rates. The maximum likelihood method, on the contrary, runs much faster with less accurate results.

Results

We propose a mixture method to optimize the inference of ancestral gene orders. This method first uses the maximum likelihood approach to identify gene adjacencies that are likely to be present in the ancestral genomes, which are then fixed in the branch-and-bound search of median calculations. This hybrid approach not only greatly speeds up the direct optimization methods, but also retains high accuracy even when the genomes are evolutionary very distant.

Conclusions

Our mixture method produces more accurate ancestral genomes compared with the maximum likelihood method while the computation time is far less than that of the parsimony-based direct optimization methods. It can effectively deal with genome data of relatively high rearrangement rates which is hard for the direct optimization methods to solve in a reasonable amount of time, thus extends the range of data that can be analyzed by the existing methods.
A common variant of the MACC1 gene is significantly associated with overall survival in colorectal cancer patients
Authors: Lang Alois H , Geller-Rhomberg Simone , Winder Thomas , Stark Nicole , Gasser Klaus , Hartmann Bernd , Kohler Bertram , Grizelj Ina , Drexel Heinz , Muendlein Axel
Published: January 2012

Background

The newly discovered metastasis-associated in colon cancer-1 (MACC1) gene is a key regulator of the HGF/MET pathway. Deregulation of HGF/MET signaling is reported as a prognostic marker for tumorigenesis, early stage invasion, and metastasis. High expression levels of MACC1 have been associated with colon cancer metastasis and reduced survival. Potential links between the genetic diversity of the MACC1 locus and overall survival are unknown. We therefore investigated the association between MACC1 tagging single nucleotide polymorphisms (SNPs) and overall survival in a large cohort of colorectal cancer patients.

Methods

The study included 318 subjects with histopathologically proven colorectal cancer at the Academic Teaching Hospital Feldkirch, Austria. Survival data were provided by the federal agency for statistics in Austria. Genomic DNA was isolated from formalin-fixed paraffin-embedded specimens; six tagging SNPs (rs1990172, rs3114446, rs10275612, rs3095007, rs3095009, and rs7780032), capturing most of the common variants of the MACC1 locus, were genotyped by SNaPshot assays.

Results

Over a mean follow up period of 5.3 (± 1.0) years, 94 deaths were recorded. Carriers of the G-allele of SNP rs1990172 showed a significantly decreased overall survival (additive HR = 1.38 [1.05-1.82]; p = 0.023). Multivariate analysis adjusted for age and UICC tumor stage confirmed this result (HR = 1.49 [1.12-1.98]; p = 0.007). Other investigated genetic variants of the MACC1 gene were not significantly associated with overall survival (p-values > 0.05).

Conclusions

For the first time, our study investigated the influence of MACC1 tagging polymorphisms on overall survival suggesting SNP rs1990172 as a predictor for reduced overall survival in colorectal cancer patients. Further studies will be required to validate our findings.
Clinical significance of serum lipids in idiopathic pulmonary alveolar proteinosis
Authors: Fang Cun S , Wang Ying C , Zhang Tao H , Wu Jing , Wang Wei , Wang Chun , Zhang Ming Y
Published: January 2012

Background

It is well known that pulmonary alveolar proteinosis(PAP) is characterised by accumulation of surfactant lipids and proteins within airspaces. However, few previous data describe the serum lipid levels associated with PAP.

Materials and methods

We retrospectively reviewed 25 patients with idiopathic PAP(iPAP). The serum lipid levels of patients with idiopathic PAP were compared with those of the healthy volunteers. In patients and healthy subjects, the LDL-C/HDL-C ratios were 2.94 ± 1.21 and 1.60 ± 0.70, respectively (p < 0.001), HDL-C were 1.11 ± 0.27 and 1.71 ± 0.71 respectively (p < 0.001). The values of LDL-C correlated significantly with those of PaO2 and PA-aO2 (r = -0.685, p = 0.003, and r = 0.688, p = 0.003, respectively). The values of LDL-C/HDL-C ratios also correlated with PaO2 levels and PA-aO2 levels (r = -0.698, p = 0.003, and r = 0.653, p = 0.006, respectively). 11 and 13 patients experienced respectively a decline in TC and LDL-C levels following whole lung lavage(WLL), the median decline was 0.71 mmol/L(p < 0.009) and 0.47 mmol/L(p < 0.003), respectively.

Conclusions

the serum lipid levels, especially the levels of LDL-C and LDL-C/HDL-C, may reflect the severity of the disease in PAP patients, and predict the therapeutic effect of WLL.
Marfan syndrome with a complex chromosomal rearrangement including deletion of the FBN1 gene
Authors: Colovati Mileny ES , da Silva Luciana RJ , Takeno Sylvia S , Mancini Tatiane I , N Dutra Ana R , Guilherme Roberta S , de Mello Cláudia B , Melaragno Maria I , A Perez Ana B
Published: January 2012

Background

The majority of Marfan syndrome (MFS) cases is caused by mutations in the fibrillin-1 gene (FBN1), mapped to chromosome 15q21.1. Only few reports on deletions including the wholeFBN1gene, detected by molecular cytogenetic techniques, were found in literature.

Results

We report here on a female patient with clinical symptoms of the MFS spectrum plus craniostenosis, hypothyroidism and intellectual deficiency who presents a 1.9 Mb deletion, including theFBN1gene and a complex rearrangement with eight breakpoints involving chromosomes 6, 12 and 15.

Discussion

This is the first report of MFS with a complex chromosome rearrangement involving a deletion ofFBN1and contiguous genes. In addition to the typical clinical findings of the Marfan syndrome due toFBN1gene haploinsufficiency, the patient presents features which may be due to the other gene deletions and possibly to the complex chromosome rearrangement.
Navigator channel adaptation to reconstruct three dimensional heart volumes from two dimensional radiotherapy planning data
Authors: Ng Angela , Nguyen Thao-Nguyen , Moseley Joanne L , Hodgson David C , Sharpe Michael B , Brock Kristy K
Published: January 2012

Background

Biologically-based models that utilize 3D radiation dosimetry data to estimate the risk of late cardiac effects could have significant utility for planning radiotherapy in young patients. A major challenge arises from having only 2D treatment planning data for patients with long-term follow-up. In this study, we evaluate the accuracy of an advanced deformable image registration (DIR) and navigator channels (NC) adaptation technique to reconstruct 3D heart volumes from 2D radiotherapy planning images for Hodgkin's Lymphoma (HL) patients.

Methods

Planning CT images were obtained for 50 HL patients who underwent mediastinal radiotherapy. Twelve image sets (6 male, 6 female) were used to construct a male and a female population heart model, which was registered to 23 HL "Reference" patients' CT images using a DIR algorithm, MORFEUS. This generated a series of population-to-Reference patient specific 3D deformation maps. The technique was independently tested on 15 additional "Test" patients by reconstructing their 3D heart volumes using 2D digitally reconstructed radiographs (DRR). The technique involved: 1) identifying a matching Reference patient for each Test patient using thorax measurements, 2) placement of six NCs on matching Reference and Test patients' DRRs to capture differences in significant heart curvatures, 3) adapting the population-to-Reference patient-specific deformation maps to generate population-to-Test patient-specific deformation maps using linear and bilinear interpolation methods, 4) applying population-to-Test patient specific deformation to the population model to reconstruct Test-patient specific 3D heart models. The percentage volume overlap between the NC-adapted reconstruction and actual Test patient's true heart volume was calculated using the Dice coefficient.

Results

The average Dice coefficient expressed as a percentage between the NC-adapted and actual Test model was 89.4 ± 2.8%. The modified NC adaptation technique made significant improvements to the population deformation heart models (p = 0.01). As standard evaluation, the residual Dice error after adaptation was comparable to the volumetric differences observed in free-breathing heart volumes (p = 0.62).

Conclusions

The reconstruction technique described generates accurate 3D heart models from limited 2D planning data. This development could potentially be used to retrospectively calculate delivered dose to the heart for historically treated patients and thereby provide a better understanding of late radiation-related cardiac effects.
Randomized clinical trial of LigaSure versus conventional suture ligation in thyroid surgery
Authors: Schiphorst Anandi HW , Twigt Bas A , Elias Sjoerd G , van Dalen Thijs
Published: January 2012

Background

In thyroid surgery vessel division and haemostasis make up an important and time consuming part of the operation. While the presence of the recurrent laryngeal nerve limits the liberal use of diathermia, the many arterial and venous branches to and from the thyroid gland necessitates the use of numerous conventional suture ligatures.This study evaluates the effect of using a vessel sealing system on operation time during thyroid surgery.

Methods

A randomized clinical trial was performed between September 2005 and October 2008 in a teaching hospital. Forty patients undergoing total hemithyroidectomy participated in the trial. Twenty were randomized to the intraoperative use of the LigaSure Precise™ vessel sealing system, and twenty to the use of conventional suture ligatures.

Results

The total median operation time was 10 minutes shorter in the LigaSure group (56 versus 66 minutes, P = 0.001). No significant differences in complications were noticed.

Conclusion

Using an electrothermal vessel sealing system during thyroid surgery is time saving.

Trial registration

This trial was registered in the international standard randomized controlled trials number register (ISRCTNR) under number ISRCTNR82389535.
Identification and evaluation of novel synovial tissue biomarkers in rheumatoid arthritis by laser scanning cytometry
Authors: Fueldner Christiane , Mittag Anja , Knauer Jens , Biskop Maria , Hepp Pierre , Scholz Roger , Wagner Ulf , Sack Ulrich , Emmrich Frank , Tárnok Attila , Lehmann Joerg
Published: January 2012

Introduction

Suitable biomarkers are essential for therapeutic strategies in personalized medicine in terms of diagnosis as well as of prognosis. With highly specific biomarkers, it is possible, for example, to identify patients with poor prognosis, which enables early intervention and intensive treatment. The aim of this study was to identify and validate biomarkers and possible combinations for a prospective use in immunoscintigraphy, which may improve diagnosis of rheumatoid arthritis (RA) patients with consideration of inflammatory activity in the affected joints. Therefore, we tested several monoclonal antibodies (mAbs) directed against cellular-surface molecules on cells likely to be involved in the pathogenesis of RA.

Methods

Synovial tissue from patients with long-standing RA (accompanied by synovitis with varying states of current activity) and patients with acute non-RA arthritis were stained for surface molecules on different cell types by using fluorochrome-labeled antibodies. Tissue analysis was done by laser scanning cytometry (LSC), and statistical evaluation, by discriminant analysis and ROC analysis.

Results

CD11b, HLA-DR, CD90, and CD64 revealed significant differences between tissues from patients with RA and acute non-RA arthritis. Especially with the expression of CD64, both patient cohorts could be discriminated with high sensitivity and specificity. RA classification was improved by simultaneously investigating the expression of two or three different surface proteins, such as HLA-DR, CD90, and CD29 in the tissue. The simultaneous analysis of CD64 together with CD304 or the combination of CD11b and CD38 was suitable for the identification of RA patients with high current activity in synovitis.

Conclusions

In this study, we showed that LSC is a novel reliable method in biomarker prevalidation in RA. Hence, identified mAbs in situ may allow their potential use in in vivo approaches. Moreover, we proved that biomarker-combination analysis resulted in better discrimination than did single-marker analysis. Combinations of these markers make a novel and reliable panel for the discrimination between RA and acute non-RA arthritis. In addition, further expedient combinations may be novel promising biomarker panels to identify current activity in synovitis in RA.
A 4-trifluoromethyl analogue of celecoxib inhibits arthritis by suppressing innate immune cell activation
Authors: Chiba Asako , Mizuno Miho , Tomi Chiharu , Tajima Ryohsuke , Alloza Iraide , di Penta Alessandra , Yamamura Takashi , Vandenbroeck Koen , Miyake Sachiko
Published: January 2012

Introduction

Celecoxib, a highly specific cyclooxygenase-2 (COX-2) inhibitor has been reported to have COX-2-independent immunomodulatory effects. However, celecoxib itself has only mild suppressive effects on arthritis. Recently, we reported that a 4-trifluoromethyl analogue of celecoxib (TFM-C) with 205-fold lower COX-2-inhibitory activity inhibits secretion of IL-12 family cytokines through a COX-2-independent mechanism that involves Ca2+-mediated intracellular retention of the IL-12 polypeptide chains. In this study, we explored the capacity of TFM-C as a new therapeutic agent for arthritis.

Methods

To induce collagen-induced arthritis (CIA), DBA1/J mice were immunized with bovine type II collagen (CII) in Freund's adjuvant. Collagen antibody-induced arthritis (CAIA) was induced in C57BL/6 mice by injecting anti-CII antibodies. Mice received 10 μg/g of TFM-C or celecoxib every other day. The effects of TFM-C on clinical and histopathological severities were assessed. The serum levels of CII-specific antibodies were measured by ELISA. The effects of TFM-C on mast cell activation, cytokine producing capacity by macophages, and neutrophil recruitment were also evaluated.

Results

TFM-C inhibited the severity of CIA and CAIA more strongly than celecoxib. TFM-C treatments had little effect on CII-specific antibody levels in serum. TFM-C suppressed the activation of mast cells in arthritic joints. TFM-C also suppressed the production of inflammatory cytokines by macrophages and leukocyte influx in thioglycollate-induced peritonitis.

Conclusion

These results indicate that TFM-C may serve as an effective new disease-modifying drug for treatment of arthritis, such as rheumatoid arthritis.
Phospholipids and insulin resistance in psychosis: a lipidomics study of twin pairs discordant for schizophrenia
Authors: Orešič Matej , Seppänen-Laakso Tuulikki , Sun Daqiang , Tang Jing , Therman Sebastian , Viehman Rachael , Mustonen Ulla , van Erp Theo G , Hyötyläinen Tuulia , Thompson Paul , Toga Arthur W , Huttunen Matti O , Suvisaari Jaana , Kaprio Jaakko , Lönnqvist Jouko , Cannon Tyrone D
Published: January 2012

Background

Several theories have been proposed to conceptualize the pathological processes inherent to schizophrenia. The 'prostaglandin deficiency' hypothesis postulates that defective enzyme systems converting essential fatty acids to prostaglandins lead to diminished levels of prostaglandins, which in turn affect synaptic transmission.

Methods

Here we sought to determine the lipidomic profiles associated with schizophrenia in twin pairs discordant for schizophrenia as well as unaffected twin pairs. The study included serum samples from 19 twin pairs discordant for schizophrenia (mean age 51 ± 10 years; 7 monozygotic pairs; 13 female pairs) and 34 age and gender matched healthy twins as controls. Neurocognitive assessment data and gray matter density measurements taken from high-resolution magnetic resonance images were also obtained. A lipidomics platform using ultra performance liquid chromatography coupled to time-of-flight mass spectrometry was applied for the analysis of serum samples.

Results

In comparison to their healthy co-twins, the patients had elevated triglycerides and were more insulin resistant. They had diminished lysophosphatidylcholine levels, which associated with decreased cognitive speed.

Conclusions

Our findings may be of pathophysiological relevance since lysophosphatidylcholines, byproducts of phospholipase A2-catalyzed phospholipid hydrolysis, are preferred carriers of polyunsaturated fatty acids across the blood-brain barrier. Furthermore, diminishment of lysophosphatidylcholines suggests that subjects at risk of schizophrenia may be more susceptible to infections. Their association with cognitive speed supports the view that altered neurotransmission in schizophrenia may be in part mediated by reactive lipids such as prostaglandins.
Patterns of Care for Non–Small-Cell Lung Cancer at an Academic Institution Affiliated With a National Cancer Institute–Designated Cancer Center
Authors: Nguyen Kim-Son H. , Sanford Rachel A. , Huberman Mark S. , Goldstein Michael A. , McDonald Danielle M. , Farquhar Mary , Gangadharan Sidharta P. , Kent Michael S. , Michaud Gaetane , Majid Adnan , Berman Stuart M. , Aronovitz Joseph A. , Nedea Elena A. , Boiselle Phillip M. , Cohen David W. , Kobayashi Susumu , Costa Daniel B.
Published: January 2012

These data point toward the need for improved evidence-based use of resources in the third-line setting of stage IV NSCLC.
Reduced Hippocampal Brain-Derived Neurotrophic Factor (BDNF) in Neonatal Rats after Prenatal Exposure to Propylthiouracil (PTU)
Authors: Chakraborty Goutam , Magagna-Poveda Alejandra , Parratt Carolyn , Umans Jason G. , MacLusky Neil J. , Scharfman Helen E.
Published: January 2012

Thyroid hormone is critical for central nervous system development. Fetal hypothyroidism leads to reduced cognitive performance in offspring as well as other effects on neural development in both humans and experimental animals. The nature of these impairments suggests that thyroid hormone may exert its effects via dysregulation of the neurotrophin brain-derived neurotrophic factor (BDNF), which is critical to normal development of the central nervous system and has been implicated in neurodevelopmental disorders. The only evidence of BDNF dysregulation in early development, however, comes from experimental models in which severe prenatal hypothyroidism occurred. By contrast, milder prenatal hypothyroidism has been shown to alter BDNF levels and BDNF-dependent functions only much later in life. We hypothesized that mild experimental prenatal hypothyroidism might lead to dysregulation of BDNF in the early postnatal period. BDNF levels were measured by ELISA at 3 or 7 d after birth in different regions of the brains of rats exposed to propylthiouracil (PTU) in the drinking water. The dose of PTU that was used induced mild maternal thyroid hormone insufficiency. Pups, but not the parents, exhibited alterations in tissue BDNF levels. Hippocampal BDNF levels were reduced at both d 3 and 7, but no significant reductions were observed in either the cerebellum or brain stem. Unexpectedly, more males than females were born to PTU-treated dams, suggesting an effect of PTU on sex determination. These results support the hypothesis that reduced hippocampal BDNF levels during early development may contribute to the adverse neurodevelopmental effects of mild thyroid hormone insufficiency during pregnancy.
Quantitative Measurement of Full-Length and C-Terminal Proteolyzed RBP4 in Serum of Normal and Insulin-Resistant Humans using a Novel Mass Spectrometry Immunoassay
Authors: Yang Qin , Eskurza Iratxe , Kiernan Urban A. , Phillips David A. , Blüher Matthias , Graham Timothy E. , Kahn Barbara B.
Published: January 2012

Serum retinol-binding protein 4 (RBP4) levels are increased in insulin-resistant humans and correlate with severity of insulin resistance in metabolic syndrome. Quantitative Western blotting (qWestern) has been the most accurate method for serum RBP4 measurements, but qWestern is technically complex and labor intensive. The lack of a reliable, high-throughput method for RBP4 measurements has resulted in variability in findings in insulin-resistant humans. Many commonly used ELISAs have limited dynamic range. Neither the current ELISAs nor qWestern distinguish among full-length and carboxyl terminus proteolyzed forms of circulating RBP4 that are altered in different medical conditions. Here, we report the development of a novel quantitative mass spectrometry immunoaffinity assay (qMSIA) to measure full-length and proteolyzed forms of RBP4. qMSIA and qWestern of RBP4 were performed in identical serum aliquots from insulin-sensitive/normoglycemic or insulin-resistant humans with impaired glucose tolerance or type 2 diabetes. Total RBP4 qMSIA measurements were highly similar to qWestern and correlated equally well with clinical severity of insulin resistance (assessed by clamp glucose disposal rate, r = −0.74), hemoglobin A1c (r = 0.63), triglyceride/high-density lipoprotein (r = 0.55), waist/hip (r = 0.61), and systolic blood pressure (r = 0.53, all P < 0.001). Proteolyzed forms of RBP4 accounted for up to 50% of total RBP4 in insulin-resistant subjects, and des(Leu)-RBP4 (cleavage of last leucine) correlated highly with insulin resistance (assessed by glucose disposal rate, r = −0.69). In multiple regression analysis, insulin resistance but not glomerular filtration rate was the strongest, independent predictor of serum RBP4 levels. Thus, qMSIA provides a novel tool for accurately measuring serum RBP4 levels as a biomarker for severity of insulin resistance and risk for type 2 diabetes and metabolic syndrome.
Thyroid Hormone Receptors Control Developmental Maturation of the Middle Ear and the Size of the Ossicular Bones
Authors: Cordas Emily A. , Ng Lily , Hernandez Arturo , Kaneshige Masahiro , Cheng Sheue-Yann , Forrest Douglas
Published: January 2012

Thyroid hormone is critical for auditory development and has well-known actions in the inner ear. However, less is known of thyroid hormone functions in the middle ear, which contains the ossicles (malleus, incus, stapes) that relay mechanical sound vibrations from the outer ear to the inner ear. During the later stages of middle ear development, prior to the onset of hearing, middle ear cavitation occurs, involving clearance of mesenchyme from the middle ear cavity while the immature cartilaginous ossicles attain appropriate size and ossify. Using in situ hybridization, we detected expression of Thra and Thrb genes encoding thyroid hormone receptors α1 and β (TRα1 and TRβ, respectively) in the immature ossicles, surrounding mesenchyme and tympanic membrane in the mouse. Thra+/PV mice that express a dominant-negative TRα1 protein exhibited deafness with elevated auditory thresholds and a range of middle ear abnormalities including chronic persistence of mesenchyme in the middle ear into adulthood, markedly enlarged ossicles, and delayed ossification of the ossicles. Congenitally hypothyroid Tshr−/− mice and TR-deficient Thra1−/−;Thrb−/− mice displayed similar abnormalities. These findings demonstrate that middle ear maturation is TR dependent and suggest that the middle ear is a sensitive target for thyroid hormone in development.
Antiapolipoprotein A-1 IgG Chronotropic Effects Require Nongenomic Action of Aldosterone on L-Type Calcium Channels
Authors: Rossier Michel F. , Pagano Sabrina , Python Magaly , Maturana Andres D. , James Richard W. , Mach François , Roux-Lombard Pascale , Vuilleumier Nicolas
Published: January 2012

Autoantibodies to apolipoprotein A-1 (antiapoA-1 IgG) have been shown to be associated with higher resting heart rate and morbidity in myocardial infarction patients and to behave as a chronotropic agent in the presence of aldosterone on isolated neonatal rat ventricular cardiomyocytes (NRVC). We aimed at identifying the pathways accounting for this aldosterone-dependent antiapoA-1 IgG-positive chronotropic effect on NRVC. The rate of regular spontaneous contractions was determined on NRVC in the presence of different steroid hormones and antagonists. AntiapoA-1 IgG chronotropic response was maximal within 20 min and observed only in aldosterone-pretreated cells but not in those exposed to other steroids. The positive antiapoA-1 IgG chronotropic effect was already significant after 5 min aldosterone preincubation, was dependent on 3-kinase and protein kinase A activities, was not inhibited by actinomycin D, and was fully abrogated by eplerenone (but not by spironolactone), demonstrating the dependence on a nongenomic action of aldosterone elicited through the mineralocorticoid receptor (MR). Under oxidative conditions (but not under normal redox state), corticosterone mimicked the permissive action of aldosterone on the antiapoA-1 IgG chronotropic response. Pharmacological and patch-clamp studies identified L-type calcium channels as crucial effectors of antiapoA-1 IgG chronotropic action, involving two converging pathways that increase the channel activity. The first one involves the rapid, nongenomic activation of the phosphatidylinositol 3-kinase enzyme by MR, and the second one requires a constitutive basal protein kinase A activity. In conclusion, our results indicate that, on NRVC, the aldosterone-dependent chronotropic effects of antiapoA-1 IgG involve the nongenomic activation of L-type calcium channels.
Antiapoptotic Actions of Exendin-4 against Hypoxia and Cytokines Are Augmented by CREB
Authors: Velmurugan Kalpana , Balamurugan A. N. , Loganathan Gopalakrishnan , Ahmad Aftab , Hering Bernhard J. , Pugazhenthi Subbiah
Published: January 2012

Islets isolated from cadaveric donor pancreas are functionally viable and can be transplanted in diabetic patients to reduce insulin requirements. This therapeutic approach is less efficient because a significant portion of functional islets is lost due to oxidative stress, inflammation, and hypoxia. Exendin-4, a glucagon-like peptide-1 receptor agonist, is known to improve islet survival through activation of the transcription factor, cAMP response element binding protein (CREB). However, isolated human islets are exposed to several stresses known to down-regulate CREB. The objective of the present study was to determine whether the cytoprotective actions of exendin-4 in human islets can be augmented by increasing the levels of CREB. Simulation of ischemia/reperfusion injury and exposure to hypoxic conditions in cultured human islets resulted in decreased CREB activation and induction of apoptosis. Islets were transduced with adenoviral CREB followed by exposure to exendin-4 as a strategy for improving their survival. This combination increased the levels of several proteins needed for β-cell survival and function, including insulin receptor substrate-2, Bcl-2, and baculoviral IAP repeat-containing 3, and suppressed the expression of proapoptotic and inflammatory genes. A combination of CREB and exendin-4 exerted enhanced antiapoptotic action in cultured islets against hypoxia and cytokines. More significantly, transplantation of human islets transduced with adenoviral CREB and treated with exendin-4 showed improved glycemic control over a 30-d period in diabetic athymic nude mice. These observations have significant implications in the therapeutic potential of exendin-4 and CREB in the islet transplantation setting as well as in preserving β-cell mass of diabetic patients.
Disruption of the Murine Glp2r Impairs Paneth Cell Function and Increases Susceptibility to Small Bowel Enteritis
Authors: Lee Seung-Jun , Lee Jennifer , Li Karen K. , Holland Dianne , Maughan Heather , Guttman David S. , Yusta Bernardo , Drucker Daniel J.
Published: January 2012

Exogenous glucagon-like peptide-2 receptor (GLP-2R) activation elicits proliferative and cytoprotective responses in the gastrointestinal mucosa and ameliorates experimental small and large bowel gut injury. Nevertheless, the essential physiological role(s) of the endogenous GLP-2R remain poorly understood. We studied the importance of the GLP-2R for gut growth, epithelial cell lineage allocation, the response to mucosal injury, and host-bacterial interactions in Glp2r−/− and littermate control Glp2r+/+ mice. Glp2r−/− mice exhibit normal somatic growth and preserved small and large bowel responses to IGF-I and keratinocyte growth factor. However, Glp2r−/− mice failed to up-regulate intestinal epithelial c-fos expression in response to acute GLP-2 administration and do not exhibit changes in small bowel conductance or small or large bowel growth after administration of GLP-2R agonists. The crypt and villus compartment and the numbers and localization of Paneth, enteroendocrine, and goblet cells were comparable in Glp2r+/+ vs. Glp2r−/− mice. Although the severity and extent of colonic mucosal injury in response to 3% oral dextran sulfate was similar across Glp2r genotypes, Glp2r−/− mice exhibited significantly increased morbidity and mortality and increased bacterial translocation after induction of enteritis with indomethacin and enhanced mucosal injury in response to irinotecan. Moreover, bacterial colonization of the small bowel was significantly increased, expression of Paneth cell antimicrobial gene products was reduced, and mucosal bactericidal activity was impaired in Glp2r−/− mice. Although the Glp2r is dispensable for gut development and the response to colonic injury, Glp2r−/− mice exhibit enhanced sensitivity to small bowel injury, and abnormal host-bacterial interactions in the small bowel.
Displacement as Narrative Structure: Refugee Time/Space in Diana Abu-Jaber's Arabian Jazz
Authors: McCullough Kate
Published: January 2012

McCullough's essay analyzes the impact of the figure of the refugee on both the story and the narrative structure of Diana Abu-Jaber's 1993 novel Arabian Jazz. What initially looks like a fairly predictable immigrant narrative rapidly engages a story of transnational movement, then, toward the novel's end, reveals an underlying refugee/exile narrative that is temporally inflected. In its simultaneous representation of exile from Palestine and emigration from Jordan, the novel employs a complex layering of spatial and temporal registers, bringing together discourses of the local (ethnic) and the global and disrupting the time/place of the nation. More specifically, Arabian Jazz offers a representation of place structured by layers of displacement, and a representation of time whose emphasis on a frozen present disrupts the teleological time of the nation. At the same time, Abu-Jaber uses the figure of the Palestinian refugee to signal the elided presence of the Native American, thus disrupting the historical homogeneity of the myth of U.S. nation formation and bringing to light instead the model of settler colonialism on which the United States is based. As such, the novel must be read as a critique of narratives of nation formation that omit the position of the indigenous.
The Desagüe Reconsidered: Environmental Dimensions of Class Conflict in Colonial Mexico
Authors: Candiani Vera
Published: January 2012

The Desagüe de Huehuetoca, as the colonial project to drain the Basin of Mexico was known, was designed to prevent flooding in the imperial City of Mexico by desiccating the lakes that surrounded it. Begun in 1607, the Desagüe sat not in the city itself but in the midst of an agropastoral district in the northwest quadrant of the basin, with pueblos de indios, haciendas, and ranchos as its neighbors. The drainage curtailed everyone’s access to and usufruct of land and water for cultivation and animal husbandry in this district by diminishing their access to these inputs. However, by additionally fixing what and where land and water were to be, the Desagüe had broader impacts on the indigenous economy, which, dependent on the seasonal inundation and recession of waters and on the ecosystemic resources of the lakes, suffered reduced access to both sustenance and marketable goods.
“The Lands with Which We Shall Struggle”: Land Reclamation, Revolution, and Development in Mexico’s Lake Texcoco Basin, 1910 – 1950
Authors: Vitz Matthew
Published: January 2012

Lake Texcoco, located on the eastern edge of Mexico City, had dried significantly during the nineteenth century, a process furthered by the Great Drainage Canal, completed in 1900. Although city boosters praised the canal for having eliminated Texcoco’s floods, dust storms arising from the briny lands began to torment the city. Intermittently from 1912 to 1950, the Mexican government carried out an ambitious drainage and fertilization project to curtail the dust storms and create an agricultural oasis. The government’s vision of a verdant and productive Texcoco bed generated widespread disputes between the state and local campesinos as well as among the urban elite. The postrevolutionary agrarian reform eventually enabled campesinos to negotiate with land reclamation authorities and turn what had been a project exclusive of the local poor into an example of agrarian justice. As engineers struggled to fertilize the briny lands at a reasonable cost, many urban planners proposed lake conservation and afforestation over drainage and farming to secure urban prosperity. But the agricultural vision remained dominant. In the 1950s and ’60s, however, urbanization, the political shift away from campesino production, and the prohibitive costs of farming the reclaimed land opened the door for a conservationist plan to resolve the incessant Texcoco problem. The study of Texcoco reclamation requires the integration of rural and urban history, two fields rarely in dialogue. Intraelite debates over the role of nature in urban growth and campesino protest shaped the evolution of this ambitious public works project. State-led development was therefore not imposed from above but negotiated, contested, and transformed from below by myriad social groups residing in the city and the countryside.
Mountaineers and Engineers: The Politics of International Science, Recreation, and Environmental Change in Twentieth-Century Peru
Authors: Carey Mark
Published: January 2012

During the 1930s, the German and Austrian Alpine Society sponsored three mountaineering-scientific expeditions to the Peruvian Andes, focusing especially on the Cordillera Blanca and adjacent valley known as the Callejón de Huaylas. They climbed mountains, conducted scientific studies, produced detailed maps, explored the highlands, and interacted with Peruvian intellectuals. Similar German expeditions went to Asia, Africa, and elsewhere in South America during this decisive period for the Nazi empire. This essay analyzes the writings and publications of the German and Austrian mountaineer-scientists who went to Peru, especially the Austrian leader Hans Kinzl, as well as examining government documents, technical reports, tourism publicity, diplomatic correspondence, and travel accounts to understand how Peruvian policy makers, engineers, scientists, intellectuals, tourism boosters, regional authorities, urban-based ruling classes, and rural residents in the mountains interacted with the European mountaineer-scientists during and after their expeditions. Most Peruvian groups initially welcomed the foreign mountaineer-scientists, using their activities to pursue their own agendas during the 1930s and 1940s. By the 1960s, however, many had become opposed to foreign mountaineers and scientists “intervening” in the Andes. World War II, natural disasters, the weak nation-state, coast-sierra divisions, growing Peruvian expertise in science and engineering, and the rise of an Andean tourism economy influenced how Peruvians perceived and interacted not only with the foreign mountaineer-scientists, but also with the Andean alpine landscape. Moreover, the dynamic physical environment also shaped historical processes: from science and engineering to landscape perceptions, tourism economies, national development, and international relations.