bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary Tumor Response to Preoperative Chemoradiation With or Without Oxaliplatin in Locally Advanced Rectal Cancer: Pathologic Results of the STAR-01 Randomized Phase III Trial
Authors: Aschele Carlo , Cionini Luca , Lonardi Sara , Pinto Carmine , Cordio Stefano , Rosati Gerardo , Artale Salvatore , Tagliagambe Angiolo , Ambrosini Giovanni , Rosetti Paola , Bonetti Andrea , Negru Maria Emanuela , Tronconi Maria Chiara , Luppi Gabriele , Silvano Giovanni , Corsi Domenico Cristiano , Bochicchio Anna Maria , Chiaulon Germana , Gallo Maurizio , Boni Luca
Published: May 2011

Purpose

To investigate oxaliplatin combined with fluorouracil-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer.

Patients and Methods

Seven hundred forty-seven patients with resectable, locally advanced (cT3-4 and/or cN1-2) adenocarcinoma of the mid-low rectum were randomly assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and concomitant infused fluorouracil (225 mg/m2/d) either alone (arm A, n = 379) or combined with oxaliplatin (60 mg/m2 weekly × 6; arm B, n = 368). Overall survival is the primary end point. A protocol-planned analysis of response to preoperative treatment is reported here.

Results

Grade 3 to 4 adverse events during preoperative treatment were more frequent with oxaliplatin plus fluorouracil and radiation than with radiation and fluorouracil alone (24% v 8% of treated patients; P < .001). In arm B, 83% of the patients treated with oxaliplatin had five or more weekly administrations. Ninety-one percent, compared with 97% in the control arm, received ≥ 45 Gy (P < .001). Ninety-six percent versus 95% of patients underwent surgery with similar rates of abdominoperineal resections (20% v 18%, arm A v arm B). The rate of pathologic complete responses was 16% in both arms (odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904). Twenty-six percent versus 29% of patients had pathologically positive lymph nodes (arm A v arm B; P = .447), 46% versus 44% had tumor infiltration beyond the muscularis propria (P = .701), and 7% versus 4% had positive circumferential resection margins (P = .239). Intra-abdominal metastases were found at surgery in 2.9% versus 0.5% of patients (arm A v arm B; P = .014).

Conclusion

Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy significantly increases toxicity without affecting primary tumor response. Longer follow-up is needed to assess the impact on efficacy end points.
Induced stem cell neoplasia in a cnidarian by ectopic expression of a POU domain transcription factor
Authors: Millane R. Cathriona , Kanska Justyna , Duffy David J. , Seoighe Cathal , Cunningham Stephen , Plickert Günter , Frank Uri
Published: May 2011

The evolutionary origin of stem cell pluripotency is an unresolved question. In mammals, pluripotency is limited to early embryos and is induced and maintained by a small number of key transcription factors, of which the POU domain protein Oct4 is considered central. Clonal invertebrates, by contrast, possess pluripotent stem cells throughout their life, but the molecular mechanisms that control their pluripotency are poorly defined. To address this problem, we analyzed the expression pattern and function of Polynem (Pln), a POU domain gene from the marine cnidarian Hydractinia echinata. We show that Pln is expressed in the embryo and adult stem cells of the animal and that ectopic expression in epithelial cells induces stem cell neoplasms and loss of epithelial tissue. Neoplasm cells downregulated the transgene but expressed the endogenous Pln gene and also Nanos, Vasa, Piwi and Myc, which are all known cnidarian stem cell markers. Retinoic acid treatment caused downregulation of Pln and the differentiation of neoplasm cells to neurosensory and epithelial cells. Pln downregulation by RNAi led to differentiation. Collectively, our results suggest an ancient role of POU proteins as key regulators of animal stem cells.
The C-terminal end of the Trypanosoma brucei editing deaminase plays a critical role in tRNA binding
Authors: Ragone Frank L. , Spears Jessica L. , Wohlgamuth-Benedum Jessica M. , Kreel Nathan , Papavasiliou F. Nina , Alfonzo Juan D.
Published: May 2011

Adenosine to inosine editing at the wobble position allows decoding of multiple codons by a single tRNA. This reaction is catalyzed by adenosine deaminases acting on tRNA (ADATs) and is essential for viability. In bacteria, the anticodon-specific enzyme is a homodimer that recognizes a single tRNA substrate (tRNAArgACG) and can efficiently deaminate short anticodon stem–loop mimics of this tRNA in vitro. The eukaryal enzyme is composed of two nonidentical subunits, ADAT2 and ADAT3, which upon heterodimerization, recognize seven to eight different tRNAs as substrates, depending on the organism, and require a full-length tRNA for activity. Although crystallographic data have provided clues to why the bacterial deaminase can utilize short substrates, residues that provide substrate binding and recognition with the eukaryotic enzymes are not currently known. In the present study, we have used a combination of mutagenesis, binding studies, and kinetic analysis to explore the contribution of individual residues in Trypanosoma brucei ADAT2 (TbADAT2) to tRNA recognition. We show that deletion of the last 10 amino acids at the C terminus of TbADAT2 abolishes tRNA binding. In addition, single alanine replacements of a string of positively charged amino acids (KRKRK) lead to binding defects that correlate with losses in enzyme activity. This region, which we have termed the KR-domain, provides a first glance at key residues involved in tRNA binding by eukaryotic tRNA editing deaminases.
Phosphodiesterases in endocrine physiology and disease
Authors: Vezzosi Delphine , Bertherat Jérôme
Published: May 2011

The cAMP–protein kinase A pathway plays a central role in the development and physiology of endocrine tissues. cAMP mediates the intracellular effects of numerous peptide hormones. Various cellular and molecular alterations of the cAMP-signaling pathway have been observed in endocrine diseases.

Phosphodiesterases (PDEs) are key regulatory enzymes of intracellular cAMP levels. Indeed, PDEs are the only known mechanism for inactivation of cAMP by catalysis to 5′-AMP. It has been suggested that disruption of PDEs could also have a role in the pathogenesis of many endocrine diseases. This review summarizes the most recent advances concerning the role of the PDEs in the physiopathology of endocrine diseases. The potential significance of this knowledge can be easily envisaged by the development of drugs targeting specific PDEs.
Cancer risk in hyperprolactinemia patients: a population-based cohort study
Authors: Berinder Katarina , Akre Olof , Granath Fredrik , Hulting Anna-Lena
Published: May 2011

Objective

Experimental evidence indicates that prolactin might play a role in tumorigenesis of several human cancers, but data on cancer risk in hyperprolactinemia patients are sparse. The aim of this study was to investigate cancer risk in hyperprolactinemia patients.

Design

A population-based matched cohort study in Sweden.

Methods

The hyperprolactinemia cohort consisted of patients hospitalized for hyperprolactinemia from 1987 to 1995 identified in the National Patient Register (n=585) and a hospital cohort of prolactinoma patients at Karolinska University Hospital (n=384). For each patient, ten matched individuals were identified via the Register of Population. Cancer occurrence was ascertained via the Swedish Cancer Registry. Hazard ratios (HRs) were estimated by Cox proportional hazards regression.

Results

Seventy-three malignant tumors were identified in the hyperprolactinemia patients and 660 tumors in the comparison group (HR 1.31; 95% confidence interval (CI): 1.02–1.68), mainly attributed to an increased risk of upper gastrointestinal cancer in both males and females (HR 3.69; 95% CI: 1.70–8.03) and hematopoietic cancer in females (HR 3.51; 95% CI: 1.06–11.6). Twelve breast cancers occurred in the female patients, corresponding to an HR of 1.09 (95% CI: 0.60–1.99). Prostate cancer risk in hyperprolactinemia men was reduced (HR 0.40; 95% CI: 0.16–0.99).

Conclusions

An increased overall cancer risk was found in hyperprolactinemia patients, but no increased risk of breast cancer in women and a reduced risk of prostate cancer in men. These findings warrant further investigations and to be confirmed in larger studies but may indicate the importance of an active treatment strategy and follow-up of hyperprolactinemia patients.
Sexual desire in female-to-male transsexual persons: exploration of the role of testosterone administration
Authors: Wierckx Katrien , Elaut Els , Van Caenegem Eva , Van De Peer Fleur , Dedecker David , Van Houdenhove Ellen , T'Sjoen Guy
Published: May 2011

Objective

To describe sexual desire in female-to-male transsexual persons post sex reassignment surgery (SRS). The associations between serum androgen levels and sexual desire are examined.

Design

Single center cross-sectional study.

Methods

Forty-five female-to-male transsexual persons post SRS completed a standardized questionnaire assessing sexual desire (Sexual Desire Inventory). In addition, participants were asked questions on sexual desire before starting hormone treatment and having SRS. Serum levels of testosterone, LH and sex hormone-binding globulin were measured on fasting morning serum samples.

Results

In retrospect, 73.9% of the participants reported an increase in sexual desire after hormone treatment and SRS. Solitary sexual desire scores were significantly correlated with frequency of masturbation (r=0.835;P<0.001), whereas frequency of sexual intercourse with a partner was not. No direct associations were found between testosterone and solitary or dyadic sexual desire. However, ANOVA showed an independent effect of LH on solitary sexual desire (P<0.001).Post hocanalysis revealed that female-to-male transsexual persons with elevated levels of LH, indicating suboptimal testosterone therapy, reported significantly lower solitary sexual desire levels (than those with low LH levels;P=0.007). Suppressed LH levels were also associated with having a higher need for sexual activities (P=0.009) and a higher frequency of excessive sexual desire (P=0.007).

Conclusion

Most female-to-male transsexual persons report on a marked increase in sexual desire after testosterone treatment and SRS. No direct associations between levels of testosterone and solitary or dyadic sexual desire were found. However, measures of sexual desire were inversely associated with LH levels.
Leptin administration to overweight and obese subjects for 6 months increases free leptin concentrations but does not alter circulating hormones of the thyroid and IGF axes during weight loss induced by a mild hypocaloric diet
Authors: Shetty Greeshma K , Matarese Giuseppe , Magkos Faidon , Moon Hyun-Seuk , Liu Xiaowen , Brennan Aoife M , Mylvaganam Geetha , Sykoutri Despina , DePaoli Alex M , Mantzoros Christos S
Published: May 2011

Objective

Short-term energy deprivation reduces leptin concentrations and alters the levels of circulating hormones of the hypothalamic–pituitary–peripheral axis in lean subjects. Whether the reduction in leptin concentration during long-term weight loss in obese individuals is linked to the same neuroendocrine changes seen in lean, leptin-sensitive subjects remains to be fully clarified.

Methods

In this study, 24 overweight and obese adults (16 women and eight men; body mass index (BMI): 27.5–38.0 kg/m2) were prescribed a hypocaloric diet (−500 kcal/day) and were randomized to receive recombinant methionyl leptin (n=18, metreleptin, 10 mg/day self-injected s.c.) or placebo (n=6, same volume and time as metreleptin) for 6 months.

Results

Metreleptin administration did not affect weight loss beyond that induced by hypocaloric diet alone (P for interaction=0.341) but increased the serum concentrations of total leptin by six- to eight-fold (P<0.001) and led to the generation of anti-leptin antibodies. Despite free leptin concentration (P for interaction=0.041) increasing from 9±1 ng/ml at baseline to 43±15 and 36±12 ng/ml at 3 and 6 months, respectively, changes in circulating hormones of the thyroid and IGF axes at 3 and 6 months were not significantly different in the placebo- and metreleptin-treated groups.

Conclusions

Leptin does not likely mediate changes in neuroendocrine function in response to weight loss induced by a mild hypocaloric diet in overweight and obese subjects.
Adrenal vein sampling using rapid cortisol assays in primary aldosteronism is useful in centers with low success rates
Authors: Betz Matthias J , Degenhart Christoph , Fischer Evelyn , Pallauf Anna , Brand Volker , Linsenmaier Ulrich , Beuschlein Felix , Bidlingmaier Martin , Reincke Martin
Published: May 2011

Objective

Adrenal vein sampling (AVS) is considered the gold standard in the differential diagnosis of primary aldosteronism (PA), but success rates vary between centers. We hypothesized that rapid (intraprocedure) cortisol measurement can improve performance in a center with initially low AVS success rate.

Design

We analyzed 46 patients with confirmed PA studied between 2008 and 2010. Forty-seven PA patients studied between 2004 and 2008 identified by retrospective chart review served as controls. All patients were treated at a single tertiary care university hospital.

Methods

Starting in 2008, rapid cortisol assays (RCA) were performed in all patients during the AVS procedure. A cortisol gradient of ≥2.0 between adrenal vein and a femoral vein sample was used as success criterion. Up to two repeat samples were drawn if adrenal vein cortisol was below this threshold.

Results

During the control period 26 of 47 AVS were successful (55%). After introduction of RCA, 39 out of 46 AVS (85%) were successful (P=0.003). In 21 of the 46 cases (46%) a resampling was necessary. The increase in overall success was due to an increase in successful right AVS (85 vs 62% before introduction of RCA; P=0.02) and a training effect (P=0.024 for trend).

Conclusion

RCA during AVS are useful in centers with an initially low AVS success rate.
Long-term DHEA substitution in female adrenocortical failure, body composition, muscle function, and bone metabolism: a randomized trial
Authors: Christiansen Jens J , Bruun Jens M , Christiansen Jens S , Jørgensen Jens Otto , Gravholt Claus H
Published: May 2011

Context

Adrenal derived androgens are low in women with adrenal failure. The physiological consequences of substitution therapy are uncertain.

Objective

To investigate the effects of DHEA substitution in women with adrenal failure on body composition, fuel metabolism, and inflammatory markers.

Design, participants and intervention

In this study, ten female patients (median age 38.5 years, range 28–52) with adrenal failure were treated with DHEA 50 mg for 6 months in a double-blind, randomized, placebo-controlled, and crossover study. The participants underwent dual-energy X-ray absorptiometry (DXA) scan, computed tomography scan of abdominal fat, indirect calorimetry, bicycle ergometry, muscle and fat biopsies, and blood samples.

Results

Baseline androgens were normalized to fertile range during active treatment. Anthropometric data were unaffected, but lean body mass (LBM) slightly increased compared with placebo (delta LBM (kg) placebo versus DHEA: −0.48±6.1 vs 1.6±3.4,P=0.02) with no alterations in total or abdominal fat mass. PTH increased with DHEA, but no significant changes were observed in other bone markers or in bone mineral content. The mRNA levels of markers of tissue inflammation (adiponectin, interleukin 6 (IL6), IL10, monocyte chemoattractant protein 1, and tumor necrosis factor α) in fat and muscle tissue were unaffected by DHEA treatment, as was indirect calorimetry and maximal oxygen uptake. A high proportion of self-reported seborrheic side effects were recorded (60%).

Conclusion

In female adrenal failure, normalization of androgens with DHEA 50 mg for 6 months had no effects on muscle, fat, and bone tissue and on fuel metabolism in this small study. A small increase in LBM was observed. Treatment was associated with a high frequency of side effects.
Quality Measures for the Care of Children With Otitis Media With Effusion
Authors: Lannon Carole , Peterson Laura E. , Goudie Anthony
Published: May 2011

BACKGROUND:

Current national efforts provide an opportunity to integrate performance measures into clinical practice and improve outcomes for children.

OBJECTIVE:

The goal of this study was to explore issues in developing and testing measures of care for children with otitis media with effusion (OME).

METHODS:

We assessed compliance with diagnostic, evaluation, and treatment measures for OME adapted from preliminary work of the Physician Consortium for Performance Improvement, using chart data in a convenience sample of practices from 2 primary care networks (Cincinnati Pediatric Research Group and the American Academy of Pediatrics Quality Improvement Innovation Network). Children aged 2 months to 12 years with at least 1 visit with a specified OME code during a 1-year period were included.

RESULTS:

Of 23 practices, 4 could not locate eligible visits. Nineteen practices submitted 378 abstractions (range: 3–37 per practice) with 15 identifying <30 eligible visits. Performance on diagnosis (33%) and hearing evaluation (29%) measures was low but high on measures of appropriate medication use (97% decongestant/antihistamine, 87% antibiotics, and 95% corticosteroids). Thirty-five percent of records documented antibiotic use concurrent with OME; only 16% of the 94 cases that cited reason for prescribing were appropriate. Using methods that consider appropriate clinical action, a more accurate rate for appropriate use of antibiotics was 68%.

CONCLUSIONS:

Coding, case finding, and evaluating appropriateness of treatment are some of the issues that will need to be considered to assess the care of children with OME. This study emphasizes the importance of testing proposed quality of care measures in “real-world” settings.
Effects of incorporating steel fibre on the properties of high-strength flowing concrete
Authors: Ramli Mahyuddin , Dawood Eethar Thanon
Published: May 2011

An experimental investigation was carried out to determine some properties of high-strength flowing concrete (HSFC) reinforced by different percentages of steel fibre (0, 0·25, 0·5, 0·75, 1·0, 1·25, 1·5, 1·75 and 2·0% as volumetric fractions). An experimental programme was planned in which various tests to determine density, compressive strength and flexural strength were conducted to investigate the properties of the concretes in a hardened state. Complete load–deflection curves under static flexural loads were achieved and the flexural toughness indices were determined according to ASTM C1018. The experimental results indicated that the inclusion of this fibre increased the density of the concrete. It can be concluded that the incorporation of 1% steel fibre in the mixed HSFC increased the compressive strength whereas for the flexural strength specimens incorporating 1·5% of steel fibre was found to be the most appropriate. The toughness indices increased as the steel fibre volume fraction increased.
Correlating washout to strength loss of underwater concrete
Authors: Assaad Joseph J. , Daou Yehia , Salman Hadi
Published: May 2011

A research project was undertaken to evaluate the effect of mixture parameters on the fresh and hardened properties of underwater concrete. Washout loss was determined using either the CRD C61 test method or a newly developed device for simulation of increased hydrostatic pressure on the concrete/water interface. Correlations between washout loss and residual compressive strength evaluated in dry conditions and after washout measurement were established. The test results showed that the incorporation of cellulose- or welan gum-based anti-washout agents can greatly reduce water dilution of underwater concrete while increasing flow resistance and cohesiveness. Increased cement and silica fume contents together with reduced free water resulted in lower washout loss. An increased depth of casting was found to increase washout loss until reaching a threshold water head beyond which significant washout loss would occur. A linear relationship with a high correlation coefficient of 0·91 was obtained between washout loss and residual compressive strength of the tested underwater concrete mixtures.
Historical paper: ‘The tragedy of the commons’
Authors: Corker Nicholas
Published: May 2011

How do we allocate natural resources in an equitable way? For many, Garret Hardin's 'The tragedy of the commons' published in Science in 1968 became a parable of its time, giving succour to both environmentalist and capitalist alike. The intervening years have seen developments in environmental economics, participatory planning, environmental regulation, governance and resource efficiency, all strands that Hardin would recognise. New multi-disciplinary fields have emerged in topics such as socio-ecological systems theory, environmental cognition and resilience, all things that Hardin alludes to. The new science of ecosystem services is providing a robust framework for natural resource evaluation as it starts to underpin exactly what nature provides to us all in common. As we face the challenges of a changing climate and other ‘wicked‘ problems, is Hardin's analysis of a ‘class of problem with no technical solution‘ still a useful one? Followers of the debate over sustainable communities and the ’big society‘ may think so. This paper aims to introduce the reader to Hardin‘s now classic tragic scenario of natural resource use, place it within an evolving corpus of environmental literature, explore a little of the author's own life and attempt to asses its impact and relevance today.
Mapping sustainability assessment with the project life cycle
Authors: Thomson Craig S. , El-Haram Mohamed A. , Emmanuel Rohinton
Published: May 2011

Traditionally viewed as a technically based exercise focused on assessing the sustainability performance of buildings, sustainability assessment is increasingly called upon to play a proactive role that supports the management of sustainability across the project life cycle. Calls are emerging for assessment to evolve as a tool that contributes to the predominantly subjective nature of decisions taken across the project life cycle and to achieve better integration between assessment and project activities. This paper aims to contribute towards this emerging understanding by considering an empirically based case study which follows a progressive approach to apply and integrate sustainability assessment with the life cycle stages of a university campus building project. The paper presents the findings of a mapping exercise that identifies the emerging phases and activities of the assessment in relation to the stakeholders involved and life cycle stages. By exploring an empirical context that is by nature forward thinking, some recommendations are drawn to facilitate the evolution of sustainability assessment towards the advocated approach.
How Standardized Is Accounting?
Authors: Madsen Paul E
Published: May 2011

There is disagreement in the accounting community about what level of standardization would be efficient for accounting. Many of the known costs and benefits of standardization have gone unmeasured and, as a result, there have been no efforts to quantitatively identify an efficient level of accounting standardization. Without guidance from researchers, the level of accounting standardization is set according to the intuition of standard-setters. Using data on a large cross-section of occupations, I provide evidence that the level of standardization in financial reporting occupations is far higher than would be expected given their characteristics. I then show with time-series data that the breadth of professional accounting discourse declined during the late 20th century, coincident with increases in the output of standard-setters. A lower quality discourse is one of many possible consequences of inefficient standardization.

Data Availability: Occupations data in the O*NET, Career One Stop, and Occupational Employment Statistics (OES) databases are available from the U.S. Department of Labor. Data from the General Social Survey (GSS) are available from the National Opinion Research Center (NORC) at The University of Chicago. Contact the author for the data collected from the Accountants' Handbook.
Impaired Insulin Secretion and Enhanced Insulin Sensitivity in Cholecystokinin-Deficient Mice
Authors: Lo Chun-Min , Obici Silvana , Dong H. Henry , Haas Michael , Lou Dawnwen , Kim Dae Hyun , Liu Min , D’Alessio David , Woods Stephen C. , Tso Patrick
Published: May 2011

OBJECTIVE

Cholecystokinin (CCK) is released in response to lipid intake and stimulates insulin secretion. We hypothesized that CCK deficiency would alter the regulation of insulin secretion and glucose homeostasis.

RESEARCH DESIGN AND METHODS

We used quantitative magnetic resonance imaging to determine body composition and studied plasma glucose and insulin secretion of CCK gene knockout (CCK-KO) mice and their wild-type controls using intraperitoneal glucose and arginine infusions. The area of anti-insulin staining in pancreatic islets was measured by immunohistochemistry. Insulin sensitivity was assessed with euglycemic-hyperinsulemic clamps.

RESULTS

CCK-KO mice fed a low-fat diet had a reduced acute insulin response to glucose but a normal response to arginine and normal glucose tolerance, associated with a trend toward greater insulin sensitivity. However, when fed a high-fat diet (HFD) for 10 weeks, CCK-KO mice developed glucose intolerance despite increased insulin sensitivity that was associated with low insulin secretion in response to both glucose and arginine. The deficiency of insulin secretion in CCK-KO mice was not associated with changes in β-cell or islet size.

CONCLUSIONS

CCK is involved in regulating insulin secretion and glucose tolerance in mice eating an HFD. The impaired insulin response to intraperitoneal stimuli that do not typically elicit CCK release suggests that this hormone has chronic effects on β-cell adaptation to diet in addition to acute incretin actions.
The Soluble CTLA-4 Splice Variant Protects From Type 1 Diabetes and Potentiates Regulatory T-Cell Function
Authors: Gerold Kay D. , Zheng Peilin , Rainbow Daniel B. , Zernecke Alma , Wicker Linda S. , Kissler Stephan
Published: May 2011

OBJECTIVE

CTLA4 gene variation associates with multiple autoimmune disorders, including type 1 diabetes. The CTLA4 susceptibility allele was found to generate decreased levels of mRNA encoding soluble CTLA-4 (sCTLA-4) relative to the full-length isoform, the functional consequence of which is as yet unknown. In this study, we investigated the contribution of sCTLA-4 to immune regulation with the aim to elucidate the functional basis of the disease association of CTLA4.

RESEARCH DESIGN AND METHODS

To model the disease-associated splicing variation of CTLA4, we generated NOD mice in which sCTLA-4 mRNA is silenced by RNA interference.

RESULTS

We found that loss of sCTLA-4 impairs the function of regulatory T (Treg) cells. This functional defect could be attributed, at least in part, to the failure of sCTLA-4 knockdown (KD) Treg cells to downregulate dendritic cell costimulation. sCTLA-4 KD Treg cells, in contrast with wild-type Treg cells, failed to inhibit colitis induced by transfer of CD4+CD45RBhi cells into NOD.SCID animals. Furthermore, diminished sCTLA-4 expression accelerated the onset of autoimmune diabetes in transgenic mice.

CONCLUSIONS

Our results demonstrate that sCTLA-4 participates in immune regulation by potentiating the function of Treg cells. The functional outcome of silencing this splice variant in the NOD model provides an explanation for the association of CTLA4 variation with autoimmunity. Lower sCTLA-4 expression from the susceptibility allele may directly affect the suppressive capacity of Treg cells and thereby modulate disease risk. Our unprecedented approach establishes the feasibility of modeling splicing variations relevant to autoimmunity.
Suppression of FoxO1 Activity by Long-Chain Fatty Acyl Analogs
Authors: Zatara Ghadeer , Hertz Rachel , Shaked Maayan , Mayorek Nina , Morad Etedal , Grad Etty , Cahan Amos , Danenberg Haim D. , Unterman Terry G. , Bar-Tana Jacob
Published: May 2011

OBJECTIVE

Overactivity of the Forkhead transcription factor FoxO1 promotes diabetic hyperglycemia, dyslipidemia, and acute-phase response, whereas suppression of FoxO1 activity by insulin may alleviate diabetes. The reported efficacy of long-chain fatty acyl (LCFA) analogs of the MEDICA series in activating AMP-activated protein kinase (AMPK) and in treating animal models of diabesity may indicate suppression of FoxO1 activity.

RESEARCH DESIGN AND METHODS

The insulin-sensitizing and anti-inflammatory efficacy of a MEDICA analog has been verified in guinea pig and in human C-reactive protein (hCRP) transgenic mice, respectively. Suppression of FoxO1 transcriptional activity has been verified in the context of FoxO1- and STAT3-responsive genes and compared with suppression of FoxO1 activity by insulin and metformin.

RESULTS

Treatment with MEDICA analog resulted in total body sensitization to insulin, suppression of lipopolysaccharide-induced hCRP and interleukin-6–induced acute phase reactants and robust decrease in FoxO1 transcriptional activity and in coactivation of STAT3. Suppression of FoxO1 activity was accounted for by its nuclear export by MEDICA-activated AMPK, complemented by inhibition of nuclear FoxO1 transcriptional activity by MEDICA-induced C/EBPβ isoforms. Similarly, insulin treatment resulted in nuclear exclusion of FoxO1 and further suppression of its nuclear activity by insulin-induced C/EBPβ isoforms. In contrast, FoxO1 suppression by metformin was essentially accounted for by its nuclear export by metformin-activated AMPK.

CONCLUSIONS

Suppression of FoxO1 activity by MEDICA analogs may partly account for their antidiabetic anti-inflammatory efficacy. FoxO1 suppression by LCFA analogs may provide a molecular rational for the beneficial efficacy of carbohydrate-restricted ketogenic diets in treating diabetes.
Diabetes and Neurodegeneration in Wolfram Syndrome
Authors: Rohayem Julia , Ehlers Christian , Wiedemann Bärbel , Holl Reinhard , Oexle Konrad , Kordonouri Olga , Salzano Giuseppina , Meissner Thomas , Burger Walter , Schober Edith , Huebner Angela , Lee-Kirsch Min Ae ,   the Wolfram Syndrome Diabetes Writing Group
Published: May 2011

OBJECTIVE

To describe the diabetes phenotype in Wolfram syndrome compared with type 1 diabetes, to investigate the effect of glycemic control on the neurodegenerative process, and to assess the genotype-phenotype correlation.

RESEARCH DESIGN AND METHODS

The clinical data of 50 patients with Wolfram syndrome-related diabetes (WSD) were reviewed and compared with the data of 24,164 patients with type 1 diabetes. Patients with a mean HbA1c during childhood and adolescence of ≤7.5 and >7.5% were compared with respect to the occurrence of additional Wolfram syndrome symptoms. The wolframin (WFS1) gene was screened for mutations in 39 patients. WFS1 genotypes were examined for correlation with age at onset of diabetes.

RESULTS

WSD was diagnosed earlier than type 1 diabetes (5.4 ± 3.8 vs. 7.9 ± 4.2 years; P < 0.001) with a lower prevalence of ketoacidosis (7 vs. 20%; P = 0.049). Mean duration of remission in WSD was 2.3 ± 2.4 vs. 1.6 ± 2.1 in type 1 diabetes (NS). Severe hypoglycemia occurred in 37 vs. 7.9% (P < 0.001). Neurologic disease progression was faster in the WSD group with a mean HbA1c >7.5% (P = 0.031). Thirteen novel WSF1 mutations were identified. Predicted functional consequence of WFS1 mutations correlated with age at WSD onset (P = 0.028).

CONCLUSIONS

Endoplasmic reticulum stress–mediated decline of β-cells in WSD occurs earlier in life than autoimmune-mediated β-cell destruction in type 1 diabetes. This study establishes a role for WFS1 in determining the age at onset of diabetes in Wolfram syndrome and identifies glucose toxicity as an accelerating feature in the progression of disease.
Long-Term and Recent Progress in Blood Pressure Levels Among U.S. Adults With Diagnosed Diabetes, 1988–2008
Authors: Wang Jing , Geiss Linda S. , Cheng Yiling J. , Imperatore Giuseppina , Saydah Sharon H. , James Cherie , Gregg Edward W.
Published: May 2011

OBJECTIVE

To examine whether there were long-term (between 1988–1994 and 2001–2008) and recent (between 2001–2004 and 2005–2008) changes in blood pressure (BP) levels among U.S. adults with diagnosed diabetes.

RESEARCH DESIGN AND METHODS

Using data from National Health and Nutrition Examination Surveys (NHANES), we examined changes in BP distributions, mean BPs, and proportion with BP <140/90 mmHg.

RESULTS

Between 1988–1994 and 2001–2008, for adults with diabetes, mean BPs decreased from 135/72 mmHg to 131/69 mmHg (P < 0.01) and the proportion with BP <140/90 mmHg increased from 64 to 69% (P = 0.01). Although hypertension prevalence increased, hypertension awareness, treatment, and control improved. However, there was no evidence of improvement for adults 20–44 years old. Between 2001–2004 and 2005–2008, there were no significant changes in BP levels.

CONCLUSIONS

BP levels among adults with diabetes improved between 1988–1994 and 2001–2008, but the progress stalled between 2001–2004 and 2005–2008. The lack of improvement among young adults is concerning.
Moment-angle complexes from simplicial posets
Authors: Lü Zhi , Panov Taras
Published: May 2011

We extend the construction of moment-angle complexes to simplicial posets by associating a certain T
m-space Z
S to an arbitrary simplicial poset S on m vertices. Face rings ℤ[S] of simplicial posets generalise those of simplicial complexes, and give rise to new classes of Gorenstein and Cohen-Macaulay rings. Our primary motivation is to study the face rings ℤ[S] by topological methods. The space Z
S has many important topological properties of the original moment-angle complex Z
K associated to a simplicial complex K. In particular, we prove that the integral cohomology algebra of Z
S is isomorphic to the Tor-algebra of the face ring ℤ[S]. This leads directly to a generalisation of Hochster’s theorem, expressing the algebraic Betti numbers of the ring ℤ[S] in terms of the homology of full subposets in S. Finally, we estimate the total amount of homology of Z
S from below by proving the toral rank conjecture for the moment-angle complexes Z
S.
Modification of the amorphous carbon films by the ns-laser irradiation
Authors: Grigonis Alfonsas , Marcinauskas Liutauras , Vinciunaite Vinga , Raciukaitis Gediminas
Published: May 2011

The effect of a nanosecond laser irradiation of thin (60 and 145 nm) amorphous, diamond-like carbon films deposited on Si substrate by an ion beam deposition (IBD) from pure acetylene and acetylene/hydrogen (1:2) gas mixture was analyzed in this work. The films were irradiated with the infrared (IR) and ultraviolet (UV) radiation of the nanosecond Nd:YAG lasers working at the first (1.16 eV) and the third (3.48 eV) harmonics, using a multi-shot regime. The IR laser irradiation stimulated a minor increase in the fraction of sp2 bonds, causing a slight decrease in the hardness of the films and initiated SiC formation. Irradiation with the UV laser caused the formation of carbides and increased hydrogenization of the Si substrate and the fraction of sp2 sites. Spalliation and ablation were observed at a higher energy density and with a large number of laser pulses per spot.
Assessment of School Performance Through a Multilevel Latent Markov Rasch Model
Authors: Bartolucci Francesco , Pennoni Fulvia , Vittadini Giorgio
Published: May 2011

An extension of the latent Markov Rasch model is described for the analysis of binary longitudinal data with covariates when subjects are collected in clusters, such as students clustered in classes. For each subject, a latent process is used to represent the characteristic of interest (e.g., ability) conditional on the effect of the cluster to which he or she belongs. The latter effect is modeled by a discrete latent variable associated to each cluster. For the maximum likelihood estimation of the model parameters, an Expectation-Maximization algorithm is outlined. Through the analysis of a data set collected in the Lombardy Region (Italy), it is shown how the proposed model may be used for assessing the development of cognitive achievement. The data set is based on test scores in mathematics observed over 3 years on middle school students attending public and non-state schools.

Manuscript received March 20, 2009 Revision received July 2, 2010 Accepted July 10, 2010
Confidence Intervals and F Tests for Intraclass Correlation Coefficients Based on Three-Way Mixed Effects Models
Authors: Zhou Hong , Muellerleile Paige , Ingram Debra , Wong Seok P.
Published: May 2011

Intraclass correlation coefficients (ICCs) are commonly used in behavioral measurement and psychometrics when a researcher is interested in the relationship among variables of a common class. The formulas for deriving ICCs, or generalizability coefficients, vary depending on which models are specified. This article gives the equations for computing confidence intervals and conducting F tests for three-way mixed models with one fixed facet, extending the work on random effects models produced by Wong and McGraw. It provides the formula for finding the confidence interval for generalizability coefficients in the situations in which [Formula: see text] is not necessarily equal to ni, where ni and [Formula: see text] are the number of levels of facet i in generalizability and decision studies, respectively. The authors provide the formulas for finding [Formula: see text] when the researcher wishes to maintain a minimum desired generalizability coefficient. Finally, the authors illustrate the analytic differences among four models using one hypothetical data set and then use real data from student course evaluations to further illustrate one of the four models.
Marseille, pouvoirs politiques et mutations économiques depuis 1945
Authors: Morel Bernard
Published: May 2011

La compréhension des relations entre les pouvoirs politiques et les pouvoirs économiques à Marseille est complexe. L'article retient trois périodes. La première va de 1945 au milieu des années 1960, c'est la période où le district marseillais s'effondre. La deuxième période va de 1965 à la mi-décennie 1980 ; 20 années durant lesquelles le pouvoir politique va éclipser les pouvoirs économiques en essayant de gérer la transition marseillaise ; 20 années paradoxales puisqu'au moment où la France se modernise à grande vitesse ; Marseille gère son déclin et ne voit pas apparaître le processus métropolitain. Enfin, la troisième période qui, de 1985 à aujourd'hui, au travers du doute politique et de la reconversion économique, est celle d'une amorce de reconstruction économique et spatiale.
¿Cómo pensamos la política de la edad moderna ? une reflexión historiográfica / personal
Authors: Martínez Bermejo Saúl
Published: May 2011

Funcionamos, día a día, con una cierta noción de política. De algún modo, sabemos lo que es un parlamento, un partido, una ideología, aunque se trate de un conocimiento impreciso y que no cuestiona, por ejemplo, la relación entre la teoría y la práctica políticas. No nos resulta difícil trasvasar estas nociones al pasado e identificar las principales características de lo político en cualquier época pasada. En la edad moderna europea podemos también, sin embargo, señalar ausencias importantes, en especial al respecto de la definición de la política como disciplina: en cuanto a su institucionalización como saber dentro de las bibliotecas, su presencia en las enseñanzas universitarias, la aparición de un intelectual con una función especializada, los límites del campo, etc.)Existen muchas maneras de salvar la tensión entre una visión extraña del pasado y un tratamiento cercano del mismo y la historiografía, entendida como reflexión teórica acerca del pasado, ha dedicado largas páginas a esta cuestión. Este artículo pretende retomar esta reflexión desde una perspectiva relativamente novedosa. En lugar de explicar teóricamente como se dilucida esta presentación de los rasgos distanciados y próximos del pasado, pretendo reflexionar sobre el modo en que se practica cotidianamente esa negociación en la labor del historiador. A través de dos ejemplos visuales que pretenden servir de contraste a nuestras imágenes naturalizadas de la política, este es un apunte preliminar (y una invitación a la reflexión personal). Se trata de exponer lo que historiadores realmente hacemos de la historiografía, entendida ahora como arte de escribir, y nuestras dificultades para comunicar estos fundamentos y para emplearlos como base de una descripción de nuestra disciplina.
Historiographie et histoire disciplinaire. Marcel Granet et les sciences sociales
Authors: Hirsch Thomas
Published: May 2011

Sinologue, sociologue, historien, ethnologue : les multiples étiquettes accolées à Marcel Granet traduisent la difficulté à lui faire place dans un récit disciplinaire particulier. Cas-limite, l’auteur de La Pensée chinoise invite ainsi à considérer la tension entre l’historiographie, comme histoire de l’histoire, et l’histoire disciplinaire, succédanée de l’histoire philosophique des idées
L’écriture de l’histoire et la compétition européenne outre-mer au tournant du xviie siècle
Authors: Delmas Adrien
Published: May 2011

Au tournant du xviie siècle, l’irruption des navires français, anglais et hollandais sur les trois océans, rompant avec le monopole ibérique sur les Indes orientales et occidentales, s’accompagne d’un déplacement de la notion de découverte. Afin de saisir les enjeux liés à l’appropriation de cette notion par les concurrents européens du Portugal et de l’Espagne, cet article se concentre sur les écrits de l’historien huguenot Henri Lancelot Voisin de La Popelinière (1541-1608) dans lesquels l’idée de « découverte » devient l’alpha et l’oméga d’une nouvelle écriture de l’histoire, supérieure en tout point, selon La Popelinière, à ce que les historiographes, Anciens ou Modernes, avaient proposé jusqu’alors. Chemin faisant, la notion se dotait également d’enjeux qui dépassaient largement la seule écriture de l’histoire : le récit des découvertes jouerait dorénavant le rôle de garant dans la revendication de prises de possessions outre-mer.
Du héros poétique au grand homme historique ?
Authors: Kokkomelis Nikolaos
Published: May 2011

Partant du roman héroïque français du xviie siècle et appuyé sur des outils méthodologiques tirés de l’historiographie, des théories de l’histoire et de la littérature, sans négliger la philosophie des Lumières, cet article de Nicolac Kokkomelis cherche à définir quelques aspects du contenu, de la morphologie et de la charge conceptuelle qui contribuèrent à la formation du genre de la biographie historique lors du xviiie siècle.
Quelle place pour l’historien dans le statut multiple des intellectuels latino-américains au début du xxe siècle ? Étude d’un cas
Authors: Reali María Laura
Published: May 2011

Notre travail porte sur le croisement entre une œuvre d’historien et son contexte de production à partir de l’étude du cas de Luis Alberto de Herrera (1873-1959), écrivain, historien et homme politique uruguayen. Comme tant d’autres hommes publics à la même époque, cet auteur a associé réflexion rétrospective et diagnostics sur l’actualité de son pays, portant aussi son regard sur des espaces géographiques plus vastes. De plus, il a déployé une intense activité dans la sphère publique. Ainsi, sa démarche intellectuelle et ses propositions dans le champ politique se sont recoupées à plusieurs reprises sans pour autant que l’un de ces domaines n’ait été entièrement tributaire de l’autre. Notre approche se propose de mettre en évidence non seulement les rapports entre ces deux niveaux, mais aussi leurs espaces d’autonomie possible, leurs écarts, tensions et conflits. Le cas d’Herrera est examiné dans le cadre d’une interrogation plus générale sur les conditions d’exercice de l’activité intellectuelle à son époque.
Les formes de l’enquête historique : John Dewey et Max Weber
Authors: Gros Aurélien
Published: May 2011

L’objet de cet article d’Aurélien Gros est de questionner la possibilité d’une étude empirique de la production des savoirs historiques. Avec quels outils peut-on rendre compte du processus de recherche historique dont le texte d’histoire constitue un aboutissement écrit ? Deux auteurs sont ici mis à contribution. D’une part John Dewey qui, proposant une théorie de l’enquête, définit celle-ci comme processus actif et en isole les séquences depuis le problème initial jusqu’à sa résolution ; d’autre part Max Weber qui, par sa méthode de l’idéaltype, décrit empiriquement le fonctionnement des sciences historiques. Les instruments proposés par ces deux auteurs permettent de saisir la pensée historique non pas comme un contenu, mais comme un processus dynamique, une pratique de pensée s’inscrivant dans des situations particulières et dans l’interaction permanente entre l’historien et son présent.
L’avènement d’une « histoire au second degré »
Authors: Brandi Felipe
Published: May 2011

Le but de ces pages est de faire un tour d’horizon, une sorte d’esquisse de reconstitution, sans souci d’exhaustivité, d’un demi-siècle de travaux historiographiques en France, entre 1940 et 1990 environ. L’historiographie ne s’est pas encore tournée sur sa propre histoire. Seule une histoire des historiens de l’historiographie saurait mettre en évidence son cheminement progressif, les obstacles surmontés, les directions prises à tel ou tel moment, celles qui ont été aujourd’hui abandonnées. Surtout, le fait que son affirmation n’a pas été possible avant que sa justification n’ait été légitimée par d’autres champs de la recherche préalablement en faveur
Former les futurs enseignants de langue en ligne par le biais de la rétrospection
Authors: Guichon Nicolas
Published: May 2011

Cette recherche se focalise sur un des aspects d'une formation professionnelle qui alterne des moments de pratique pendant lesquels des apprentis enseignants animent des cours de langue en ligne par le biais d'une plateforme de visioconférence (Visu) et des moments où des échantillons vidéo de l'activité déployée en situation sont examinés par ces mêmes apprentis. Il est postulé que la rétrospection, définie comme l'analyse critique d'une activité professionnelle par le biais de la confrontation d'un collectif d'individus en formation à des traces de leur activité en situation de travail, peut contribuer à leur développement professionnel.Cette étude se concentre sur le discours des apprentis aux prises avec une situation pédagogique aux contours mal définis, celle de l'enseignement d'une langue en ligne, en vue d'analyser les processus d'évaluation et les stratégies pour rendre compte et organiser l'activité de rétrospection. Cet article se termine sur la présentation du salon de rétrospection de la plateforme Visu, une application développée dans le cadre d'un projet de recherche-développement, dont la spécification s'est en partie nourrie des recherches présentées dans cette étude.
Análisis lingüístico-comunicativo del tratamiento informativo de la guerra de Irak en la prensa venezolana
Authors: Franco Sylvia Fernández
Published: May 2011

Les pratiques médiatiques de communication reproduisent un modèle de production et de compréhension, de construction et de déconstruction rationnelle de la connaissance de la réalité, ce qui suppose la formulation d’arguments et la mise en scène de stratégies discursives qui impliquent une compétence communicative chez les participants. Il est donc essentiel d’avoir une approche linguistique et communicative pour son étude. En appliquant un modèle éclectique de l’analyse du discours, nous présentons la définition des stratégies utilisées par les journalistes vénézuéliens dans la reformulation de la guerre en Irak. Cet article propose les grandes lignes d’un modèle pour comprendre la couverture des nouvelles du conflit: le modèle PACEM (Pragmatique, Action communicationnelle, Stratégies et Médiation).