bluuebunny/crossref_metadata_2025 huggingface dataset:
Granulocyte-macrophage stimulating factor (GM-CSF) increases circulating dendritic cells but does not abrogate suppression of adaptive cellular immunity in patients with metastatic colorectal cancer receiving chemotherapy
Authors: Martinez Micaela , Ono Nadia , Planutiene Marina , Planutis Kestutis , Nelson Edward L , Holcombe Randall F
Published: January 2012

Background

Advanced cancer and chemotherapy are both associated with immune system suppression. We initiated a clinical trial in patients receiving chemotherapy for metastatic colorectal cancer to determine if administration of GM-CSF in this setting was immunostimulatory.

Methods

Between June, 2003 and January, 2007, 20 patients were enrolled in a clinical trial (NCT00257322) in which they received 500 ug GM-CSF daily for 4 days starting 24 hours after each chemotherapy cycle. There were no toxicities or adverse events reported. Blood was obtained before chemotherapy/GM-CSF administration and 24 hours following the final dose of GM-CSF and evaluated for circulating dendritic cells and adaptive immune cellular subsets by flow cytometry. Peripheral blood mononuclear cell (PBMC) expression of γ-interferon and T-bet transcription factor (Tbx21) by quantitative real-time PCR was performed as a measure of Th1 adaptive cellular immunity. Pre- and post-treatment (i.e., chemotherapy and GM-CSF) samples were evaluable for 16 patients, ranging from 1 to 5 cycles (median 3 cycles, 6 biologic sample time points). Dendritic cells were defined as lineage (-) and MHC class II high (+).

Results

73% of patients had significant increases in circulating dendritic cells of ~3x for the overall group (5.8% to 13.6%, p = 0.02) and ~5x excluding non-responders (3.2% to 14.5%, p < 0.001). This effect was sustained over multiple cycles for approximately half of the responders, but tachyphylaxis over subsequent chemotherapy cycles was noted for the remainder. Treatment also led to a significant reduction in the proportion of circulating regulatory T-cells (Treg; p = 0.0042). PBMC Tbx21 levels declined by 75% following each chemotherapy cycle despite administration of GM-CSF (p = 0.02). PBMC γ-interferon expression, however was unchanged.

Conclusions

This clinical trial confirms the suppressive effects of chemotherapy on Th1 cellular immunity in patients with metastatic colorectal cancer but demonstrates that mid-cycle administration of GM-CSF can significantly increase the proportion of circulating dendritic cells. As the role of dendritic cells in anti-tumor immunity becomes better defined, GM-CSF administration may provide a non-toxic intervention to augment this arm of the immune system for cancer patients receiving cytotoxic therapy.

Trial Registration

ClinicalTrials.gov: NCT00257322
Eating behaviour patterns in Chinese children aged 12-18 months and association with relative weight - factorial validation of the Children's Eating Behaviour Questionnaire
Authors: Cao Ying-Ting , Svensson Viktoria , Marcus Claude , Zhang Jing , Zhang Jian-Duan , Sobko Tanja
Published: January 2012

Background

Eating behaviours have been suggested relating to obesity development. The Children's Eating Behaviour Questionnaire (CEBQ) is a parent-report measure constructed to assess multiple dimensions of eating behavior for children. This study aimed to test the validity of the Chinese version of Children's Eating Behaviour Questionnaire (CEBQ) in Chinese children aged 12-18 months. We examined factor structure and the reliability of the Chinese version of the CEBQ, the associations between children's eating behaviours and children's weight (BMI SDS) were assessed.

Methods

219 questionnaires were filled out by the caregivers, approached in community health care centers in two cities in China. BMI of each child was calculated and converted to BMI SDS. Factor validation (Principal Component Analysis, exploratory factor analysis) on all CEBQ items was performed and gender difference in eating behaviours was examined. Correlations between eating behaviours and the child's BMI SDS were analyzed by linear regression analysis controlling for gender, parental combined weight, and education.

Results

The factor analysis revealed a seven-factor solution, with factor 'food responsiveness' (FR) split into two. 'Satiety responsiveness' (SR) and 'Enjoyment of food' (EF) factors were not detected. Interestingly, boys scored higher than girls in the FR scales, whereas girls had a higher score in 'food fussiness' (FF) scale.

Conclusions

We conclude that although a valuable psychometric instrument, CEBQ might be affected by age and cultural differences. Therefore, adjusting it in order to fit the Chinese population was suggested. We did not find an association between eating behaviours and children's BMI SDS, when it was controlled for gender and parental weight.
A high calcium diet containing nonfat dry milk reduces weight gain and associated adipose tissue inflammation in diet-induced obese mice when compared to high calcium alone
Authors: Thomas Anthony P , Dunn Tamara N , Drayton Josephine B , Oort Pieter J , Adams Sean H
Published: January 2012

Background

High dietary calcium (Ca) is reported to have anti-obesity and anti-inflammatory properties. Evidence for these properties of dietary Ca in animal models of polygenic obesity have been confounded by the inclusion of dairy food components in experimental diets; thus, effect of Caper secould not be deciphered. Furthermore, potential anti-inflammatory actions of Cain vivocould not be dissociated from reduced adiposity.

Methods

We characterized adiposity along with metabolic and inflammatory phenotypes in diet-induced obese (DIO) mice fed 1 of 3 high fat diets (45% energy) for 12 wk: control (n= 29), high-Ca (n= 30), or high-Ca + nonfat dry milk (NFDM) (n= 30).

Results

Mice fed high-Ca + NFDM had reduced body weight and adiposity compared to high-Ca mice (P< 0.001). Surprisingly, the high-Ca mice had increased adiposity compared to lower-Ca controls (P< 0.001). Hyperphagia and increased feed efficiency contributed to obesity development in high-Ca mice, in contrast to NFDM mice that displayed significantly reduced weight gain despite higher energy intake compared to controls (P < 0.001). mRNA markers of macrophages (e.g., CD68, CD11d) strongly correlated with body weight in all diet treatment groups, and most treatment differences in WAT inflammatory factor mRNA abundances were lost when controlling for body weight gain as a covariate.

Conclusions

The results indicate that high dietary Ca is not sufficient to dampen obesity-related phenotypes in DIO mice, and in fact exacerbates weight gain and hyperphagia. The data further suggest that putative anti-obesity properties of dairy emanate from food components beyond Ca.
Atypical presentation and transabdominal treatment of chylothorax complicating esophagectomy for cancer
Authors: Rottoli Matteo , Russo Iris S , Bernardi Daniele , Bonavina Luigi
Published: January 2012

Chylotorax is a relatively uncommon and difficult to treat complication after esophagectomy for cancer. We report a case of a young adult male who underwent neoadjuvant chemoradiationtherapy followed by Ivor-Lewis esophagectomy for a squamous-cell carcinoma of the distal esophagus. During the postoperative course the patient presented recurrent episodes of hemodynamic instability mimicking cardiac tamponade, secondary to compression of the left pulmonary vein and the left atrium by a mediastinal chylocele. Mediastinal drainage and ligation of the cisterna chyli and the thoracic duct was successfully performed through a transhiatal approach.
Novel C16orf57 mutations in patients with Poikiloderma with Neutropenia: bioinformatic analysis of the protein and predicted effects of all reported mutations
Authors: Colombo Elisa A , Bazan J Fernando , Negri Gloria , Gervasini Cristina , Elcioglu Nursel H , Yucelten Deniz , Altunay Ilknur , Cetincelik Umram , Teti Anna , Fattore Andrea Del , Luciani Matteo , Sullivan Spencer K , Yan Albert C , Volpi Ludovica , Larizza Lidia
Published: January 2012

Background

Poikiloderma with Neutropenia (PN) is a rare autosomal recessive genodermatosis caused byC16orf57mutations. To date 17 mutations have been identified in 31 PN patients.

Results

We characterize six PN patients expanding the clinical phenotype of the syndrome and the mutational repertoire of the gene. We detect the two novelC16orf57mutations, c.232C>T and c.265+2T>G, as well as the already reported c.179delC, c.531delA and c.693+1G>T mutations. cDNA analysis evidences the presence of aberrant transcripts, and bioinformatic prediction of C16orf57 protein structure gauges the mutations effects on the folded protein chain.

Computational analysis of the C16orf57 protein shows two conserved H-X-S/T-X tetrapeptide motifs marking the active site of a two-fold pseudosymmetric structure recalling the 2H phosphoesterase superfamily. Based on this model C16orf57 is likely a 2H-active site enzyme functioning in RNA processing, as a presumptive RNA ligase.

According to bioinformatic prediction, all knownC16orf57mutations, including the novel mutations herein described, impair the protein structure by either removing one or both tetrapeptide motifs or by destroying the symmetry of the native folding.

Finally, we analyse the geographical distribution of the recurrent mutations that depicts clusters featuring a founder effect.

Conclusions

In cohorts of patients clinically affected by genodermatoses with overlapping symptoms, the molecular screening ofC16orf57gene seems the proper way to address the correct diagnosis of PN, enabling the syndrome-specific oncosurveillance.

The bioinformatic prediction of the C16orf57 protein structure denotes a very basic enzymatic function consistent with a housekeeping function. Detection of aberrant transcripts, also in cells from PN patients carrying early truncated mutations, suggests they might be translatable. Tissue-specific sensitivity to the lack of functionally correct protein accounts for the main cutaneous and haematological clinical signs of PN patients.
Measuring quality of life after intensive care using the Arabic version for Morocco of the EuroQol 5 Dimensions
Authors: Khoudri Ibtissam , Belayachi Jihane , Dendane Tarek , Abidi Khalid , Madani Naoufel , Zekraoui Aicha , Zeggwagh Amine Ali , Abouqal Redouane
Published: January 2012

Background

Health-related quality of life (HRQL) is a relevant outcome measures in intensive care unit (ICU). The aim of this study was to evaluate HRQL of ICU patients 3 months after discharge using the Arabic version for Morocco of the EuroQol-5-Dimension (EQ-5D), and to examine the psychometric properties of the questionnaire.

Results

The Arabic version for Morocco of the EQ-5D was approved by the EuroQol group. A prospective cohort study was conducted after medical ICU discharge. At 3-month follow up, the EQ-5D (self classifier and EQ-VAS) was administered in consultation or by telephone. EQ-VAS varies from 0 (better HRQL) to 100 (worst HRQL). An unweighted scoring for EQ5D-index was calculated. EQ5D-index ranges from -0.59 to 1. Test-retest reliability of the EQ-5D was tested using Kappa coefficient and intraclass correlation coefficient (ICC). Criterion validity was assessed by correlating EQ-VAS and EQ5D-index with the Short Form 36 (SF-36). Construct validity was tested using simple and multiple liner regression to assess factors influencing patients'HRQL. 145 survivors answered the EQ-5D. Median EQ5D-index was 0.52 [0.20-1]. Mean EQ-VAS was 62 ± 20. Test-retest reliability was conducted in 83 patients. ICCs of EQ5D-index and EQ-VAS were 0.95 and 0.92 respectively. For EQ-5D self classifier, agreement by kappa was above 0.40. Significant correlations were noted between EQ5D-index, EQ-VAS and SF-36 (p < 0.001). In multivariate analysis, factors associated with poorer HRQL for EQ5D-index were longer ICU length of stay (β = -0.01; p = 0.017) and higher educational level (β = -0.2; p = 0.001). For EQ-VAS men were associated with better HRQL (β = 6.5; p = 0.048).

Conclusions

The Arabic version for Morocco of the EQ-5D is reliable and valid. Women, high educational level and longer ICU length of stay were associated with poorer HRQL.
Risk factors for low birth weight in Botucatu city, SP state, Brazil: a study conducted in the public health system from 2004 to 2008
Authors: da Fonseca Cátia Regina Branco , Strufaldi Maria Wany Louzada , de Carvalho Lídia Raquel , Puccini Rosana Fiorini
Published: January 2012

Background

Low birth weight (LBW), defined as birth weight less than 2500 g, has a complex etiology and may be a result of premature interruption of pregnancy or intrauterine growth restriction. The objective of this study was to provide information on determinants of LBW and contribute to the understanding of the problem in Brazil.

Methods

A case-control study was conducted in Botucatu city, SP state, Brazil. The study population consisted of 2 groups with 860 newborns in each group as follows: low weight newborns (LWNB) and a control group (weight ≥ 2500 g). Secondary data from 2004 to 2008 were collected using the Live Birth Certificate (LBC) and records from medical charts of pregnant women in Basic Health Units (BHU) and in the Public University Hospital (UH). Variables were as follows: maternal socio-demographic characteristics, pregnancy and birth conditions including quality of prenatal care according to 3 criteria. They were based on parameters established by the Ministry of Health (MH), one of them, the modified Kessner Index. The multivariable analysis by logistic regression was used to evaluate the association between variables and LBW.

Results

According to the analysis, the factors associated with LBW were as follows: prematurity (OR = 56.98, 95% CI 29.52-109.95), twin pregnancy (OR = 20.00, 95% CI 6.25-100.00), maternal smoking (OR = 2.12, 95% CI 1.33-3.45), maternal malnourishment (OR = 2.30, 95% CI 1.08-5.00), maternal obesity (OR = 2.30, 95% IC 1.18-4.48), weight gain during pregnancy less than 5 kg (OR = 2.63, 95% CI 1.35-5.00) and weight gain during pregnancy more than 15 kg (OR = 2.26, 95% CI 1.16-4.41). Adequacy of prenatal care visits adjusted to gestational age was less frequent in the LBW group than in the control group (68.7% vs. 80.5%, x2
p < 0.001). According to the modified Kessner Index, 64.4% of prenatal visits in the LWNB group were adequate.

Conclusion

LWNB are a quite heterogeneous group of infants concerning their determinants and prevention actions against LBW and the follow-up of these infants have also been very complex. Therefore, improvement in the quality of care provided should be given priority through concrete actions for prevention of LBW.
Speciation of arsenic trioxide metabolites in peripheral blood and bone marrow from an acute promyelocytic leukemia patient
Authors: Iriyama Noriyoshi , Yoshino Yuta , Yuan Bo , Horikoshi Akira , Hirabayashi Yukio , Hatta Yoshihiro , Toyoda Hiroo , Takeuchi Jin
Published: January 2012

Background

Speciation of arsenic trioxide (ATO) metabolites in clinical samples such as peripheral blood (PB) from acute promyelocytic leukemia (APL) patients has been conducted. However, speciation of arsenicals in bone marrow (BM) has not yet been performed. Profiles of arsenic speciation in plasma of BM were thus investigated and compared with those of PB plasma from a relapsed APL patient. The total arsenic concentrations in high molecular weight fraction (HMW-F) of BM and PB plasma were also determined.

Methods

Response assessment was evaluated by BM aspirate examination and fluorescence in situ hybridization analysis. The analyses of total arsenic concentrations and speciation were preformed by inductively coupled plasma mass spectrometry (ICP-MS), and high-performance liquid chromatography (HPLC)/ICP-MS, respectively.

Results

Response assessment showed that the patient achieved complete remission. The total arsenic concentrations in BM plasma increased with time during the consecutive administration. The PB plasma concentrations of methylated arsenic metabolites substantially increased after the start of administration, while those of inorganic arsenic were still kept at a low level, followed by substantially increase from day-14 after administration. The arsenic speciation profiles of PB plasma were very similar to those of BM plasma. Furthermore, the total arsenic concentrations of HMW-F in BM plasma were much higher than those in PB plasma.

Conclusions

The behaviors of arsenic speciation suggested for the first time that arsenic speciation analysis of PB plasma could be predicative for BM speciation, and showed relatively higher efficiency of drug metabolism in the patient. These results may further provide not only significance of clinical application of ATO, but also a new insight into host defense mechanisms in APL patients undergoing ATO treatment, since HMW proteins-bound arsenic complex could be thought to protect BM from the attack of free arsenic species.
A calmodulin inhibitor, W-7 influences the effect of cyclic adenosine 3', 5'-monophosphate signaling on ligninolytic enzyme gene expression in Phanerochaete chrysosporium
Authors: Sakamoto Takaiku , Yao Yuki , Hida Yoshifumi , Honda Yoichi , Watanabe Takashi , Hashigaya Wataru , Suzuki Kazumi , Irie Toshikazu
Published: January 2012

The capacity of white-rot fungi to degrade wood lignin may be highly applicable to the development of novel bioreactor systems, but the mechanisms underlying this function are not yet fully understood. Lignin peroxidase (LiP) and manganese peroxidase (MnP), which are thought to be very important for the ligninolytic property, demonstrated increased activity in Phanerochaete chrysosporium RP-78 (FGSC #9002, ATCC MYA-4764™) cultures following exposure to 5 mM cyclic adenosine 3', 5'-monophosphate (cAMP) and 500 μM 3'-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor. Real-time reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that transcription of most LiP and MnP isozyme genes was statistically significantly upregulated in the presence of the cAMP and IBMX compared to the untreated condition. However, 100 μM calmodulin (CaM) inhibitor N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), which had insignificant effects on fungal growth and intracellular cAMP concentration, not only offset the increased activity and transcription induced by the drugs, but also decreased them to below basal levels. Like the isozyme genes, transcription of the CaM gene (cam) was also upregulated by cAMP and IBMX. These results suggest that cAMP signaling functions to increase the transcription of LiP and MnP through the induction of cam transcription.
Neutralization of IL-17 ameliorates uveitis but damages photoreceptors in a murine model of spondyloarthritis
Authors: Kezic Jelena M , Glant Tibor T , Rosenbaum James T , Rosenzweig Holly L
Published: January 2012

Introduction

Uveitis, or intraocular inflammatory disease, is a frequent extra-articular manifestation of several forms of arthritis. Despite the frequent co-occurrence of uveitis and arthritis, little is understood of the eye's predisposition to this disease. We recently described a previously unreported uveitis in a murine model of spondyloarthropathy triggered by autoimmunity to aggrecan, a prominent proteoglycan (PG) macromolecule in cartilage. In contrast to the joint and spine, wherein interferon-gamma (IFNγ) deficiency reduced disease, IFNγ deficiency worsened uveitis. Given the regulatory role of IFNγ on the Th17 response and the current focus of anti-interleukin-17 therapeutics in patients with uveitis and spondyloarthritis, we sought to determine the extent to which interleukin (IL)-17 mediates uveitis in the absence of IFNγ.

Methods

Antigen specific T cell cytokine production was measured in splenocyte cultures using multiplex-ELISA. Transgenic (Tg) mice expressing the T cell receptor (TCR) recognizing the dominant arthritogenic epitope in the G1 domain of PG (TCR-Tg), also lacking IFNγ, were immunized with PG. Mice were then systemically administered an anti-IL-17 neutralizing antibody. The onset and severity of peripheral arthritis was evaluated by clinical scoring criteria and histology. Uveitis was assessed using intravital videomicroscopy, which visualizes leukocyte trafficking within the vasculature and tissue of the iris, and by histology.

Results

TCR-Tg splenocytes stimulated in vitro with recombinant G1 peptide demonstrated exacerbated production of cytokines, such as macrophage inflammatory protein (MIP)-1α, MIP-1β, IL-1β, and most notably IL-17A as a consequence of IFNγ deficiency. In vivo, IL-17 inhibition prevented the component of PG-induced arthritis that occurs independently of IFNγ. Blockade of IL-17 ameliorated the ongoing leukocyte trafficking responses within the iris vasculature and tissue, which coincided with reduced infiltration of leukocytes within the anterior and posterior eye segments. However, the anti-IL-17 treatment resulted in unanticipated photoreceptor toxicity.

Conclusions

These data support a protective, regulatory role for IFNγ in suppression of IL-17-mediated intraocular disease and to a lesser extent, joint disease. The unanticipated photoreceptor toxicity raises some caution regarding the use of anti-IL-17 therapeutics until the mechanism of this potential effect is determined.
Geophysics Master’s Theses
Authors: Akerberg Peter
Published: January 2012

Geophysics publishes titles of relevant master's theses in print and online. URL links to full theses also will be published if provided. To submit a title for consideration, complete the appropriate submission form at http://seg.org/dissertationabstracts and e-mail it to dissertationabstracts@seg.org.
Dose-Intensification in Early Unfavorable Hodgkin's Lymphoma: Final Analysis of the German Hodgkin Study Group HD14 Trial
Authors: von Tresckow Bastian , Plütschow Annette , Fuchs Michael , Klimm Beate , Markova Jana , Lohri Andreas , Kral Zdenek , Greil Richard , Topp Max S. , Meissner Julia , Zijlstra Josée M. , Soekler Martin , Stein Harald , Eich Hans T. , Mueller Rolf P. , Diehl Volker , Borchmann Peter , Engert Andreas
Published: January 2012

Purpose

In patients with early unfavorable Hodgkin's lymphoma (HL), combined modality treatment with four cycles of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) and 30 Gy involved-field radiotherapy (IFRT) results in long-term tumor control of approximately 80%. We aimed to improve these results using more intensive chemotherapy.

Patients and Methods

Patients with newly diagnosed early unfavorable HL were randomly assigned to either four cycles of ABVD or an intensified treatment consisting of two cycles of escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by two cycles of ABVD (2 + 2). Chemotherapy was followed by 30 Gy IFRT in both arms. The primary end point was freedom from treatment failure (FFTF); secondary end points included progression-free survival (PFS) and treatment-related toxicity.

Results

With a total of 1,528 qualified patients included, the 2 + 2 regimen demonstrated superior FFTF compared with four cycles of ABVD (P < .001; hazard ratio, 0.44; 95% CI, 0.30 to 0.66), with a difference of 7.2% at 5 years (95% CI, 3.8 to 10.5). The difference in 5-year PFS was 6.2% (95% CI, 3.0% to 9.5%). There was more acute toxicity associated with 2 + 2 than with ABVD, but there were no overall differences in treatment-related mortality or secondary malignancies.

Conclusion

Intensified chemotherapy with two cycles of BEACOPP escalated followed by two cycles of ABVD followed by IFRT significantly improves tumor control in patients with early unfavorable HL.
Expanding Dependent Coverage for Young Adults: Lessons from State Initiatives
Authors: Cantor Joel C. , Belloff Dina , Monheit Alan C. , DeLia Derek , Koller Margaret
Published: January 2012

The Patient Protection and Affordable Care Act (ACA) requires that adults up to age twenty-six be permitted to enroll as dependents on their parents' health plans. This article examines the experiences of states that enacted dependent expansion laws. Drawing on public information from thirty-one enacting states and case studies of four diverse reform states, it derives lessons that are pertinent to the implementation of this ACA provision. Dependent coverage laws vary across the states, but most impose residency, marital status, and other restrictions. The federal Employee Retirement Income Security Act further limits the reach of state laws. Eligibility for expanded coverage under the ACA is much broader. Rules in some states requiring or allowing separate premiums for adult dependents may also discourage enrollment compared with rules in other states (and the ACA), where these costs must be factored into family premiums. Business opposition in some states led to more restrictive regulations, especially for how premiums are charged, which in turn raised greater implementation challenges. Case study states did not report substantial young adult dependent coverage take-up, but early enrollment experience under ACA appears to be more positive. Long-term questions remain about the implications of this policy for risk pooling and the distribution of premium costs.
Nodal mutant e

X

traembryonic

EN

doderm (XEN) stem cells upregulate markers for the anterior visceral endoderm and impact the timing of cardiac differentiation in mouse embryoid bodies
Authors: Liu Wenrui , Brown Kemar , Legros Stephanie , Foley Ann C.
Published: January 2012

Interactions between the endoderm and mesoderm that mediate myocardial induction are difficult to study in vivo because of the small size of mammalian embryos at relevant stages. However, we and others have demonstrated that signals from endodermal cell lines can influence myocardial differentiation from both mouse and human embryoid bodies (EBs), and because of this, assays that utilize embryonic stem (ES) cells and endodermal cell lines provide excellent in vitro models to study early cardiac differentiation. Extraembryonic endoderm (XEN) stem cells have a particular advantage over other heart-inducing cell lines in that they can easily be derived from both wild type and mutant mouse blastocysts. Here we describe the first isolation of a Nodal mutant XEN stem cell line. Nodal−/− XEN cell lines were not isolated at expected Mendelian ratios, and those that were successfully established, showed an increase in markers for the anterior visceral endoderm (AVE). Since AVE represents the heart-inducing endoderm in the mouse, cardiac differentiation was compared in EBs treated with conditioned medium (CM) collected from wild type or Nodal−/− XEN cells. EBs treated with CM from Nodal−/− cells began beating earlier and showed early activation of myocardial genes, but this early cardiac differentiation did not cause an overall increase in cardiomyocyte yield. By comparison, CM from wild type XEN cells both delayed cardiac differentiation and caused a concomitant increase in overall cardiomyocyte formation. Detailed marker analysis suggested that early activation of cardiac differentiation by Nodal−/− XEN CM caused premature differentiation and subsequent depletion of cardiac progenitors.
Patterning embryos with oscillations: structure, function and dynamics of the vertebrate segmentation clock
Authors: Oates Andrew C. , Morelli Luis G. , Ares Saúl
Published: January 2012

The segmentation clock is an oscillating genetic network thought to govern the rhythmic and sequential subdivision of the elongating body axis of the vertebrate embryo into somites: the precursors of the segmented vertebral column. Understanding how the rhythmic signal arises, how it achieves precision and how it patterns the embryo remain challenging issues. Recent work has provided evidence of how the period of the segmentation clock is regulated and how this affects the anatomy of the embryo. The ongoing development of real-time clock reporters and mathematical models promise novel insight into the dynamic behavior of the clock.
Rapid Characterization of N-Linked Glycosylation Site Using Non-Specific Protease Digestion of Gel-Separated Glycoproteins and Matrix-Assisted Laser Desorption/Ionization Tandem Time-of-Flight Mass Spectrometry
Authors: Yu Tingting , Luo Yuanming , Yang Keqian
Published: January 2012

Rapid identification of glycosylation sites of glycoproteins is urgently needed in the study of glycoproteomics. In the present work, a rapid and simple method based on non-specific digestion of gel-separated glycoproteins and matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry was described, which can efficiently identify the N-linked glycosylation sites. One-step in-gel digestion of ribonuclease B (RNase B) by proteinase K was employed to generate glycopeptides with short and discrepant peptide composition. When compared with glycopeptides prepared by two-step in-gel digestion using trypsin–proteinase K or trypsin-pronase, the direct proteinase K treatment showed obvious superiority in both glycopeptide recovery and preparation simplicity. Most importantly, it helps to generate greater variety of glycopeptide series with rich information for glycosylation site identification. In addition, binary matrices 5-chloro-2-mercaptobenzothiazole/2,5-dihydroxybenzoic acid were found to form homogeneous microcrystals on the target with the purified glycopeptides, leading to improved detection sensitivity. Thus, the present work provides an optimized solution to speed up the characterization of N-linked glycosylation sites in glycoproteins.
Collision-Induced Dissociation of Flavonoid 7-O-Diglycoside Cations: Elucidation of Important Structural Motifs by Selection of the Cationizing Reaction
Authors: Ilboudo Ousmane , Tapsoba Issa , Bonzi-Coulibaly Yvonne L. , Gerbaux Pascal
Published: January 2012

Flavonoids are ubiquitous molecules in nature and are found in almost all plants, including fruits and vegetables. Although flavonoids are structurally similar, subtle differences in their structures lead to important changes in their biological activities. Over the years, mass spectrometry has become an ideal tool for the characterization of those important molecules. In particular, to overcome the challenge of structure assignment, tandem mass spectrometry has been used in numerous studies. In the present study, we submitted selected flavonoid 7- O-diglycosides to electrospray ionization to prepare different types of flavonoid ions, i.e. protonated, sodium-cationized and copper-cationized molecules. Most of the investigated reactions are already described in the literature in several papers and the aim of the present study is to present concise and coherent relations between collision-induced dissociation reactions, cationizing agents and flavonoid 7- O-diglycoside structures. Some insights into the reaction mechanisms and the role of the cationizing particles will also be attempted.
Formation of Peptide Radical Ions through Dissociative Electron Transfer in Ternary Metal—Ligand—Peptide Complexes
Authors: Chu Ivan K. , Laskin Julia
Published: January 2012

The formation and fragmentation of odd-electron ions of peptides and proteins is of interest to applications in biological mass spectrometry. Gas-phase redox chemistry occurring during collision-induced dissociation of ternary metal–ligand–peptide complexes enables the formation of a variety of peptide radicals, including the canonical radical cations, M+*, radical dications, [M+H]2+*, radical anions, [M-2H]−* and phosphorylated radical cations. In addition, odd-electron peptide ions with well-defined initial location of the radical site are produced through side-chain losses from the radical ions. Subsequent fragmentation of these species provides information regarding the role of charge and location of the radical site on the competition between radical-induced and proton-driven fragmentation of odd-electron peptide ions. This account summarizes current understanding of the factors that control the efficiency of the intramolecular electron transfer (ET) in ternary metal–ligand–peptide complexes resulting in formation of odd-electron peptide ions. Specifically, we discuss the effect of the metal center, the ligand and the peptide structure on the competition between the ET, proton transfer (PT) and loss of neutral peptide and neutral peptide fragments from the complex. Fundamental studies of the structures, stabilities and the energetics and dynamics of fragmentation of these complexes are also important for detailed molecular-level understanding of photosynthesis and respiration in biological systems.
Explanatory models are needed to integrate RCT and observational data with the patient's unique biology
Authors: Sharma Vijay , Minhas Rubin
Published: January 2012

In this review, we make the case for evidence-based medicine (EBM) to include models of disease underscored by evidence in order to integrate evidence, as it is currently defined, with the patient's unique biology. This would allow clinicians to use a pathophysiologic rationale, but underscoring the pathophysiological model with evidence would create an objective evidence base for extrapolating randomized controlled trial evidence. EBM encourages practitioners not to be passive receivers of information, but to question the information. By the same token, practitioners should not be passive executors of the process by which information is generated, appraised and applied, but should question the process. We use the historical examples of the evolution of EBM to show that its subordination of a pathophysiological perspective was unintentional, and of essential hypertension to illustrate the importance of disease models and the fact that evidence supporting them comes from many sources. We follow this with an illustration of the benefits a pathophysiological perspective can bring and a suggested model of how inclusion of pathophysiological models in the EBM approach would work. From a practical perspective, information cannot be integrated with the patient's unique biology without knowledge of that biology; this is why EBM is currently so silent on how to carry out its fourth stage. It is also clear that, regardless of whether a philosophical or practical definition of evidence is used, pathophysiology is evidence and should be regarded as such.
Two-Step Biochemical Differential Diagnosis of Classic 21-Hydroxylase Deficiency and Cytochrome P450 Oxidoreductase Deficiency in Japanese Infants by GC-MS Measurement of Urinary Pregnanetriolone/ Tetrahydroxycortisone Ratio and 11β-Hydroxyandrosterone
Authors: Koyama Yuhei , Homma Keiko , Fukami Maki , Miwa Masayuki , Ikeda Kazushige , Ogata Tsutomu , Hasegawa Tomonobu , Murata Mitsuru
Published: January 2012

BACKGROUND

The clinical differential diagnosis of classic 21-hydroxylase deficiency (C21OHD) and cytochrome P450 oxidoreductase deficiency (PORD) is sometimes difficult, because both deficiencies can have similar phenotypes and high blood concentrations of 17α-hydroxyprogesterone (17OHP). The objective of this study was to identify biochemical markers for the differential diagnosis of C21OHD, PORD, and transient hyper 17α-hydroxyprogesteronemia (TH17OHP) in Japanese newborns. We established a 2-step biochemical differential diagnosis of C21OHD and PORD.

METHODS

We recruited 29 infants with C21OHD, 9 with PORD, and 67 with TH17OHP, and 1341 control infants. All were Japanese and between 0 and 180 days old; none received glucocorticoid treatment before urine sampling. We measured urinary pregnanetriolone (Ptl), the cortisol metabolites 5α- and 5β-tetrahydrocortisone (sum of these metabolites termed THEs), and metabolites of 3 steroids, namely dehydroepiandrosterone, androstenedione (AD4), and 11β-hydroxyandrostenedione (11OHAD4) by GC-MS.

RESULTS

At a cutoff of 0.020, the ratio of Ptl to THEs differentiated C21OHD and PORD from TH17OHP and controls with no overlap. Among metabolites of DHEA, AD4, and 11OHAD4, only 11β-hydroxyandrosterone (11HA), a metabolite of 11OHAD4, showed no overlap between C21OHD and PORD at a cutoff of 0.35 mg/g creatinine.

CONCLUSIONS

A specific cutoff for the ratio of Ptl to THEs can differentiate C21OHD and PORD from TH17OHP and controls. Additionally, the use of a specific cutoff of 11HA can distinguish between C21OHD and PORD.
Skin Lesions in a Boy With X-linked Lymphoproliferative Disorder: Comparison of 5 SH2D1A Deletion Cases
Authors: Mejstříková Ester , Janda Aleš , Hrušák Ondřej , Bučková Hana , Vlčková Markéta , Hančárová Miroslava , Freiberger Tomáš , Ravčuková Barbora , Veselý Karel , Fajkusová Lenka , Kopečková Lenka , Sumerauer David , Kabíčková Edita , Šedivá Anna , Starý Jan , Sedláček Zdeněk
Published: January 2012

SH2D1A gene defects are the cause of X-linked lymphoproliferative disorder (XLP-1), a rare condition characterized by severe immune dysregulation. We present a patient lacking the typical symptoms of XLP-1, but experiencing a severe unusual skin condition encompassing features of dermatosclerosis and vesiculobullous skin disease. A maternal cousin of the patient was diagnosed with XLP-1 and found to carry a deletion of the SH2D1A gene. SH2D1A deletion was also identified in our patient, which offered a possible explanation for his skin symptoms. Subsequent analysis showed that the deletion in both cousins was identical and involved the whole SH2D1A gene and a part of the adjacent ODZ1 gene. High phenotypic variability of XLP-1 observed in this family prompted us to analyze the genotype-phenotype correlation of 2 different-sized deletions involving SH2D1A and ODZ1 in 5 patients from 2 families, and we report the clinical and laboratory data on these individuals. Our findings illustrate the wide clinical variability of XLP-1, both inter- and intrafamilial, which may complicate the diagnosis of this condition. The comparison of phenotypes of our patients argues against a strong involvement of the ODZ1 gene in the skin disorder and other symptoms observed in our index patient. His hitherto not described severe skin condition extends the phenotypic range of XLP-1.
Development of Electrochemiluminescence and Surface Plasmon Resonance based Immunosensors with Surface Accumulable Molecules.
Authors: Kurita Ryoji
Published: January 2012

The electrochemiluminescence (ECL) and surface plasmon resonance (SPR) based immunosensors for measuring a trace level of disease markers are shown. It is well known that thiols form a self-assembled monolayer on a metal surface, and this has been widely used to modify metal surfaces. We employed this characteristic for a highly sensitive immunosensors by obtaining a surface pre-concentration of thiol molecules formed by the enzymatic reaction of labeled antibody.
Expert variability provides perspective on the strengths and weaknesses of citizen‐driven intertidal monitoring program
Authors: Cox T. E. , Philippoff J , Baumgartner E , Smith C. M.
Published: January 2012

Citizen scientist programs are a means to efficiently conduct large‐scale surveys of ecosystems or managed species, provided that concerns over the quality and use of data generated by nonexperts can be addressed. This study presents actions taken in a citizen science program to assure data quality and demonstrates the validity of citizen‐generated data. In this case the accuracy of data collected by secondary school students as citizens in a program that quantitatively sampled benthic rocky intertidal communities at 13 sites on Maui, Molokai, Oahu, and Hawai‘i island during the years 2004–2007 was evaluated. In 2007, two independent research teams collected data simultaneously with students at five sites on eight sampling dates. Comparisons of Shannon diversity and Bray‐Curtis similarity values computed and simulated from student and researcher collected data revealed that nonexpert students accurately collect community‐level data within the range of the variation that occurs between researchers. Students were, however, likely to misidentify cryptic and rare species. These findings have direct implications for the conservation goals of the monitoring program as the assessment reveals that students are likely to misidentify early alien introductions but are able to monitor the abundances of native and introduced species once they become established. The validity assessment designed for this investigation is unique in that it directly compares consistent errors made by citizens in data collection to expert variability to identify usage limitations and can be a guide for future studies that involve the efforts of trained volunteers.
Competitive outcomes between herbivorous consumers can be predicted from their stoichiometric demands
Authors: Iwabuchi Tsubasa , Urabe Jotaro
Published: January 2012

Exploitative competition for food resources is one of the crucial biological interactions in nature. However, few studies have experimentally tested if competitive ability of consumer species changes depending on elemental contents of the food, although it has been suggested by the theories of resource ratio for competition and ecological stoichiometry. To verify if competitive superiority actually changes according to elemental contents of the food, competition experiments were conducted using high and low P algal food and three Daphnia species (D. galeata, D. pulicaria, and D. tanakai) with different threshold levels of carbon (TFC) and phosphorus (TFP) necessary for individual growth. Since the TFCs of D. tanakai and D. pulicaria were similar to each other but lower than that of D. galeata, we specifically predicted that when fed high P food (i.e., limited by C), D. tanakai and D. pulicaria would be competitively equal to each other but superior to D. galeata. We also predicted from their TFPs that when fed low P food, D. pulicaria would outcompete D. tanakai and D. galeata, while neither of the latter two would be competitively superior to the other. The results showed that when one of the two competitors was predicted to be competitively superior, the food level under competition was similar to the TFC (or TFP) of the superior species but lower than that of the other inferior species, and that the biomass of the former was much less affected by the competition. Also, when the two competing species were predicted to be competitively equal, the food levels under competition were generally similar to the TFC (or TFP) of both species and their biomasses decreased by the same magnitude. The results thus accorded well with the predictions from the TFC and TFP, and indicate that competitive superiority between the same two Daphnia species changes depending on P:C ratio of algal food. This study provides firm evidence for the first time that resource ratio theory can be applied to competition between animal consumers for essential substances packaged within a single food resource.
Capital Gains Taxes and Expected Rates of Return
Authors: Sikes Stephanie A. , Verrecchia Robert E.
Published: January 2012

Prior literature predicts a positive relation between firms' expected pre-tax rates of return and investor-level capital gains tax rates. We show that this relation is more nuanced than suggested by prior literature and that in three circumstances the relation can actually be negative. The first circumstance is when a firm's systematic risk is very high. The second circumstance is when the market risk premium is very high. The third circumstance is when the risk-free rate of return is very low. The circumstances arise because, in addition to reducing investors' expected after-tax cash proceeds, capital gains taxes reduce the risk that investors associate with the expected after-tax cash proceeds.
Distinct β-Cell Defects in Impaired Fasting Glucose and Impaired Glucose Tolerance
Authors: Kanat Mustafa , Mari Andrea , Norton Luke , Winnier Diedre , DeFronzo Ralph A. , Jenkinson Chris , Abdul-Ghani Muhammad A.
Published: January 2012

To characterize the defects in β-cell function in subjects with impaired fasting glucose (IFG) and compare the results to impaired glucose tolerance (IGT) and normal glucose tolerance (NGT) subjects, β-cell glucose sensitivity and rate sensitivity during the oral glucose tolerance test were measured with the model by Mari in 172 Mexican Americans. A subgroup (n = 70) received a 2-h hyperglycemic clamp (+125 mg/dL), and first- and second-phase insulin secretion were quantitated. Compared with NGT, subjects with IFG and IGT manifested a decrease in β-cell glucose sensitivity; IFG subjects, but not IGT subjects, had decreased β-cell rate sensitivity. In IFG subjects, the defect in β-cell glucose sensitivity was time dependent, began to improve after 60 min, and was comparable to NGT after 90 min. The incremental area under the plasma C-peptide concentration curve during the first 12 min of the hyperglycemic clamp (ΔC-pep[AUC]0–12) was inversely related with the increase in FPG concentration (r = −36, r = 0.001), whereas ΔC-pep[AUC]15–120 positively correlated with FPG concentration (r = 0.29, r < 0.05). When adjusted for the prevailing level of insulin resistance, first-phase insulin secretion was markedly decreased in both IFG and IGT, whereas second-phase insulin secretion was decreased only in IGT. These results demonstrate distinct defects in β-cell function in IFG and IGT.
Screening for Dysglycemia in Overweight Youth Presenting for Weight Management
Authors: Morrison Katherine M. , Xu Liqin , Tarnopolsky Mark , Yusuf Zaheera , Atkinson Stephanie A. , Yusuf Salim
Published: January 2012

OBJECTIVE

To examine the performance of current screening recommendations for detecting dysglycemia in children and adolescents with obesity.

RESEARCH DESIGN AND METHODS

In a cross-sectional study, an oral glucose tolerance test and demographic (age, sex, family history of diabetes, and ethnicity), clinical (BMI z score, waist circumference, and pubertal stage), and laboratory variables used in current pediatric screening criteria for type 2 diabetes mellitus were measured in 259 overweight or obese youth aged 5–17 years. Glycemic status was based on American Diabetes Association (ADA) thresholds. The performance (sensitivity and specificity) of current screening criteria and newly developed models to identify isolated IGT were compared.

RESULTS

Dysglycemia was present in 20.8% of the cohort. Of the 54 participants with dysglycemia, 68% had a normal fasting glucose and were identified with the 2-h glucose test. Current ADA criteria had low sensitivity (41.7% [95% CI 25.6–57.8]) and moderate specificity (69.5% [63.5–75.6]) to identify IGT. In receiver operating characteristic (ROC) analysis, the addition of hemoglobin A1c (HbA1c) or FPG did not improve the ROC area under the curve (AUC) (HbA1c: 0.64 vs. 0.63; P = 0.54; HbA1c + FPG: 0.66; P = 0.42), but adding triglyceride level did (AUC 0.72 vs. 0.63; P = 0.03). A simple model with fasting triglyceride level >1.17 mmol/L improved AUC compared with ADA screening criteria (0.68 vs. 0.57; P = 0.04).

CONCLUSIONS

The prevalence of IGT is high among obese children and youth. Current screening criteria have low sensitivity to detect isolated IGT. Although adding nonfasting laboratory values to history and physical measures does not improve diagnostic accuracy, adding fasting lipid profile improves predictive value.