bluuebunny/crossref_metadata_2025 huggingface dataset:
How the Interpretation of Drivers' Behavior in Virtual Environment Can Become a Road Design Tool: A Case Study
Authors: Pasetto Marco , Barbati Stefano Damiano
Published: April 2011

Driving is the result of a psychological process that translates data, signals and direct/indirect messages into behavior, which is continuously adapted to the exchange of varying stimuli between man, environment and vehicle. These stimuli are at times not perceived and at others perceived but not understood by the driver, even if they derive from tools (vertical signs, horizontal marking) specifically conceived for his safety. The result is unsafe behavior of vehicle drivers. For this reason, the road environment needs to be radically redesigned. The paper describes a research, based on real and virtual environment surveys, aimed to better understand drivers' action-reaction mechanisms inside different scenarios, in order to gain informations useful for a correct organization (design) of the road space. The driving simulator can help in developing, from road to laboratory, the study of new road design tools (geometrical, compositional, constructive ones, street furniture, etc.), because it can be used to evaluate solutions before their usefulness is proved on the road.
Severe Hypoglycemia due to Isolated ACTH Deficiency in Children: A New Case Report and Review of the Literature
Authors: Torchinsky Michael Y. , Wineman Robert , Moll George W.
Published: March 2011

Isolated ACTH deficiency causes life-threatening severe hypoglycemia. A 7-year-old girl with hypoglycemia due to this rare disorder is described. Our patient had undetectable plasma ACTH repeatedly and cortisol 0 mcg/dl before and after ACTH 1-24 stimulation. There was no evidence of other pituitary hormone deficiency. Glucocorticoid replacement therapy resulted in resolution of all symptoms and normalization of blood glucose. Previously published data on isolated ACTH deficiency in children is summarized. Review of the literature showed that the prevalence of this condition could be underestimated in the neonatal period and in Prader-Willi syndrome. Isolated ACTH deficiency occurs in older children as well as in neonates.
Repression of Vascular Endothelial Growth Factor Expression by the Runt-Related Transcription Factor 1 in Acute Myeloid Leukemia
Authors: ter Elst Arja , Ma Bin , Scherpen Frank J.G. , de Jonge Hendrik J.M. , Douwes Jenny , Wierenga Albertus T.J. , Schuringa Jan Jacob , Kamps Willem A. , de Bont Eveline S.J.M.
Published: March 2011

VEGFA is considered one of the most important regulators of tumor-associated angiogenesis in cancer. In acute myeloid leukemia (AML) VEGFA is an independent prognostic factor for reduced overall and relapse-free survival. Transcriptional activation of the VEGFA promoter, a core mechanism for VEGFA regulation, has not been fully elucidated. We found a significant (P < 0.0001) inverse correlation between expression of VEGFA and AML1/RUNX1 in a large set of gene expression array data. Strikingly, highest VEGFA levels were demonstrated in AML blasts containing a t(8;21) translocation, which involves the AML1/RUNX1 protein (AML1/ETO). Overexpression of AML1/RUNX1 led to downregulation of VEGFA expression, whereas blocking of AML1/RUNX1 with siRNAs resulted in increased VEGFA expression. Cotransfection of AML1/RUNX1 and VEGFA promoter luciferase promoter constructs resulted in a decrease in VEGFA promoter activity. ChIP analysis shows a direct binding of AML1/RUNX1 to the promoter of VEGFA on three AML1/RUNX1 binding sites. Silencing of AML1/ETO caused a decrease in VEGFA mRNA expression and a decrease in secreted VEGFA protein levels in AML1/ETO-positive Kasumi-1 cells. Taken together, these data pinpoint to a model whereby in normal cells AML1/RUNX1 acts as a repressor for VEGFA, while in AML cells VEGFA expression is upregulated due to AML1/RUNX1 aberrations, for example, AML1/ETO. In conclusion, these observations give insight in the regulation of VEGFA at the mRNA level in AML. Cancer Res; 71(7); 2761–71. ©2011 AACR.
Antiangiogenesis Enhances Intratumoral Drug Retention
Authors: Ma Jie , Chen Chong-Sheng , Blute Todd , Waxman David J.
Published: March 2011

The tumor vasculature delivers nutrients, oxygen, and therapeutic agents to tumor cells. Unfortunately, the delivery of anticancer drugs through tumor blood vessels is often inefficient and can constitute an important barrier for cancer treatment. This barrier can sometimes be circumvented by antiangiogenesis-induced normalization of tumor vasculature. However, such normalizing effects are transient; moreover, they are not always achieved, as shown here, when 9L gliosarcoma xenografts were treated over a range of doses with the VEGF receptor-selective tyrosine kinase inhibitors axitinib and AG-028262. The suppression of tumor blood perfusion by antiangiogenesis agents can be turned to therapeutic advantage, however, through their effects on tumor drug retention. In 9L tumors expressing the cyclophosphamide-activating enzyme P450 2B11, neoadjuvant axitinib treatment combined with intratumoral cyclophosphamide administration significantly increased tumor retention of cyclophosphamide and its active metabolite, 4-hydroxycyclophosphamide. Similar increases were achieved using other angiogenesis inhibitors, indicating that increased drug retention is a general response to antiangiogenesis. This approach can be extended to include systemic delivery of an anticancer prodrug that is activated intratumorally, where antiangiogenesis-enhanced retention of the therapeutic metabolite counterbalances the decrease in drug uptake from systemic circulation, as exemplified for cyclophosphamide. Importantly, the increase in intratumoral drug retention induced by neoadjuvant antiangiogenic drug treatment is shown to increase tumor cell killing and substantially enhance therapeutic activity in vivo. Thus, antiangiogenic agents can be used to increase tumor drug exposure and improve therapeutic activity following intratumoral drug administration, or following systemic drug administration in the case of a therapeutic agent that is activated intratumorally. Cancer Res; 71(7); 2675–85. ©2011 AACR.
Gene Expression Signature–Based Prognostic Risk Score in Gastric Cancer
Authors: Cho Jae Yong , Lim Jae Yun , Cheong Jae Ho , Park Yun-Yong , Yoon Se-Lyun , Kim Soo Mi , Kim Sang-Bae , Kim Hoguen , Hong Soon Won , Park Young Nyun , Noh Sung Hoon , Park Eun Sung , Chu In-Sun , Hong Waun Ki , Ajani Jaffer A. , Lee Ju-Seog
Published: March 2011

Purpose: Despite continual efforts to develop a prognostic model of gastric cancer by using clinical and pathologic parameters, a clinical test that can discriminate patients with good outcomes from those with poor outcomes after gastric cancer surgery has not been established. We aim to develop practical biomarker-based risk score that can predict relapse of gastric cancer after surgical treatment.

Experimental Design: Microarray technologies were used to generate and analyze gene expression profiling data from 65 gastric cancer patients to identify biomarker genes associated with relapse. The association of expression patterns of identified genes with relapse and overall survival was validated in independent gastric cancer patients.

Results: We uncovered two subgroups of gastric cancer that were strongly associated with the prognosis. For the easy translation of our findings into practice, we developed a scoring system based on the expression of six genes that predicted the likelihood of relapse after curative resection. In multivariate analysis, the risk score was an independent predictor of relapse in a cohort of 96 patients. We were able to validate the robustness of the six-gene signature in an additional independent cohort.

Conclusions: The risk score derived from the six-gene set successfully prognosticated the relapse of gastric cancer patients after gastrectomy. Clin Cancer Res; 17(7); 1850–7. ©2011 AACR.
Impact of White Matter Changes on Activities of Daily Living in Mild to Moderate Dementia
Authors: Moon So Young , Na Duk L. , Seo Sang Won , Lee Jun-Young , Ku Bon D. , Kim Seong Yoon , Park Kyung Won , Shim Yong S. , Youn Young Chul , Chung Chan-Seung , Cheong Hae-Kwan , Choi Seong Hye , Cha Kyung Ryeol , Kim Jung-Eun , Jeong Jee H.
Published: March 2011

The association between white matter changes and activities of daily living (ADL) in a large, well-defined cohort of patients with mild-to-moderate dementia (either Alzheimer’s disease or subcortical vascular dementia) were investigated. A total of 289 patients were divided into three groups (140 mild, 99 moderate, and 50 severe) depending on the degree of white matter changes as indicated on brain magnetic resonance image scans. Further, we analyzed the three groups’ performances on basic and instrumental ADL. The degree of white matter changes was associated with greater age, hypertension, previous history of stroke, higher Hachinski Ischemic Score, worse global cognitive and functional status, and an increased impairment of basic ADL and instrumental ADL. The increased impairment with regard to the severe group’s performance on both the basic and instrumental ADL remained significant after adjustment for age and hypertension. Tasks involving physical activities were most significant. This was the first study investigating the association between white matter changes and ADL in a large, well-defined dementia cohort. The present study suggests that severe white matter changes may be associated with higher impairment on both basic and instrumental ADL.
Knowledge and Attitudes of Adolescents towards Asthma: Questionnaire Results before and after a School-Based Education Program
Authors: Razi Cem Hasan , Bakırtaş Arzu , Demirsoy Sadık
Published: March 2011

Background: Previous studies on school-based education programs have reported that asthmatic and nonasthmatic adolescents, teachers and school personnel do not have enough information on asthma. However, the number of education programs including adolescents without asthma is not sufficient. The aim of the present study was to determine the knowledge of school children about asthma and to investigate whether their knowledge of asthma can be increased by an education program through a booklet distributed as a handout. Methods: This cross-sectional prospective questionnaire survey was carried out in a private school in Ankara, Turkey, between February and April 2006. 720 adolescents in grades 6, 7 and 8 were included. Knowledge about asthma was evaluated by a scoring system before and after the education offered by means of a booklet. Results: The final analysis was conducted on 642 students in total. The number of right answers in 5 categories, percentage of right answers and total questionnaire score improved significantly after the education received (p < 0.001). The total questionnaire scores of the girls (p = 0.002), those students with a university graduate mother (p = 0.006) and those with a physician parent (p = 0.041) were higher than those of the other pupils. Conclusion: Theoretical material in the form of a booklet can be used in a school-based asthma education program in order to improve the knowledge of adolescents about asthma.
Three Days Rush Venom Immunotherapy in Bee Allergy: Safe, Inexpensive and Instantaneously Effective
Authors: Goldberg Arnon , Yogev Ayala , Confino-Cohen Ronit
Published: March 2011

Background: Rush venom immunotherapy (VIT) is highly effective in vespid venom allergy, but comparable data regarding bee venom (BV) allergy are sparse. We evaluated its safety, efficacy and cost in BV-allergic patients. Methods: Conventional or rush VIT were offered to all patients with systemic reaction to insect sting. Rush VIT was also given to hyperreactive patients who failed to reach the maintenance dose with conventional VIT due to multiple systemic reactions. In BV-allergic patients, honeybee sting challenge was performed within 1 week after reaching the maintenance dose. Results: 179 patients, some of them allergic to more than one venom, received 246 rush VIT courses. Bee VIT was administered to 132 patients (73.7%); 173 patients (96.6%) reached the maintenance dose. The incidence of systemic reactions was 29.6%. They were more common in VIT with BV than with vespid venoms (31.1 and 16.3%, respectively, p = 0.01). After excluding the hyperreactive subgroup (n = 20), this difference was not significant (23.7 and 16%, respectively, p = 0.19). Despite the high incidence of systemic reactions (15 of 20, 75%) among hyperreactive patients, 17 patients (85%) achieved the maintenance dose. Sting challenges resulted in systemic reaction in 4 of 8 (50%) hyperreactive patients and in 2 of 47 (4.3%) ordinary patients. The cost of rush VIT was 41% of that of conventional VIT. Conclusions: Rush VIT with BV is safe, instantaneously effective, less expensive and enables most patients with previous failures of conventional VIT to reach the maintenance dose.
Regional Variability in Hospital Mortality in Patients Hospitalized with ST-Segment Elevation Myocardial Infarction: Findings from the Gulf Registry of Acute Coronary Events
Authors: Thalib Lukman , Zubaid Mohammad , Rashed Wafa , Almahmeed Wael , Al-Lawati Jawad , Sulaiman Kadhim , Al-Motarreb Ahmed , Amin Haitham , Al Suwaidi Jassim , Alhabib Khalid F.
Published: March 2011

Objectives: To study the short-term mortality from ST-segment elevation myocardial infarction (STEMI) in the Arabian Gulf region of the Middle East, and to examine whether these geographically and culturally related countries had similar or different outcomes. Subjects and Methods: The Gulf Registry of Acute Coronary Events recruited consecutive acute coronary syndrome patients from six Middle Eastern countries over a 5-month period. Results: Of 6,706 patients recruited, 2,626 (39%) had STEMI, and a total of 165 patients died in hospital, with a crude mortality rate of 6.3%. However, mortality rates varied geographically between 10% in Yemen, 9.6% in Oman and 3.3% in the other countries. The unadjusted odds ratio of mortality for Yemen was 3.2 (95% CI: 2.2–4.7), and 3.1 (95% CI: 1.9–4.8) for Oman, compared to other Gulf countries. Even after adjusting for age and gender, the mortality remained significantly higher, almost double, in Oman and Yemen compared to other countries. This could be understood in the light of significant differences in a number of practice pattern variables such as reperfusion therapy, timely presentation and use of evidence-based medications. Conclusion: We found significant variability in STEMI mortality among Gulf Arab countries and identified areas requiring further efforts to reduce excess mortality in the region.
Probing Dry-Weight Improves Left Ventricular Mass Index
Authors: Agarwal Rajiv , Bouldin J. Michael , Light Robert P. , Garg Ashok
Published: March 2011

Background: Although probing dry-weight improves blood pressure control, its effect on echocardiographic left ventricular mass index (LVMI) is unknown. Methods: Shortly following dialysis, 292 echocardiograms in 150 patients participating in the DRIP trial were obtained at baseline and longitudinally every 4 weeks on 2 occasions. Results: At baseline, LVMI was 136.3 g/m2 in the control group and 138.7 g/m2 in the ultrafiltration group (p > 0.2 for difference). The change from baseline in LVMI in the control group was +3.5 g/m2 at 4 weeks and +0.3 g/m2 at 8 weeks (p > 0.2 for both changes). The change from baseline in LVMI in the ultrafiltration group was –7.4 g/m2 at 4 weeks (p = 0.005) and –6.3 g/m2 at 8 weeks (p = 0.045). With ultrafiltration, the change in LVMI diameter was –10.9 g/m2 more compared to the control group at 4 weeks (p = 0.012) and –6.6 g/m2 more compared to the control group at 8 weeks (p = 0.21). The reduction in interdialytic ambulatory blood pressure was also greater in response to probing dry-weight in those in the top half of LVMI at baseline (p = 0.02 for interaction effect at week 8). Conclusion: LVMI, an important determinant of prognosis among long-term dialysis patients, is responsive to probing dry-weight.
Specificity for the tumor-associated self-antigen WT1 drives the development of fully functional memory T cells in the absence of vaccination
Authors: Pospori Constandina , Xue Shao-An , Holler Angelika , Voisine Cecile , Perro Mario , King Judith , Fallah-Arani Farnaz , Flutter Barry , Chakraverty Ronjon , Stauss Hans J. , Morris Emma C.
Published: March 2011

Recently, vaccines against the Wilms Tumor antigen 1 (WT1) have been tested in cancer patients. However, it is currently not known whether physiologic levels of WT1 expression in stem and progenitor cells of normal tissue result in the deletion or tolerance induction of WT1-specific T cells. Here, we used an human leukocyte antigen-transgenic murine model to study the fate of human leukocyte antigen class-I restricted, WT1-specific T cells in the thymus and in the periphery. Thymocytes expressing a WT1-specific T-cell receptor derived from high avidity human CD8 T cells were positively selected into the single-positive CD8 population. In the periphery, T cells specific for the WT1 antigen differentiated into CD44-high memory phenotype cells, whereas T cells specific for a non–self-viral antigen retained a CD44low naive phenotype. Only the WT1-specific T cells, but not the virus-specific T cells, displayed rapid antigen-specific effector function without prior vaccination. Despite long-term persistence of WT1-specific memory T cells, the animals did not develop autoimmunity, and the function of hematopoietic stem and progenitor cells was unimpaired. This is the first demonstration that specificity for a tumor-associated self-antigen may drive differentiation of functionally competent memory T cells.
Monosomal karyotype in primary myelofibrosis is detrimental to both overall and leukemia-free survival
Authors: Vaidya Rakhee , Caramazza Domenica , Begna Kebede H. , Gangat Naseema , Van Dyke Daniel L. , Hanson Curtis A. , Pardanani Animesh , Tefferi Ayalew
Published: March 2011

Survival in cytogenetically high-risk patients with acute myeloid leukemia or myelodysplastic syndromes is significantly worse in the presence of a monosomal karyotype (MK). The objective of the present study was to determine whether the same held true for primary myelofibrosis. Among 793 primary myelofibrosis patients seen at our institution, 62 displayed an unfavorable karyotype by way of complex karyotype (n = 41) or sole trisomy 8 (n = 21). Seventeen (41%) of the 41 patients with complex karyotype were classified as having an MK. Median survival was 6, 24, and 20 months in patients with MK, complex karyotype without monosomies, and sole trisomy 8, respectively (P < .0001). The corresponding 2-year leukemic transformation rates were 29.4%, 8.3%, and 0 (P < .0001); hazard ratios (95% confidence intervals) were 6.9 (1.3-37.3) and 14.8 (1.7-130.8). The prognostic relevance of MK was not accounted for by the Dynamic International Prognostic Scoring System. We conclude that MK in primary myelofibrosis is associated with extremely poor overall and leukemia-free survival.
TIP110/p110nrb/SART3/p110 regulation of hematopoiesis through CMYC
Authors: Liu Ying , Timani Khalid , Mantel Charlie , Fan Yan , Hangoc Giao , Cooper Scott , He Johnny J. , Broxmeyer Hal E.
Published: March 2011

Intracellular factors are involved in and essential for hematopoiesis. HIV-1 Tat-interacting protein of 110 kDa (TIP110; p110nrb/SART3/p110) is an RNA-binding nuclear protein implicated in the regulation of HIV-1 gene and host gene transcription, pre-mRNA splicing, and cancer immunology. In the present study, we demonstrate a role for TIP110 in the regulation of hematopoiesis. TIP110 was expressed in human CD34+ cells and decreased with differentiation of CD34+ cells. TIP110 mRNA was also expressed in phenotyped mouse marrow hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). Using TIP110 transgenic (TIP110TG) and haploinsufficient (TIP110+/−) mice, we found that increased TIP110 expression enhanced HPC numbers, survival, and cell cycling, whereas decreased TIP110 expression had the opposite effects. Moreover, TIP110+/− bone marrow HPCs responded more effectively, and TIP110TG HPCs less effectively, than those of wild-type control mice to recovery from the cell-cycle–active drug 5-fluorouracil (5-FU). Unexplained sex differences were noted in HSC competitive repopulating ability, but not HPC numbers, in TIP110TG mice. Intracellularly, TIP110 regulated CMYC and GATA2 expression at the transcriptional level, and TIP110 and CMYC reciprocally regulated the expression of each other. These results demonstrate a role for TIP110 in the regulation of hematopoiesis, effects that are likely linked to TIP110 regulation of CMYC.
Variant Philadelphia translocations: molecular-cytogenetic characterization and prognostic influence on frontline imatinib therapy, a GIMEMA Working Party on CML analysis
Authors: Marzocchi Giulia , Castagnetti Fausto , Luatti Simona , Baldazzi Carmen , Stacchini Monica , Gugliotta Gabriele , Amabile Marilina , Specchia Giorgina , Sessarego Mario , Giussani Ursula , Valori Laura , Discepoli Giancarlo , Montaldi Anna , Santoro Alessandra , Bonaldi Laura , Giudici Giovanni , Cianciulli Anna Maria , Giacobbi Francesca , Palandri Francesca , Pane Fabrizio , Saglio Giuseppe , Martinelli Giovanni , Baccarani Michele , Rosti Gianantonio , Testoni Nicoletta ,   for the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Working Party on Chronic Myeloid Leukemia
Published: March 2011

Variant Philadelphia (Ph) chromosome translocations have been reported in 5%-10% of patients with newly diagnosed chronic myeloid leukemia (CML). Variant translocations may involve one or more chromosomes in addition to 9 and 22, and can be generated by 2 different mechanisms, 1-step and 2-step rearrangements, as revealed by fluorescence in situ hybridization. The prognostic significance of the occurrence of variant translocations has been discussed in previous studies. The European LeukemiaNet recommendations do not provide a “warning” for patients with variant translocations, but there is limited information about their outcome after therapy with tyrosine kinase inhibitors. To identify the role of variant translocations in early chronic phase (CP) CML patients treated with imatinib mesylate, we performed an analysis in a large series of 559 patients enrolled in 3 prospective imatinib trials of the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Working Party on CML. Variant translocations occurred in 30 patients (5%). Our data show that the presence of variant translocations has no impact on the cytogenetic and molecular response or on outcome, regardless of the involvement of different mechanisms, the number of involved chromosomes, or the presence of deletions. Therefore, we suggest that patients with variant translocations do not constitute a “warning” category in the imatinib era. This study is registered at www.clinicaltrials.gov as NCT00514488 and NCT00510926.
Bortezomib induction of C/EBPβ mediates Epstein-Barr virus lytic activation in Burkitt lymphoma
Authors: Shirley Courtney M. , Chen Jianmeng , Shamay Meir , Li Huili , Zahnow Cynthia A. , Hayward S. Diane , Ambinder Richard F.
Published: March 2011

Epstein-Barr virus (EBV) is associated with a variety of lymphoid malignancies. Bortezomib activates EBV lytic gene expression. Bortezomib, a proteasome inhibitor, leads to increased levels of CCAAT/enhancer-binding proteinβ (C/EBPβ) in a variety of tumor cell lines. C/EBPβ activates the promoter of the EBV lytic switch gene ZTA. Bortezomib treatment leads to increased binding of C/EBP to previously recognized binding sites in the ZTA promoter. Knockdown of C/EBPβ inhibits bortezomib activation of EBV lytic gene expression. Bortezomib also induces the unfolded protein response (UPR), as evidenced by increases in ATF4, CHOP10, and XBP1s and cleavage of ATF6. Thapsigargin, an inducer of the UPR that does not interfere with proteasome function, also induces EBV lytic gene expression. The effects of thapsigargin on EBV lytic gene expression are also inhibited by C/EBPβ knock-down. Therefore, C/EBPβ mediates the activation of EBV lytic gene expression associated with bortezomib and another UPR inducer.
Neural Controls of Prostaglandin 2 Pyrogenic, Tachycardic, and Anorexic Actions Are Anatomically Distributed
Authors: Skibicka Karolina P. , Alhadeff Amber L. , Leichner Theresa M. , Grill Harvey J.
Published: March 2011

Fever and anorexia are induced by immune system challenges. Because these responses are adaptive when short lasting but deleterious when prolonged, an understanding of the mediating neural circuitry is important. Prostaglandins (PGE) are a critical signaling element for these immune responses. Despite the widespread distribution of PGE receptors throughout the brain, research focuses on the hypothalamic preoptic area as the mediating site of PGE action. Paraventricular nucleus of the hypothalamus (PVH), parabrachial nucleus (PBN), and nucleus tractus solitarius (NTS) neurons also express PGE receptors and are activated during systemic pathogen infection. A role for these neurons in PGE-induced fever, tachycardia, and anorexia is unexplored and is the subject of this report. A range of PGE2 doses was microinjected into third or fourth ventricles (v), or directly into the dorsal PVH, lateral PBN, and medial NTS, and core and brown adipose tissue temperature, heart rate, locomotor activity, and food intake were measured in awake, behaving rats. PGE2 delivery to multiple brain sites (third or fourth v, PVH, or PBN) induced a short- latency (<10 min) fever and tachycardia. By contrast, an anorexic effect was observed only in response to third v and PVH stimulation. NTS PGE2 stimulation was without effect; locomotor activity was not affected for any of the sites. The data are consistent with a view of PGE2-induced effects as mediated by anatomically distributed sites rather than a single center. The data also underscore a potential anatomical dissociation of the neural pathways mediating pyrogenic and anorexic effects of PGE2.
Separate Critical Periods Exist for Testosterone-Induced Differentiation of the Brain and Genitals in Sheep
Authors: Roselli Charles E. , Estill Charles T. , Stadelman Henry L. , Meaker Mary , Stormshak Fred
Published: March 2011

Sheep exposed to testosterone during a critical period from gestational day (GD) 30 to GD 90 develop masculine genitals and an enlarged male-typical ovine sexually dimorphic nucleus of the preoptic area (oSDN). The present study tested the hypothesis that separate critical periods exist for masculinization of these two anatomical end points. Pregnant ewes were treated with testosterone propionate (TP) either from GD 30 to GD 60 (early TP) or GD 60 to GD 90 (late TP). Control (C) pregnant ewes were treated with corn oil. Fetuses were delivered at GD 135 and the volume of the oSDN was measured. Early TP females possessed a penis and a scrotum devoid of testes, whereas late TP and C females had normal female genitals. Neither period of TP exposure grossly affected the genitals of male fetuses. Despite masculinized genitals, the mean volume of the oSDN in early TP females (0.32 ± 0.06 mm3) was not different from C females (0.24 ± 0.02 mm3) but was significantly enlarged in late TP females (0.49 ± 0.04 mm3; P < 0.05 vs. C) when the genitals appeared normal. In contrast, the volume of the oSDN in late TP males (0.51 ± 0.02 mm3) was not different from C males (0.51 ± 0.04 mm3) but was significantly smaller in the early TP males (0.35 ± 0.04 mm3; P < 0.05 vs. C). These results demonstrate that the prenatal critical period for androgen-dependent differentiation of the oSDN occurs later than, and can be separated temporally from, the period for development of masculine genitals.
Occurrence of Two Distinct Urotensin II-Related Peptides in Zebrafish Provides New Insight into the Evolutionary History of the Urotensin II Gene Family
Authors: Parmentier Caroline , Hameury Emilie , Dubessy Christophe , Quan Feng B. , Habert Damien , Calas André , Vaudry Hubert , Lihrmann Isabelle , Tostivint Hervé
Published: March 2011

The urotensin II (UII) family is currently known to consist of two paralogous peptides, namely UII and UII-related peptide (URP). In contrast to UII, which has been identified in all vertebrate classes so far, URP has only been characterized in tetrapods. We report here the occurrence of two distinct URP genes in teleosts, which we have named URP1 and URP2. Synteny analysis revealed that teleost URP1 and URP2 genes and tetrapod URP genes represent three distinct paralog genes that, together with the UII gene, probably arose from the two rounds of tetraploidization, which took place early in vertebrate evolution. The absence of URP in fish indicates that the corresponding gene has been lost in the teleost lineage, whereas it is likely that both the URP1 and URP2 genes have been lost in the tetrapod lineage. Quantitative RT-PCR analysis revealed that the URP2 gene is mainly expressed in the spinal cord and the brain in adult zebrafish. In situ hybridization experiments showed that in zebrafish embryos, URP2 mRNA-containing cells are located in the floor plate of the neural tube. In adult, URP2-expressing cells occur in close contact with the ventral side of the ependymal canal along the whole spinal cord, whereas in the brain, they are located below the fourth ventricle. These URP-expressing cells may correspond to cerebrospinal fluid-contacting neurons. In conclusion, our study reveals the occurrence of four distinct UII paralogous systems in vertebrates that may exert distinct functions, both in tetrapods and teleosts.
Reducing the Number of Drug Plans for Seniors: A Proposal and Analysis of Three Case Studies
Authors: Rice Thomas , Cummings Janet
Published: March 2011

The Medicare prescription drug benefit relies on private insurers. In most states, there are nearly fifty competing insurance plans available. The sheer number of choices makes it extremely difficult for Medicare beneficiaries, many of whom must cope with declining cognitive abilities, to choose the best plan for themselves. This article proposes an alternative to the current system, where government acts as a broker to winnow the number of choices so that beneficiaries face a small subset of those judged to be best on several dimensions. The study is based on three case studies where government has acted as such a broker. Two are from health (Medicaid's system of competitive bidding in Arizona, and a Medicare demonstration project on selective contracting for medical equipment and supplies), and one from the pension field (so-called 457 plans). The case studies were used to help evaluate the proposal based on competition, choice, quality, simplicity, and stability. We conclude that the proposal meets most of the positive features embodied in these five evaluation criteria. Consideration of this idea can ultimately result in a Medicare prescription drug benefit that best serves the needs of Medicare beneficiaries.
Community Benefit Activities of Private, Nonprofit Hospitals
Authors: Bazzoli Gloria J. , Clement Jan P. , Hsieh Hui-Min
Published: March 2011

The definition of hospital community benefits has been intensely debated for many years. Recently, consensus has developed about one group of activities being central to community benefits because of its focus on care for the poor and on needed community services for which any payments received are low relative to costs. Disagreements continue, however, about the treatment of bad debt expense and Medicare shortfalls. A recent revision of the Internal Revenue Service's Form 990 Schedule H, which is required of all nonprofit hospitals, highlights the agreed-on set of activities but does not dismiss the disputed items. Our study is the first to apply definitions used in the new IRS form to assess how conclusions about the adequacy of nonprofit hospital community benefits could be affected if bad debt expenses and Medicare shortfalls are included or excluded. Specifically, we examine 2005 financial data for California and Florida hospitals. Overall, we find that conclusions about community benefit adequacy are very different depending on which definition of community benefits is used. We provide thoughts on new directions for the current policy debate about the treatment of bad debts and Medicare shortfalls in light of these findings.
Latin American Social Movements at the Start of the Twenty-First Century: A Colombian Case Study
Authors: Archila Mauricio
Published: March 2011

This article is an overview of contemporary social movements in Latin America, with a focus on the Colombian case. Based upon different sources, it provides data on the recent protests, and analyzes the main trends of social movements in the continent, which are determined by two complementary processes: neoliberal globalization and increasing democratization. The Colombian case also highlights another process, one which is not entirely absent in the rest of Latin America: political violence against social actors and leftist activists.
Interactions between Shh, Sostdc1 and Wnt signaling and a new feedback loop for spatial patterning of the teeth
Authors: Cho Sung-Won , Kwak Sungwook , Woolley Thomas E. , Lee Min-Jung , Kim Eun-Jung , Baker Ruth E. , Kim Hee-Jin , Shin Jeon-Soo , Tickle Cheryll , Maini Philip K. , Jung Han-Sung
Published: March 2011

Each vertebrate species displays specific tooth patterns in each quadrant of the jaw: the mouse has one incisor and three molars, which develop at precise locations and at different times. The reason why multiple teeth form in the jaw of vertebrates and the way in which they develop separately from each other have been extensively studied, but the genetic mechanism governing the spatial patterning of teeth still remains to be elucidated. Sonic hedgehog (Shh) is one of the key signaling molecules involved in the spatial patterning of teeth and other ectodermal organs such as hair, vibrissae and feathers. Sostdc1, a secreted inhibitor of the Wnt and Bmp pathways, also regulates the spatial patterning of teeth and hair. Here, by utilizing maternal transfer of 5E1 (an anti-Shh antibody) to mouse embryos through the placenta, we show that Sostdc1 is downstream of Shh signaling and suggest a Wnt-Shh-Sostdc1 negative feedback loop as a pivotal mechanism controlling the spatial patterning of teeth. Furthermore, we propose a new reaction-diffusion model in which Wnt, Shh and Sostdc1 act as the activator, mediator and inhibitor, respectively, and confirm that such interactions can generate the tooth pattern of a wild-type mouse and can explain the various tooth patterns produced experimentally.
The microRNA pathway regulates the temporal pattern of Notch signaling in Drosophila follicle cells
Authors: Poulton John S. , Huang Yi-Chun , Smith Laila , Sun Jianjun , Leake Nicholas , Schleede Justin , Stevens Leslie M. , Deng Wu-Min
Published: March 2011

Multicellular development requires the correct spatial and temporal regulation of cell division and differentiation. These processes are frequently coordinated by the activities of various signaling pathways such as Notch signaling. From a screen for modifiers of Notch signaling in Drosophila we have identified the RNA helicase Belle, a recently described component of the RNA interference pathway, as an important regulator of the timing of Notch activity in follicle cells. We found that loss of Belle delays activation of Notch signaling, which results in delayed follicle cell differentiation and defects in the cell cycle. Because mutations in well-characterized microRNA components phenocopied the Notch defects observed in belle mutants, Belle might be functioning in the microRNA pathway in follicle cells. The effect of loss of microRNAs on Notch signaling occurs upstream of Notch cleavage, as expression of the constitutively active intracellular domain of Notch in microRNA-defective cells restored proper activation of Notch. Furthermore, we present evidence that the Notch ligand Delta is an important target of microRNA regulation in follicle cells and regulates the timing of Notch activation through cis inhibition of Notch. Here we have uncovered a complex regulatory process in which the microRNA pathway promotes Notch activation by repressing Delta-mediated inhibition of Notch in follicle cells.
How Notch establishes longitudinal axon connections between successive segments of the Drosophila CNS
Authors: Kuzina Irina , Song Jeong K. , Giniger Edward
Published: March 2011

Development of the segmented central nerve cords of vertebrates and invertebrates requires connecting successive neuromeres. Here, we show both how a pathway is constructed to guide pioneer axons between segments of the Drosophila CNS, and how motility of the pioneers along that pathway is promoted. First, canonical Notch signaling in specialized glial cells causes nearby differentiating neurons to extrude a mesh of fine projections, and shapes that mesh into a continuous carpet that bridges from segment to segment, hugging the glial surface. This is the direct substratum that pioneer axons follow as they grow. Simultaneously, Notch uses an alternate, non-canonical signaling pathway in the pioneer growth cones themselves, promoting their motility by suppressing Abl signaling to stimulate filopodial growth while presumably reducing substratum adhesion. This propels the axons as they establish the connection between successive segments.
Electron Conductivity in Modified Models of Artificial Metal–DNA Using Green’s Function-Based Elastic Scattering Theory
Authors: Nakanishi Yasuyuki , Matsui Toru , Kitagawa Yasutaka , Shigeta Yasuteru , Saito Toru , Kataoka Yusuke , Kawakami Takashi , Okumura Mitsutaka , Yamaguchi Kizashi
Published: March 2011

In this paper, we investigate the current–voltage (I–V) characteristics between adjacent bases in two types of artificial metal–DNA (M–DNA) models, i.e., hydroxypyridone (=2-methyl-3-hydroxy-4-pyridone, H) and salen (=N,N′-bis(salicylidene)ethylenediamine, S) complexes, using an elastic scattering Green’s function method together with a density functional theory. In order to estimate quantitative behaviors of the I–V characteristics of the artificial M–DNAs, we considered I–V characteristics from the following viewpoints: the effect of spin states, the effect of backbone, and the effect of metal ions. We have found that the magnitude of the current of the H complex tends to become larger than that of the S complex. We also found that a difference in the spin states drastically changes the I–V characteristics. These behaviors suggest the possibility of the control of the I–V characteristics in the artificial M–DNA by an external magnetic field.
Translation, stability, and resistance to decapping of mRNAs containing caps substituted in the triphosphate chain with BH3, Se, and NH
Authors: Su Wei , Slepenkov Sergey , Grudzien-Nogalska Ewa , Kowalska Joanna , Kulis Marta , Zuberek Joanna , Lukaszewicz Maciej , Darzynkiewicz Edward , Jemielity Jacek , Rhoads Robert E.
Published: March 2011

Decapping is an essential step in multiple pathways of mRNA degradation. Previously, we synthesized mRNAs containing caps that were resistant to decapping, both to dissect the various pathways for mRNA degradation and to stabilize mRNA for more sustained protein expression. mRNAs containing an α-β CH2group are resistant to in vitro cleavage by the decapping enzyme hDcp2 but poorly translated. mRNAs containing an S substitution at the β-phosphate are well translated but only partially resistant to hDcp2. We now describe seven new cap analogs substituted at the β-phosphate with BH3or Se, or substituted at either the α-β or β-γ O with NH. The analogs differ in affinity for eIF4E and efficiency of in vitro incorporation into mRNA by T7 RNA polymerase. Luciferase mRNAs capped with these analogs differ in resistance to hDcp2 hydrolysis in vitro, translational efficiency in rabbit reticulocyte lysate and in HeLa cells, and stability in HeLa cells. Whereas mRNAs capped with m27,2′-OGppSpG were previously found to have the most favorable properties of translational efficiency and stability in mammalian cells, mRNAs capped with m7GppBH3pm7G are translated with the same efficiency but are more stable. Interestingly, some mRNAs exhibit a lag of up to 60 min before undergoing first-order decay (t1/2≅ 25 min). Only mRNAs that are efficiently capped, resistant to decapping in vitro, and actively translated have long lag phases.
The Known Unknowns: Neural Representation of Second-Order Uncertainty, and Ambiguity
Authors: Bach Dominik R. , Hulme Oliver , Penny William D. , Dolan Raymond J.
Published: March 2011

Predictions provided by action-outcome probabilities entail a degree of (first-order) uncertainty. However, these probabilities themselves can be imprecise and embody second-order uncertainty. Tracking second-order uncertainty is important for optimal decision making and reinforcement learning. Previous functional magnetic resonance imaging investigations of second-order uncertainty in humans have drawn on an economic concept of ambiguity, where action-outcome associations in a gamble are either known (unambiguous) or completely unknown (ambiguous). Here, we relaxed the constraints associated with a purely categorical concept of ambiguity and varied the second-order uncertainty of gambles continuously, quantified as entropy over second-order probabilities. We show that second-order uncertainty influences decisions in a pessimistic way by biasing second-order probabilities, and that second-order uncertainty is negatively correlated with posterior cingulate cortex activity. The category of ambiguous (compared with nonambiguous) gambles also biased choice in a similar direction, but was associated with distinct activation of a posterior parietal cortical area; an activation that we show reflects a different computational mechanism. Our findings indicate that behavioral and neural responses to second-order uncertainty are distinct from those associated with ambiguity and may call for a reappraisal of previous data.
Properties of a Distinct Subpopulation of GABAergic Commissural Interneurons That Are Part of the Locomotor Circuitry in the Neonatal Spinal Cord
Authors: Wu Linying , Sonner Patrick M. , Titus David J. , Wiesner Erik P. , Alvarez Francisco J. , Ziskind-Conhaim Lea
Published: March 2011

Commissural inhibitory interneurons (INs) are integral components of the locomotor circuitry that coordinate left–right motor activity during movements. We have shown that GABA-mediated synaptic transmission plays a key role in generating alternating locomotor-like activity in the mouse spinal cord (Hinckley et al., 2005a). The primary objective of our study was to determine whether properties of lamina VIII (LVIII) GABAergic INs in the spinal cord of GAD67::GFP transgenic mice fit the classification of rhythm-coordinating neurons in the locomotor circuitry. The relatively large green fluorescent protein-expressing (GFP+) INs had comparable morphological and electrophysiological properties, suggesting that they comprised a homogenous neuronal population. They displayed multipolar and complex dendritic arbors in ipsilateral LVII–LVIII, and their axonal projections crossed the ventral commissure and branched into contralateral ventral, medial, and dorsal laminae. Putative synaptic contacts evident as bouton-like varicosities were detected in close apposition to lateral motoneurons, Renshaw cells, other GFP+INs, and unidentified neurons. Exposure to a rhythmogenic mixture triggered locomotor-like rhythmic firing in the majority of LVIII GFP+INs. Their induced oscillatory activity was out-of-phase with bursts of contralateral motoneurons and in-phase with bouts of ipsilateral motor activity. Membrane voltage oscillations were elicited by rhythmic increases in excitatory synaptic drive and might have been augmented by three types of voltage-activated cationic currents known to increase neuronal excitability. Based on their axonal projections and activity pattern, we propose that this population of GABAergic INs forms a class of local commissural inhibitory interneurons that are integral component of the locomotor circuitry.
Task-Load-Dependent Activation of Dopaminergic Midbrain Areas in the Absence of Reward
Authors: Boehler Carsten N. , Hopf Jens-Max , Krebs Ruth M. , Stoppel Christian M. , Schoenfeld Mircea A. , Heinze Hans-Jochen , Noesselt Toemme
Published: March 2011

Dopamine release in cortical and subcortical structures plays a central role in reward-related neural processes. Within this context, dopaminergic inputs are commonly assumed to play an activating role, facilitating behavioral and cognitive operations necessary to obtain a prospective reward. Here, we provide evidence from human fMRI that this activating role can also be mediated by task-demand-related processes and thus extends beyond situations that only entail extrinsic motivating factors. Using a visual discrimination task in which varying levels of task demands were precued, we found enhanced hemodynamic activity in the substantia nigra (SN) for high task demands in the absence of reward or similar extrinsic motivating factors. This observation thus indicates that the SN can also be activated in an endogenous fashion. In parallel to its role in reward-related processes, reward-independent activation likely serves to recruit the processing resources needed to meet enhanced task demands. Simultaneously, activity in a wide network of cortical and subcortical control regions was enhanced in response to high task demands, whereas areas of the default-mode network were deactivated more strongly. The present observations suggest that the SN represents a core node within a broader neural network that adjusts the amount of available neural and behavioral resources to changing situational opportunities and task requirements, which is often driven by extrinsic factors but can also be controlled endogenously.
Probing the Functional Equivalence of Otoferlin and Synaptotagmin 1 in Exocytosis
Authors: Reisinger Ellen , Bresee Chris , Neef Jakob , Nair Ramya , Reuter Kirsten , Bulankina Anna , Nouvian Régis , Koch Manuel , Bückers Johanna , Kastrup Lars , Roux Isabelle , Petit Christine , Hell Stefan W. , Brose Nils , Rhee Jeong-Seop , Kügler Sebastian , Brigande John V. , Moser Tobias
Published: March 2011

Cochlear inner hair cells (IHCs) use Ca2+-dependent exocytosis of glutamate to signal sound information. Otoferlin (Otof), a C2domain protein essential for IHC exocytosis and hearing, may serve as a Ca2+sensor in vesicle fusion in IHCs that seem to lack the classical neuronal Ca2+sensors synaptotagmin 1 (Syt1) and Syt2. Support for the Ca2+sensor of fusion hypothesis for otoferlin function comes from biochemical experiments, but additional roles in late exocytosis upstream of fusion have been indicated by physiological studies. Here, we tested the functional equivalence of otoferlin and Syt1 in three neurosecretory model systems: auditory IHCs, adrenal chromaffin cells, and hippocampal neurons. Long-term and short-term ectopic expression of Syt1 in IHCs ofOtof−/−mice by viral gene transfer in the embryonic inner ear and organotypic culture failed to rescue their Ca2+influx-triggered exocytosis. Conversely, virally mediated overexpression of otoferlin did not restore phasic exocytosis in Syt1-deficient chromaffin cells or neurons but enhanced asynchronous release in the latter. We further tested exocytosis inOtof−/−hippocampal neurons and inSyt1−/−IHCs but found no deficits in vesicle fusion. Expression analysis of different synaptotagmin isoforms indicated that Syt1 and Syt2 are absent from mature IHCs. Our data argue against a simple functional equivalence of the two C2domain proteins in exocytosis of IHC ribbon synapses, chromaffin cells, and hippocampal synapses.