bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term follow-up of benign multiple sclerosis in Hordaland County, Western Norway
Authors: Glad SB , Nyland HI , Aarseth JH , Riise T , Myhr KM
Published: July 2009

Objective

To study the frequency of benign multiple sclerosis (MS) after 20 years disease duration and identify early clinical and demographic prognostic factors of a benign course.

Methods

A population-based cohort including all 230 MS patients with clinical disease onset during 1976–1986 in Hordaland County, Western Norway was followed up with clinical examination in 1995 and 2003. Benign MS was defined as an Expanded Disability Status Scale (EDSS) score ≤3.0, at least 10 years after disease onset.

Results

A relapsing–remitting disease course at onset, female gender, and younger age at onset were significantly associated with a benign course, but could only explain 23.0% of the variation in the benign course. A low annual relapse rate was also associated with a benign course. When including this variable in the model, 42.3% of the variation could be explained. The number of benign MS cases decreased significantly from 37.6% in 1995 to 24.2% in 2003.

Conclusion

Benign MS is frequently a temporary condition. Only a small part of the variation in the long-term benign course could be explained by clinical data present in the early phase of the disease. With several new emerging therapies in MS, the need for more reliable prognostic factors is increasing, to improve and individualize patient treatment.
Indoor Environmental Quality Related to Occupant Satisfaction and Performance in LEED-certified Buildings
Authors: Lee Young S. , Guerin Denise A.
Published: July 2009

The purpose of this study was to identify whether the indoor environmental quality design criteria: office layout, office furnishing, thermal comfort, indoor air quality, lighting, acoustics, and cleanliness and maintenance in relation to the overall workspace for LEED®-acreditation, could significantly affect occupants’ perception of their overall workspace satisfaction and their work performances. Occupants’ self-assessed satisfaction and performances were measured and these were correlated with occupants’ satisfaction and performances in their overall workspaces in 15 LEED-certified buildings in the US. The findings showed office furnishing quality has a significant impact on occupants’ satisfaction and performances; and indoor air quality affected only the occupants’ performances
Numerical Investigation of Indoor Aerosol Particle Dispersion under Stratum Ventilation and under Displacement Ventilation
Authors: Lin Tian  , Zhang Lin  , Qiuwang Wang  , Jing Liu
Published: July 2009

Particle dispersion in a room under stratum ventilation and under displacement ventilation have been investigated by numerical simulation. In addition, an experiment was carried out involving the newer stratum ventilation. The agreements between simulated velocity, temperature by the RNG k-ε turbulent model and the measured data were quite good. A discrete trajectory model was adopted to simulate the particle movement in a room. The results showed that the flow patterns created by different ventilation modes have great influence on the fates of particles. The particle concentrations for the entire room and for the breathing zone under stratum ventilation are less than that under displacement ventilation, which implies that the risk of particle inhalation under stratum ventilation is less than that under displacement ventilation. The deposited particle mass on room walls and furniture surfaces under stratum ventilation is greater than that under displacement ventilation. The particle mass deposited on the floor plays an important role in the process of particle deposition. The mass of particles that escaped under stratum ventilation was less than that under displacement ventilation. Moreover, the influence of particle diameter on particle dispersion is also considered in the present paper.
Ethics and Patient Education: Health Literacy and Cultural Dilemmas
Authors: Marks Ray
Published: July 2009

This article discusses health literacy and cultural factors that have implications for the ethical practice of health education. It specifically focuses on recent data that speaks to the challenges in carrying out patient education from the perspective of comprehension and equitable distribution of health-related information across diverse cultures and communities. It discusses strategies for reducing the negative impact of low health literacy among diverse groups and the importance of acknowledging this pervasive problem in the context of ensuring equity in the optimal delivery of health promotion messages.
The Caregiver’s Burden of Alzheimer Patients: Differences Between Live-In and Non-Live-In
Authors: Raccichini Alessandra , Castellani Simona , Civerchia Patrizia , Fioravanti Paola , Scarpino Osvaldo
Published: July 2009

The objective of our study was to describe the burden of a sample of 208 live-in/non-live-in caregivers of patients with Alzheimer’s disease (AD). We analyzed the statistical correlation between Caregiver Burden Inventory (CBI) and the live-in/non-live-in caregiver status, and between the ‘‘objective burden,’’ the cognitive deterioration, functional ability, and psychic and behavioral disorders. Using analysis of variance (ANOVA), the live-in groups of caregivers were compared to each subscale and to the total CBI. Living with a patient causes a bigger burden associated to the ‘‘developmental and physical burden,’’ which is affected more by the functional impairment than by the cognitive-behavioral aspect. Understanding the aspects of this burden in the initial-intermediate phase of the disease and being able to monitor it over time could contribute to improving the interventions already in place, which affect burden, stress, and quality of life of caregivers and their sick family members.
Acoustic Radiation Force Impulse Imaging
Authors: Iyo Allison Y.
Published: July 2009

Acoustic radiation force impulse (ARFI) imaging uses high-energy, focused acoustic pulses and conventional diagnostic sonography methods to measure tissue elasticity. Using a modified sonography transducer, a series of high-intensity pushing beams and low PRF tracking beams is transmitted, measuring the magnitude of tissue displacement in response to the applied force. The response to this force can determine the tissue's state of health. Currently, magnetic resonance imaging, computed tomography, and B-mode sonography are considered gold standards for soft tissue imaging. This article presents how ARFI compares to B-mode sonography and reviews the current literature.
Segmented lanthanum cerium oxide thermal barrier coatings by atmospheric plasma spray
Authors: Wang Y. , Guo H. B. , Li Z. Y. , Gong S. K.
Published: July 2009

Recently, efforts have been focussed on seeking for new candidates as ceramic topcoat in thermal barrier coating (TBC) system, instead of yttria stabilised zirconia (YSZ) currently used for TBC topcoat. Among the candidates, lanthanum cerium oxide (La2Ce2O7, LCO) is a promising TBC topcoat material, because of its higher temperature stability and better thermal insulation performance relative to yttria stabilised zirconia. In this work, the LCO TBC with high segmentation crack density was prepared by atmospheric plasma spraying, while keeping the stoichiometric composition of the coating. High plasma power and high substrate temperature Ts contribute to the formation of the segmentation structure. The segmented LCO TBC had a lifetime of >730 cycles, exhibiting a significant improvement in thermal shock resistance as compared to the nonsegmented coating. Spallation failure of the segmented TBC was caused by both chipping and delamination cracking.
Iron overload in Asia
Authors: Hershko Chaim
Published: July 2009

In a remarkable study in this issue of Blood, Lok and colleagues describe the genotypic and phenotypic characteristics of hereditary hemochromatosis in 42 cases in 8 distinct families of Asian origin.1
Mighty mouse
Authors: Johnson Amy J.
Published: July 2009

In this issue of Blood, ter Brugge and colleagues describe the results of their efforts to express SV40 T antigen in mature B cells of mice.1 As a consequence of T antigen expression, B cells develop normally but, upon aging, mice show an accumulation of monoclonal CD5+ B cells and have a chronic lymphocytic leukemia-like phenotype.
Megakaryocytes survive without survivin
Authors: Ravid Katya
Published: July 2009

Survivin has been described as an important regulator of late mitosis and as antiapoptotic in various cells. In this issue of Blood, Wen and colleagues describe a megakaryocyte-specific knockout of survivin, with no influence on megakaryocyte survival, and a stimulating effect on polyploidy.1
Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1–mediated vascular endothelial barrier enhancement
Authors: Van Sluis Geerte L. , Niers Tatjana M.H. , Esmon Charles T. , Tigchelaar Wikky , Richel Dick J. , Buller Harry R. , Van Noorden Cornelis J.F. , Spek C. Arnold
Published: July 2009

Activated protein C (APC) has both anticoagulant activity and direct cell-signaling properties. APC has been reported to promote cancer cell migration/invasion and to inhibit apoptosis and therefore may exacerbate metastasis. Opposing these activities, APC signaling protects the vascular endothelial barrier through sphingosine-1-phosphate receptor-1 (S1P1)activation, which may counteract cancer cell extravasation. Here, we provide evidence that endogenous APC limits cancer cell extravasation, with in vivo use of monoclonal antibodies against APC. The protective effect of endogenous APC depends on its signaling properties. The MAPC1591 antibody that only blocks anticoagulant activity of APC does not affect cancer cell extravasation as opposed to MPC1609 that blocks anticoagulant and signaling properties of APC. Combined administration of anti-APC antibodies and S1P1 agonist (SEW2871) resulted in a similar number of pulmonary foci in mice in presence and absence of APC, indicating that the protective effect of APC depends on the S1P1 pathway. Moreover, endogenous APC prevents cancer cell–induced vascular leakage as assessed by the Evans Blue Dye assay, and SEW2871 treatment reversed MPC1609-dependent vascular leakage. Finally, we show that cancer cells combined with MPC1609 treatment diminished endothelial VE-cadherin expression. In conclusion, endogenous APC limits cancer cell extravasation because of S1P1-mediated VE-cadherin–dependent vascular barrier enhancement.
Identification of valid reference genes during the differentiation of human myoblasts
Authors: Stern-Straeter Jens , Bonaterra Gabriel A , Hörmann Karl , Kinscherf Ralf , Goessler Ulrich R
Published: July 2009

Background

Analysis of RNA expression using real-time PCR (qRT-PCR) traditionally includes reference genes (RG) as an internal control. This practice is being questioned as it becomes increasingly clear that RG may vary considerably under certain experimental conditions. Thus, the validity of a particular RG must be determined for each experimental setting. We used qRT-PCR to measure the levels of six RG, which have been reported in the literature to be invariant. The RG were analyzed in human myoblast cultures under differentiation conditions. We examined the expression by qRT-PCR of mRNA encoding Beta-actin (ACTB), Beta-2-microglobulin (B2M), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), peptidylprolyl isomerase A (PPIA), TATA box binding protein (TBP) and ribosomal protein, large, P0 (RPLPO). The mRNA expression of the following genes of interest (GOI) were analyzed: skeletal muscle alpha 1 actin (ACTA1), myogenin/myogenic factor 4 (MYOG), embryonic skeletal muscle myosin heavy chain 3 (MYH3) and the activity of creatine phosphokinase (CK). The geNorm, NormFinder and BestKeeper software programs were used to ascertain the most suitable RG to normalize the RNA input.

Results

Using the geNorm program, RPLPO and TBP were found to be the most stable genes, additionally a suitable normalization factor (NF) was calculated. The NormFinder software showed that RPLPO was the most stable, whereas TBP ranked second. BestKeeper program also revealed that RPLPO and TBP as stable genes, but PPIA was the most stable reference gene, whereas GAPDH and ACTB were the worst ranked.

Conclusion

RNA expression analyses including three independent softwares revealed that RPLPO, TBP as reference genes or NF calculated by geNorm software, are suitable to normalize the mRNA expression in myoblast after culture under differentiation conditions. Significant correlations can be identified between the differentiations markers ACTA1, MYOG, MYH3 and creatine phosphokinase (CK) activity, when the expression is normalized with the NF calculated with RPLPO and TBP.
Optimizing expression of the pregnancy malaria vaccine candidate, VAR2CSA in Pichia pastoris
Authors: Avril Marion , Hathaway Marianne J , Cartwright Megan M , Gose Severin O , Narum David L , Smith Joseph D
Published: June 2009

Background

VAR2CSA is the main candidate for a vaccine against pregnancy-associated malaria, but vaccine development is complicated by the large size and complex disulfide bonding pattern of the protein. Recent X-ray crystallographic information suggests that domain boundaries of VAR2CSA Duffy binding-like (DBL) domains may be larger than previously predicted and include two additional cysteine residues. This study investigated whether longer constructs would improve VAR2CSA recombinant protein secretion from Pichia pastoris and if domain boundaries were applicable across different VAR2CSA alleles.

Methods

VAR2CSA sequences were bioinformatically analysed to identify the predicted C11 and C12 cysteine residues at the C-termini of DBL domains and revised N- and C-termimal domain boundaries were predicted in VAR2CSA. Multiple construct boundaries were systematically evaluated for protein secretion in P. pastoris and secreted proteins were tested as immunogens.

Results

From a total of 42 different VAR2CSA constructs, 15 proteins (36%) were secreted. Longer construct boundaries, including the predicted C11 and C12 cysteine residues, generally improved expression of poorly or non-secreted domains and permitted expression of all six VAR2CSA DBL domains. However, protein secretion was still highly empiric and affected by subtle differences in domain boundaries and allelic variation between VAR2CSA sequences. Eleven of the secreted proteins were used to immunize rabbits. Antibodies reacted with CSA-binding infected erythrocytes, indicating that P. pastoris recombinant proteins possessed native protein epitopes.

Conclusion

These findings strengthen emerging data for a revision of DBL domain boundaries in var-encoded proteins and may facilitate pregnancy malaria vaccine development.
Survey of smokers' reasons for not switching to safer sources of nicotine and their willingness to do so in the future
Authors: Heavner Karyn K , Rosenberg Zale , Phillips Carl V
Published: July 2009

Despite the well-known risks of smoking, policy, social pressure, and accessible cessation programs, tens of millions of North American adults continue smoking rather than quitting or switching to less harmful non-combustion nicotine products. We surveyed people smoking in public in Edmonton, Canada (n = 242, year = 2007) to investigate smokers' reasons for resisting switching to low-risk nicotine sources. 43% had used low-risk products (mostly pharmaceutical nicotine). 75% indicated willingness to consider switching to low-risk products. Smokers cited similar reasons for not switching to smokeless tobacco and pharmaceutical nicotine, largely based on misinformation. Accurate risk information may lead many to try low-risk nicotine products.
Primary hepatic embryonal sarcoma masquerading as metastatic ovarian cancer
Authors: Kullar Peter , Stonard Christopher , Jamieson Neville , Huguet Emmanuel , Praseedom Raaj , Jah Asif
Published: July 2009

Background

Hepatic embryonal sarcoma (HES) is a rare but aggressive primary tumor of the liver occurring most frequently in childhood.

Case presentation

We report a case of a 52 year old woman having previously undergone treatment for ovarian serous papillary carcinoma who subsequently presented with a large solitary mass in the liver. Initially this was presumed to be metastasis from the ovarian primary however, on further examination it was shown to be a primary hepatic embryonal sarcoma.

Conclusion

Primary liver tumors should be considered in differential diagnoses in patients with ovarian cancer who subsequently present with liver tumors. This is particularly important when there is no direct evidence of recurrence of ovarian cancer.
Plasma TF activity predicts cardiovascular mortality in patients with acute myocardial infarction
Authors: Steppich Birgit A , Braun Siegmund Lorenz , Stein Andreas , Demetz Gabriele , Groha Philip , Schömig Albert , von Beckerath Nicolas , Kastrati Adnan , Ott Ilka
Published: July 2009

Objectives and Background

Tissue factor (TF) contributes to thrombosis following plaque disruption in acute coronary syndromes (ACS). Aim of the study was to investigate the impact of plasma TF activity on prognosis in patients with ACS.

Methods and Results

One-hundred seventy-four patients with unstable Angina pectoris (uAP) and 112 patients with acute myocardial infarction (AMI) were included with a mean follow up time of 3.26 years. On admission, plasma TF activity was assessed. Patients were categorized into 2 groups: a high-TF activity group with TF >24 pmol/L and low TF activity group with TF ≤ 24 pmol/L. Fifteen cardiovascular deaths occurred in the uAP group and 16 in the AMI group. In AMI TF activity was 24,9 ± 2,78 pmol/l (mean ± SEM) in survivors and 40,9 ± 7,96 pmol/l in nonsurvivors (P = 0.024). In uAP no differences were observed (25.0 ± 8.04 pmol/L nonsurvivors vs. 25.7 ± 2.14 pmol/L survivors; P = 0.586). Kaplan-Meier estimates of survival at 3.26 years regarding TF activity in AMI were 81.3% and 92.2% with an hazard ratio of 3.02 (95% CI [1.05–8.79], P = 0.03). The Cox proportional hazards model adjusting for correlates of age and risk factors showed that plasma TF activity was an independent correlate of survival (hazard ratio 9.27, 95% CI [1.24–69.12], P = 0.03). In an additional group of patients with uAP and AMI, we identified circulating microparticles as the prevailing reservoir of plasma TF activity in acute coronary syndromes.

Conclusion

Systemic TF activity in AMI has an unfavorable prognostic value and as a marker for dysregulated coagulation may add to predict the atherothrombotic risk.
Studies on membrane topology, N-glycosylation and functionality of SARS-CoV membrane protein
Authors: Voß Daniel , Pfefferle Susanne , Drosten Christian , Stevermann Lea , Traggiai Elisabetta , Lanzavecchia Antonio , Becker Stephan
Published: July 2009

The glycosylated membrane protein M of the severe acute respiratory syndrome associated coronavirus (SARS-CoV) is the main structural component of the virion and mediates assembly and budding of viral particles. The membrane topology of SARS-CoV M and the functional significance of its N-glycosylation are not completely understood as is its interaction with the surface glycoprotein S. Using biochemical and immunofluorescence analyses we found that M consists of a short glycosylated N-terminal ectodomain, three transmembrane segments and a long, immunogenic C-terminal endodomain. Although the N-glycosylation site of M seems to be highly conserved between group 1 and 3 coronaviruses, studies using a recombinant SARS-CoV expressing a glycosylation-deficient M revealed that N-glycosylation of M neither influence the shape of the virions nor their infectivity in cell culture. Further functional analysis of truncated M proteins showed that the N-terminal 134 amino acids comprising the three transmembrane domains are sufficient to mediate accumulation of M in the Golgi complex and to enforce recruitment of the viral spike protein S to the sites of virus assembly and budding in the ERGIC.
CSF/serum quotient graphs for the evaluation of intrathecal C4synthesis
Authors: Padilla-Docal Barbara , Dorta-Contreras Alberto J , Bu-Coifiu-Fanego Raisa , Rey Alexis Rodriguez
Published: July 2009

Background

Cerebrospinal fluid (CSF)/serum quotient graphs have been used previously to determine local synthesis in brain of immunoglobulins and C3complement component. The aim of this study was to use the same technique to construct quotient graphs, or Reibergrams, for the beta globulin C4and to evaluate the method for assessing intrathecal synthesis in neurological disease.

Methods

The constants in the previously-defined Reibergram for immunoglobulin IgA were used to calculate the CSF/serum quotient for C4. CSF and serum were analyzed for C4, IgA and albumin from a total of 12 patients with meningoencephalitis caused by encapsulated microorganisms and 10 subjects without infections or inflammatory neurological disease, some of which had dysfunction of the blood-CSF barrier,

Results

The formula and C4Reibergram with the constants previously found for IgA, determined the intrathecal C4synthesis in CSF. The intrathecal C4fraction in CSF (C4loc in mg/l) was compared to the C4-Index (fraction of CSF: serum for C4/fraction of CSF: serum for albumin). There was a significant correlation between the two formulae. The CSF/Serum quotient graph was superior for detecting intrathecal synthesis of C4under variable conditions of blood-CSF barrier permeability.

Conclusion

The C4Reibergram can be used to quantify the intrathecal synthesis of this component of the complement system in different infectious diseases of the central nervous system and is especially useful for patients with blood-brain barrier dysfunction.
Unstable angina early after aortic valve replacement surgery in a female patient with normal coronary arteries preoperatively – a case report
Authors: Gruber Sybille , Ng Choi-Keung , Schwarz Christian , Auer Johann
Published: July 2009

Background

Angina pectoris early after aortic valve replacement surgery in patients with previously normal coronary arteries may be life threatening and has to be assessed immediately.

Case report

12 weeks after aortic valve replacement surgery, a 60-year-old female patient was referred for evaluation of recent onset of severe chest pain on mild exertion and at rest. Coronary angiography showed severe stenosis nvolving the left coronary ostium and the left main stem. The patient was urgently referred for bypass surgery and had an uneventful postoperative recovery.

Conclusion

A high degree of suspicion is needed for early recognition and aggressive management of this rare but serious complication.
Effects of triptolide from Radix Tripterygium wilfordii (Leigongteng) on cartilage cytokines and transcription factor NF-κB: a study on induced arthritis in rats
Authors: Xiao Cheng , Zhou Jing , He Yinghui , Jia Hongwei , Zhao Linhua , Zhao Ning , Lu Aiping
Published: July 2009

Background

Triptolide, an active compound ofRadix Tripterygium wilfordii, is immunosuppressive, cartilage protective and anti-inflammatory both in human and animal studies of various inflammatory and autoimmune diseases, including rheumatoid arthritis, but its therapeutic mechanism remains unclear. The aim of this study is to investigate the effects of triptolide on cartilage cytokines in the CIA model.

Methods

Sprague Dawley rats were immunized with type II collagen and orally administered with triptolide. The arthritic scores and incidence changes of the rats were observed. The expression of TNF-α, IL-6, COX-2 and NF-κB in paw cartilage was studied with immunohistochemical staining.

Results

Triptolide, at both high and low doses, significantly lowered the arthritic scores, delayed the onset of arthritis and lowered the arthritis incidence. Triptolide treatment at both high and low doses lowered the expression of TNF-α, IL-6, COX-2 and NF-κB in paw cartilage in arthritic rats.

Conclusion

Triptolide lowers the arthritic scores, delays the onset of collagen induced arthritis and reduces the expressions of TNF-α, IL-6, NF-κB and COX-2 in paw cartilage in arthritic rats.
Application of an iterative Bayesian variable selection method in a genome-wide association study of rheumatoid arthritis
Authors: Kwon Soonil , Wang Dai , Guo Xiuqing
Published: June 2009

Genome-wide association studies usually involve several hundred thousand of single-nucleotide polymorphisms (SNPs). Conventional approaches face challenges when there are enormous number of SNPs but a relatively small number of samples and, in some cases, are not feasible. We introduce here an iterative Bayesian variable selection method that provides a unique tool for association studies with a large number of SNPs (p) but a relatively small sample size (n). We applied this method to the simulated case-control sample provided by the Genetic Analysis Workshop 15 and compared its performance with stepwise variable selection method. We demonstrated that the results of iterative Bayesian variable selection applied to when p » n are as comparable as those of stepwise variable selection implemented to when n » p. When n > p, the iterative Bayesian variable selection performs better than stepwise variable selection does.
Cladistic analysis of genotype data-application to GAW15 Problem 3
Authors: Jung Hsuan , Zhao Keyan , Marjoram Paul
Published: June 2009

Given the increasing size of modern genetic data sets and, in particular, the move towards genome-wide studies, there is merit in considering analyses that gain computational efficiency by being more heuristic in nature. With this in mind, we present results of cladistic analyses methods on the Genetic Analysis Workshop 15 Problem 3 simulated data (answers known). Our analysis attempts to capture similarities between individuals using a series of trees, and then looks for regions in which mutations on those trees can successfully explain a phenotype of interest. Existing varieties of such algorithms assume haplotypes are known, or have been inferred, an assumption that is often unrealistic for genome-wide data. We therefore present an extension of these methods that can successfully analyze genotype, rather than haplotype, data.
A logistic mixture model for a family-based association study
Authors: Xing Guan , Xing Chao , Lu Qing , Elston Robert C
Published: June 2009

A family-based association study design is not only able to localize causative genes more precisely than linkage analysis, but it also helps explain the genetic mechanism underlying the trait under study. Therefore, it can be used to follow up an initial linkage scan. For an association study of binary traits in general pedigrees, we propose a logistic mixture model that regresses the trait value on the genotypic values of markers under investigation and other covariates such as environmental factors. We first tested both the validity and power of the new model by simulating nuclear families inheriting a simple Mendelian trait. It is powerful when the correct disease model is specified and shows much loss of power when the dominance of a model is inversely specified, i.e., a dominant model is wrongly specified as recessive or vice versa. We then applied the new model to the Genetic Analysis Workshop (GAW) 15 simulation data to test the performance of the model when adjusting for covariates in the case of complex traits. Adjusting for the covariate that interacts with disease loci improves the power to detect association. The simplest version of the model only takes monogenic inheritance into account, but analysis of the GAW simulation data shows that even this simple model can be powerful for complex traits.
The role of heritability in mapping expression quantitative trait loci
Authors: Huang Song , Ballard David , Zhao Hongyu
Published: June 2009

Gene expression, as a heritable complex trait, has recently been used in many genome-wide linkage studies. The estimated overall heritability of each trait may be considered as evidence of a genetic contribution to the total phenotypic variation, which implies the possibility of mapping genome regions responsible for the gene expression variation via linkage analysis. However, heritability has been found to be an inconsistent predictor of significant linkage signals. To investigate this issue in human studies, we performed genome-wide linkage analysis on the 3554 gene expression traits of 194 Centre d'Etude du Polymorphisme Humain individuals provided by Genetic Analysis Workshop 15. Out of the 422 expression traits with significant linkage signals identified (LOD > 5.3), 89 traits have low estimated heritability (h
2 < 10%), among which 23 traits have an estimated heritability equal to 0. The linkage analysis on individual pedigree shows that the overall LOD scores may result from a few pedigrees with strong linkage signals. Screening gene expressions before linkage analysis using a relatively low heritability (h
2 < 20%) may result in a loss of significant linkage signals, especially for trans-acting expression quantitative trait loci (49%).
The Gene expression Grade Index: a potential predictor of relapse for endocrine-treated breast cancer patients in the BIG 1–98 trial
Authors: Desmedt Christine , Giobbie-Hurder Anita , Neven Patrick , Paridaens Robert , Christiaens Marie-Rose , Smeets Ann , Lallemand Françoise , Haibe-Kains Benjamin , Viale Giuseppe , Gelber Richard D , Piccart Martine , Sotiriou Christos
Published: July 2009

Background

We have previously shown that the Gene expression Grade Index (GGI) was able to identify two subtypes of estrogen receptor (ER)-positive tumors that were associated with statistically distinct clinical outcomes in both untreated and tamoxifen-treated patients. Here, we aim to investigate the ability of the GGI to predict relapses in postmenopausal women who were treated with tamoxifen (T) or letrozole (L) within the BIG 1–98 trial.

Methods

We generated gene expression profiles (Affymetrix) and computed the GGI for a matched, case-control sample of patients enrolled in the BIG 1–98 trial from the two hospitals where frozen samples were available. All relapses (cases) were identified from patients randomized to receive monotherapy or from the switching treatment arms for whom relapse occurred before the switch. Each case was randomly matched with four controls based upon nodal status and treatment (T or L). The prognostic value of GGI was assessed as a continuous predictor and divided at the median. Predictive accuracy of GGI was estimated using time-dependent area under the curve (AUC) of the ROC curves.

Results

Frozen samples were analyzable for 48 patients (10 cases and 38 controls). Seven of the 10 cases had been assigned to receive L. Cases and controls were comparable with respect to menopausal and nodal status, local and chemotherapy, and HER2 positivity. Cases were slightly older than controls and had a larger proportion of large, poorly differentiated ER+/PgR- tumors. The GGI was significantly and linearly related to risk of relapse: each 10-unit increase in GGI resulted in an increase of approximately 11% in the hazard rate (p = 0.02). Within the subgroups of patients with node-positive disease or who were treated with L, the hazard of relapse was significantly greater for patients with GGI at or above the median. AUC reached a maximum of 78% at 27 months.

Conclusion

This analysis supports the GGI as a good predictor of relapse for ER-positive patients, even among patients who receive L. Validation of these results, in a larger series from BIG 1–98, is planned using the simplified GGI represented by a smaller set of genes and tested by qRT-PCR on paraffin-embedded tissues.
Apoptotic cell-mediated suppression of streptococcal cell wall-induced arthritis is associated with alteration of macrophage function and local regulatory T-cell increase: a potential cell-based therapy?
Authors: Perruche Sylvain , Saas Philippe , Chen Wanjun
Published: July 2009

Introduction

Experimental streptococcal cell wall (SCW)-induced arthritis is characterized by two successive phases of the disease. The acute phase occurs early and is associated with an inflammatory process and neutrophil infiltration into the synovium. The second chronic phase is related to effector T-cell activation and the dysregulation of macrophage function. Creation of an immunomodulatory environment has been attributed to apoptotic cells themselves, apoptotic cell uptake by phagocytes as well as a less sensibility of phagocytes capturing apoptotic bodies to activation. Therefore we evaluated the potential of apoptotic cell injection to influence the course of inflammation in SCW-induced arthritis in rats.

Methods

Rat apoptotic thymocytes were injected intraperitoneally (2 × 108) in addition to an arthritogenic dose of systemic SCW in LEW female rats. Control rats received SCW immunization and PBS. Rats were then followed for arthritis occurrence and circulating cytokine detection. At sacrifice, regulatory T cells (Tregs) and macrophages were analyzed.

Results

Apoptotic cell injection profoundly suppressed joint swelling and destruction typically observed during the acute and chronic phases of SCW-induced arthritis. Synovial inflammatory cell infiltration and bone destruction were also markedly suppressed. Ex vivo experiments revealed reduced levels of TNF in cultures of macrophages from rats challenged with SCW in the presence of apoptotic thymocytes as well as reduced macrophage response to lipopolysaccharide. Moreover, apoptotic cell injection induced higher Foxp3+ Tregs in the lymphoid organs, especially in the draining lymph nodes.

Conclusions

Our data indicate that apoptotic cells modulate macrophage function and result in Treg generation/increase. This may be involved in inhibition of inflammation and amelioration of arthritis. This highlights and confirms previous studies showing that in vivo generation of Tregs using apoptotic cell injection may be a useful tool to prevent and treat inflammatory autoimmune responses.
The extracellular domain of CD11d regulates its cell surface expression
Authors: McKillop William M , Barrett John W , Pasternak Stephen H , Chan Bosco M C , Dekaban Gregory A
Published: July 2009

CD11d’s extracellular domain is responsible for intracellular retention of the protein to the Golgi apparatus, a restriction which is relieved upon CD11d/CD18 heterodimerization resulting in release of the integrin to the cell surface.

A mAb targeting the CD11d subunit of the leukocyte integrin CD11d/CD18 decreases intraspinal inflammation and oxidative damage leading to improved neurological outcomes in rodent models of SCI. CD11d/CD18 is the fourth member of the β2-integrin family. Current evidence indicates that CD11d/CD18 is regulated differently than other β2-integrins, suggesting that CD11d+ leukocytes play a distinct role in inflammation. Although the transcriptional control of CD11d expression has been evaluated, control of the intracellular distribution of CD11d has not been addressed. For this reason and as a result of the potential of CD11d as a therapeutic target for SCI and possibly other CNS injuries, we investigated the intracellular localization and surface expression of CD11d in cultured cells. CD11d and CD18 were fused at their C-termini with YFP and mRFP, respectively. Flow cytometry and confocal microscopy demonstrated that rCD11d-YFP is expressed on the cell surface of leukocyte cell lines expressing CD18. In contrast, in heterologous cell lines, CD11d-YFP is retained intracellularly in the TGN. Coexpression of CD11d-YFP and CD18-mRFP relieves this intracellular restriction and allows the CD11d/CD18 heterodimer to be surface-expressed. Based on domain-swapping experiments with CD25, the extracellular domain of CD11d is required and sufficient for the observed intracellular retention in heterologous cells. Furthermore, the transmembrane and C-terminus are also required for proper heterodimerization with CD18 and localization to the plasma membrane. These findings suggest that multiple CD11d domains play a role in controlling intracellular location and association with CD18.
Zebrafish mutations ingartandpaicsidentify crucial roles for de novo purine synthesis in vertebrate pigmentation and ocular development
Authors: Ng Anthony , Uribe Rosa A. , Yieh Leah , Nuckels Richard , Gross Jeffrey M.
Published: July 2009

Although purines and purinergic signaling are crucial for numerous biochemical and cellular processes, their functions during vertebrate embryonic development have not been well characterized. We analyze two recessive zebrafish mutations that affect de novo purine synthesis, gart and paics. gart encodes phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase,phosphoribosylaminoimidazole synthetase, a trifunctional enzyme that catalyzes steps 2, 3 and 5 of inosine monophosphate (IMP) synthesis. paicsencodes phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase, a bifunctional enzyme that catalyzes steps 6 and 7 of this process. Zygotic gart and paics mutants have pigmentation defects in which xanthophore and iridophore pigmentation is almost completely absent, and melanin-derived pigmentation is significantly decreased, even though pigment cells are present in normal amounts and distributions. Zygotic gart and paics mutants are also microphthalmic, resulting from defects in cell cycle exit of proliferative retinoblasts within the developing eye. Maternal-zygotic and maternal-effect mutants demonstrate a crucial requirement for maternally derived gartand paics; these mutants show more severe developmental defects than their zygotic counterparts. Pigmentation and eye growth phenotypes in zygotic gart and paics mutants can be ascribed to separable biosynthetic pathways: pigmentation defects and microphthalmia result from deficiencies in a GTP synthesis pathway and an ATP synthesis pathway,respectively. In the absence of ATP pathway activity, S phase of proliferative retinoblasts is prolonged and cell cycle exit is compromised, which results in microphthalmia. These results demonstrate crucial maternal and zygotic requirements for de novo purine synthesis during vertebrate embryonic development, and identify independent functions for ATP and GTP pathways in mediating eye growth and pigmentation, respectively.
The ENTH domain protein Clint1 is required for epidermal homeostasis in zebrafish
Authors: Dodd M. Ernest , Hatzold Julia , Mathias Jonathan R. , Walters Kevin B. , Bennin David A. , Rhodes Jennifer , Kanki John P. , Look A. Thomas , Hammerschmidt Matthias , Huttenlocher Anna
Published: July 2009

Epidermal hyperproliferation and inflammation are hallmarks of the human condition psoriasis. Here, we report that a zebrafish line with a mutation in the cargo adaptor protein Clint1 exhibits psoriasis-like phenotypes including epithelial hyperproliferation and leukocyte infiltration. Clint1 is an ENTH domain-containing protein that binds SNARE proteins and functions in vesicle trafficking; however, its in vivo function in animal models has not been reported to date. The clint1 mutants exhibit chronic inflammation characterized by increased Interleukin 1β expression, leukocyte infiltration, bidirectional trafficking and phagocytosis of cellular debris. The defects in clint1 mutants can be rescued by expression of zebrafish clint1 and can be phenocopied with clint1-specific morpholinos, supporting an essential role for Clint1 in epidermal development. Interaction studies suggest that Clint1 and Lethal giant larvae 2 function synergistically to regulate epidermal homeostasis. Accordingly, clint1 mutants show impaired hemidesmosome formation, loss of cell-cell contacts and increased motility suggestive of epithelial to mesenchymal transition. Taken together, our findings describe a novel function for the ENTH domain protein Clint1 in epidermal development and inflammation and suggest that its deficiency in zebrafish generates a phenotype that resembles the human condition psoriasis.
Are Women More Credit Constrained? Experimental Evidence on Gender and Microenterprise Returns
Authors: de Mel Suresh , McKenzie David , Woodruff Christopher
Published: July 2009

We report on a field experiment providing random grants to microenterprise owners. The grants generated large profit increases for male owners but not for female owners. We show that the gender gap does not simply mask differences in ability, risk aversion, entrepreneurial attitudes, or differences in reporting behavior, but there is some evidence that the gender gap is larger in female-dominated industries. The data are not consistent with a unitary household model, and imply an inefficiency of resource allocation within households. We show evidence that this inefficiency is reduced in more cooperative households. (JEL D13, D14, J16, L25, L26, O12, O16)
Early Childhood Intervention and Life-Cycle Skill Development: Evidence from Head Start
Authors: Deming David
Published: July 2009

This paper provides new evidence on the long-term benefits of Head Start using the National Longitudinal Survey of Youth. I compare siblings who differ in their participation in the program, controlling for a variety of pre-treatment covariates. I estimate that Head Start participants gain 0.23 standard deviations on a summary index of young adult outcomes. This closes one-third of the gap between children with median and bottom quartile family income, and is about 80 percent as large as model programs such as Perry Preschool. The long-term impact for disadvantaged children is large despite “fade-out” of test score gains. (JEL H52, J13, I28, I38)
Task Specialization, Immigration, and Wages
Authors: Peri Giovanni , Sparber Chad
Published: July 2009

Large inflows of less educated immigrants may reduce wages paid to comparably-educated, native-born workers. However, if less educated foreign- and native-born workers specialize in different production tasks, because of different abilities, immigration will cause natives to reallocate their task supply, thereby reducing downward wage pressure. Using occupational task-intensity data from the O*NET dataset and individual US census data, we demonstrate that foreign-born workers specialize in occupations intensive in manual-physical labor skills while natives pursue jobs more intensive in communication-language tasks. This mechanism can explain why economic analyses find only modest wage consequences of immigration for less educated native-born workers. (JEL J24, J31, J61)
Legal Reform and Loan Repayment: The Microeconomic Impact of Debt Recovery Tribunals in India
Authors: Visaria Sujata
Published: July 2009

In 1993, the Indian government introduced debt recovery tribunals to speed up the resolution of debt recovery claims larger than a threshold. This paper exploits the staggered introduction of tribunals across states and the link between overdues and claim size to implement a differences-in-differences strategy on project loan data. It finds that the tribunals reduced delinquency for the average loan by 28 percent. They also lowered the interest rates charged on larger loans, holding constant borrower quality. This suggests that the speedier processing of debt recovery suits can lower the cost of credit. (JEL G21, K41, O16, O17)
To Work or Not to Work? Child Development and Maternal Labor Supply
Authors: Frijters Paul , Johnston David W , Shah Manisha , Shields Michael A
Published: July 2009

We estimate the effect of early child development on maternal labor force participation. Mothers of poorly developing children may remain at home to care for their children. Alternatively, mothers may enter the labor force to pay for additional educational and health resources. Which action dominates is the empirical question we answer in this paper. We control for the potential endogeneity of child development by using an instrumental variables approach, uniquely exploiting exogenous variation in child development associated with child handedness. We find that a one unit increase in poor child development decreases maternal labor force participation by approximately 10 percentage points. (JEL J13, J16, J22)
Optimal Monetary Policy Rules in an Estimated Sticky-Information Model
Authors: Reis Ricardo
Published: July 2009

This paper uses a dynamic stochastic general equilibrium (DSGE) model with sticky information as a laboratory to study monetary policy. It characterizes the model's predictions for macro dynamics and optimal policy at prior parameters, and then uses data on five US macroeconomic series to update the parameters and provide an estimated model that can be used for policy analysis. The model answers a few policy questions. How does sticky information affect optimal monetary policy? What is the optimal interest rate rule? What is the optimal elastic price-level targeting rule? How does parameter uncertainty affect optimal policy? Are the conclusions for the Euro area different? (JEL E13, E31, E43, E52)
Understanding the Forward Premium Puzzle: A Microstructure Approach
Authors: Burnside Craig , Eichenbaum Martin , Rebelo Sergio
Published: July 2009

High interest rate currencies tend to appreciate relative to low interest rate currencies. We argue that adverse selection problems between participants in foreign exchange markets can account for this “forward premium puzzle.” The key feature of our model is that the adverse selection problem facing market makers is worse when an agent wants to trade against a public information signal. So, when based on public information, the currency is expected to appreciate, there is more adverse selection associated with a sell order than with a buy order. (JEL E43, F31, G15)
The International Diversification Puzzle When Goods Prices Are Sticky: It's Really about Exchange-Rate Hedging, Not Equity Portfolios
Authors: Engel Charles , Matsumoto Akito
Published: July 2009

This paper develops a two-country monetary DSGE model in which households choose a portfolio of home and foreign equities, and a forward position in foreign exchange. Some nominal goods prices are sticky. Trade in these assets achieves the same allocations as trade in a complete set of nominal state-contingent claims in our linearized model. When there is a high degree of price stickiness, we show that not much equity diversification is required to replicate the complete-markets equilibrium when agents are able to hedge foreign exchange risk sufficiently. Moreover, temporarily sticky nominal goods prices can have large effects on equity portfolios even when dividend processes are very persistent. (JEL E13, F41, G11, G15)
A Century of Work and Leisure
Authors: Ramey Valerie A , Francis Neville
Published: July 2009

We develop comprehensive measures of time spent in market work, home production, schooling, and leisure in the United States for the last 106 years. We find that hours of work for prime age individuals are essentially unchanged, with the rise in women's hours fully compensating for the decline in men's hours. Hours worked by those 14 to 24 years old have declined noticeably, but most of this decline was offset by a rise in hours spent in school. Overall, per capita leisure and average annual lifetime leisure increased by only four or five hours per week during the last 100 years. (JEL D13, J16, J22)
How Is Foreign Aid Spent? Evidence from a Natural Experiment
Authors: Werker Eric , Ahmed Faisal Z , Cohen Charles
Published: July 2009

We use oil price fluctuations to test the impact of transfers from wealthy OPEC nations to their poorer Muslim allies. The instrument identifies plausibly exogenous variation in foreign aid. We investigate how aid is spent by tracking its short-run effect on aggregate demand, national accounts, and balance of payments. Aid affects most components of GDP though it has no statistically identifiable impact on prices or economic growth. Much aid is consumed, primarily in the form of imported noncapital goods. Aid substitutes for domestic savings, has no effect on the financial account, and leads to unaccounted capital flight. (JEL F35, O19)