bluuebunny/crossref_metadata_2025 huggingface dataset:
Obesity and Risk of Recurrence or Death After Adjuvant Endocrine Therapy With Letrozole or Tamoxifen in the Breast International Group 1-98 Trial
Authors: Ewertz Marianne , Gray Kathryn P. , Regan Meredith M. , Ejlertsen Bent , Price Karen N. , Thürlimann Beat , Bonnefoi Hervé , Forbes John F. , Paridaens Robert J. , Rabaglio Manuela , Gelber Richard D. , Colleoni Marco , Láng István , Smith Ian E. , Coates Alan S. , Goldhirsch Aron , Mouridsen Henning T.
Published: October 2012

Purpose

To examine the association of baseline body mass index (BMI) with the risk of recurrence or death in postmenopausal women with early-stage breast cancer receiving adjuvant tamoxifen or letrozole in the Breast International Group (BIG) 1-98 trial at 8.7 years of median follow-up.

Patients and Methods

This report analyzes 4,760 patients with breast cancer randomly assigned to 5 years of monotherapy with letrozole or tamoxifen in the BIG 1-98 trial with available information on BMI at randomization. Multivariable Cox modeling assessed the association of BMI with disease-free survival, overall survival (OS), breast cancer–free interval, and distant recurrence-free interval and tested for treatment-by-BMI interaction. Median follow-up was 8.7 years.

Results

Seventeen percent of patients have died. Obese patients (BMI ≥ 30 kg/m2) had slightly poorer OS (hazard ratio [HR] = 1.19; 95% CI, 0.99 to 1.44) than patients with normal BMI (< 25 kg/m2), whereas no trend in OS was observed in overweight (BMI 25 to < 30 kg/m2) versus normal-weight patients (HR = 1.02; 95% CI, 0.86 to 1.20). Treatment-by-BMI interactions were not statistically significant. The HRs for OS comparing obese versus normal BMI were HR = 1.22 (95% CI, 0.93 to 1.60) and HR = 1.18 (95% CI, 0.91 to 1.52) in the letrozole and tamoxifen groups, respectively.

Conclusion

There was no evidence that the benefit of letrozole over tamoxifen differed according to patients' BMI.
HIV Status Does Not Influence Outcome in Patients With Classical Hodgkin Lymphoma Treated With Chemotherapy Using Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine in the Highly Active Antiretroviral Therapy Era
Authors: Montoto Silvia , Shaw Kate , Okosun Jessica , Gandhi Shreyans , Fields Paul , Wilson Andrew , Shanyinde Milensu , Cwynarski Kate , Marcus Robert , de Vos Johannes , Young Anna Marie , Tenant-Flowers Melinda , Orkin Chloe , Johnson Margaret , Chilton Daniella , Gribben John G. , Bower Mark
Published: October 2012

Purpose

The prognosis of HIV-infected patients with non-Hodgkin lymphoma in the highly active antiretroviral therapy (HAART) era approaches that of the general population when they are treated with the same protocols. We analyzed the outcome of patients with Hodgkin lymphoma (HL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in the HAART era according to HIV serostatus to establish whether this also holds true for HL.

Patients and Methods

From 1997 to 2010, 224 patients newly diagnosed with HL, of whom 93 were HIV positive, were consecutively treated with ABVD chemotherapy. HIV-positive patients had more high-risk disease according to the International Prognostic Score (IPS) than HIV-negative patients (IPS ≥ 3: 68% v 26%, respectively; P < .001). Forty-seven HIV-positive patients had a CD4 count less than 200/μL, and 92 patients received HAART during chemotherapy.

Results

The complete response rate was 74% for HIV-positive patients and 79% for HIV-negative patients (P = not significant). After a median follow-up of 60 months (range, 8 to 174 months), 23 patients (16 HIV-negative and seven HIV-positive patients) have experienced relapse at a median time of 6 months (range, 1 to 106 months). Five-year event-free survival (EFS) was 59% (95% CI, 47% to 70%) for HIV-positive patients and 66% (95% CI, 57% to 74%) for HIV-negative patients (P = not significant). Five-year overall survival (OS) was 81% (95% CI, 69% to 89%) and 88% (95% CI, 80% to 93%) for HIV-positive and HIV-negative patients, respectively (P = not significant). HIV status did not predict OS or EFS on multivariate analysis including IPS and HIV status.

Conclusion

This mature study demonstrates that HIV-positive patients with HL have more extensive disease with more adverse prognostic factors than HIV-negative patients, but when treated with ABVD, HIV infection does not adversely affect OS or EFS.
Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies
Authors: Advani Ranjana H. , Buggy Joseph J. , Sharman Jeff P. , Smith Sonali M. , Boyd Thomas E. , Grant Barbara , Kolibaba Kathryn S. , Furman Richard R. , Rodriguez Sara , Chang Betty Y. , Sukbuntherng Juthamas , Izumi Raquel , Hamdy Ahmed , Hedrick Eric , Fowler Nathan H.
Published: October 2012

Purpose

Survival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton tyrosine kinase (BTK) is a critical signaling kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies.

Patients and Methods

Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximum-tolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles.

Results

Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months.

Conclusion

Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies.
Out of Work or Out of Time? Rethinking Labor after the Financial Crisis
Authors: Adkins Lisa
Published: October 2012

Prior to the recent global crisis a consensus was emerging that post-Fordism had ushered in a new sexual contract, one characterized not by exclusion and containment, but by the prospecting for potential, a prospecting that located women’s labor not as a reserve for capital but as a site of vitality and possibility. The global financial crisis and ongoing recession, however, have been positioned as undoing these radical transformations in women’s labor by threatening a return of the social formations characteristic of Fordism. Yet in this essay I suggest that to understand the ongoing recession as producing such a return is to thoroughly misapprehend value production in post-Fordism and, in particular, to bracket the process of the folding of the economy into society. To illustrate this process, I focus on unemployment, specifically the eventful productiveness of unemployment in recessionary post-Fordism. Confronting this eventful productiveness necessitates not only a recognition of a material reworking of unemployment in post-Fordism, but also undoes the idea that the ongoing recession is linked to a return to the social formations of Fordism. This essay therefore posits that unemployment is a crucial site for the theorization of post-Fordist labor, including the ongoing, radical reworking of the potentialities of female labor.
The Time of the Contract: Insurance, Contingency, and the Arrangement of Risk
Authors: Mitropoulos Angela
Published: October 2012

This essay contends that the contractual is a technique for the reinstatement of a specifically capitalist determinism in the midst of uncertain circumstances and in the face of an indefinite future. Taking the indistinction between the time of life and that of work that characterizes post-Fordism and contingent labor as a point of departure, I note that this marks a traversal of the classically contractarian boundary between the temporally circumscribed sale of “one’s own labor” and life construed as property. Yet, rather than follow theories of the biopolitical in positing an ethics of life assumed to be prior to capitalism and that might furnish “natural limits” to it, or those of governmentality, which suggest that the amplified logics of risk and insurance have displaced right and its temporally delimited conditions, I present an analysis of the contractual through a critique of oikonomia (the law of the household). Focusing on the history of debates around insurance, the family wage and slavery, the actuarial and inoculation, I underline Locke’s reworkings of Aristotle, Pascal, and the Thomist transformation of contingency into necessity through the delineation of divine and temporal orders. Locke’s three temporal orders (divine providence, prudential self-management, and the naturalized, heritable properties of servitude) are not only recapitulated as assumption in ostensibly critical theory, but they have also—in the wake of a contested politics of the household that precipitated neoliberalism—been reconstituted as the neocontractualism of infinite and unbreakable contracts, interminable preparedness, and the displacement of capitalist incertitude onto the uninsurable risks of contingent labor.
Life-Times in Fate Playing
Authors: Tadiar Neferti X. M.
Published: October 2012

Examining the recent post-Marxist conception of labor in the contemporary context of financialization and global crisis, this essay contests prevailing ideas about the contemporary eradication of the distinction between production and reproduction, between labor and life, encapsulated in the notion of “real subsumption.” Departing from these ideas I argue that the extraction of value from “life” takes place through multiple and contradictory modalities, and propose the concept of “life-times” as a way to foreground important differences in the social uses, practices, understanding, valorization, and inhabitation of the times of life and their relations in a global economy in which the “production time” of capital has encompassed all of life. Drawing on the social contexts of undocumented immigrants, guest workers, refugees, and displaced persons, I elaborate on differential life-times from the side of life destined for disposable superfluity. I look at acts of “fate playing” in the contexts of migrant Filipina workers and the urban lumpenproletariat to view those dimensions of social reproductive work on the part of disposable peoples that persist beyond and despite capitalist subsumption and exceed most theoretical accounts of labor. An attention to such remaindered life-times raises questions about the limits of our political imagination and of our vision of the time line of global capitalism’s duration and end.
No Dal Molin: The Antibase Movement in Vicenza
Authors: Palma Marco
Published: October 2012

In 2006 the citizens of Vicenza, Italy, discovered that for three years US authorities, the Italian government, and city officials had been negotiating secretly to approve the construction of a new military base on the only large undeveloped area in the northern part of the city and the largest aquifer in northern Italy. Beginning in the adjacent neighborhoods, a mobilization arose against the construction of the military installation. In a few months hundreds of thousands of residents were demonstrating in the city, and various forms of direct action against the base became a daily occurrence. Thus was born an extraordinary experiment in democratic political participation.
Challenging US Military Presence in the Philippines
Authors: Yeo Andrew
Published: October 2012

This essay examines antibase movements in the Philippines, giving attention to the development, organization, and role of antibase movements leading to the ouster of US military forces in 1991. Additionally, I discuss how the return of the US military in the late 1990s under a visiting forces agreement rekindled mobilization efforts, albeit more weakly than during the early 1990s, against US military presence. Although no permanent US base exists in the Philippines today, peace activists continue to rally against the US military influence both at home and abroad.
Convergent extension: using collective cell migration and cell intercalation to shape embryos
Authors: Tada Masazumi , Heisenberg Carl-Philipp
Published: October 2012

Body axis elongation represents a common and fundamental morphogenetic process in development. A key mechanism triggering body axis elongation without additional growth is convergent extension (CE), whereby a tissue undergoes simultaneous narrowing and extension. Both collective cell migration and cell intercalation are thought to drive CE and are used to different degrees in various species as they elongate their body axis. Here, we provide an overview of CE as a general strategy for body axis elongation and discuss conserved and divergent mechanisms underlying CE among different species.
Combinatorial regulation of tissue specification by GATA and FOG factors
Authors: Chlon Timothy M. , Crispino John D.
Published: October 2012

The development of complex organisms requires the formation of diverse cell types from common stem and progenitor cells. GATA family transcriptional regulators and their dedicated co-factors, termed Friend of GATA (FOG) proteins, control cell fate and differentiation in multiple tissue types from Drosophila to man. FOGs can both facilitate and antagonize GATA factor transcriptional regulation depending on the factor, cell, and even the specific gene target. In this review, we highlight recent studies that have elucidated mechanisms by which FOGs regulate GATA factor function and discuss how these factors use these diverse modes of gene regulation to control cell lineage specification throughout metazoans.
Water Aerosol Formation upon Irradiation of Air Using KrF Laser at 248 nm
Authors: Yoshihara Keitaro , Takatori Yoshiki , Kajii Yoshizumi
Published: October 2012

We report water aerosol formation upon irradiation of wet air with a KrF laser at 248 nm. It occurred at temperatures ranging from 0 to 50 °C and at relative humidity values from ca. 10% to 100%. Aerosols were detected either by light scattering or by differential mobility analyses, and particle growth from 10 nm to sub-micrometers was observed. Photodissociation of oxygen was proposed as the initial step of the reactions leading to formation of the final stable molecule of hydrogen peroxide as a nucleus with a low vapor pressure. Simulations of the chemical kinetics by considering wet air revealed that the amount of the final product could be controlled by laser operational conditions such as laser repetition rates and pulse energies. KrF laser light can reach a few kilometers in the atmosphere owing to a small absorption cross section of oxygen and yet can produce water aerosol.
Theory of Quadrupole Contributions from Interface and Bulk in Second-Order Optical Processes
Authors: Shiratori Kazuya , Morita Akihiro
Published: October 2012

A unified treatment of the dipole and quadrupole contributions to the second-order optical response is developed. The concept of the effective susceptibility is expanded to incorporate both the surface and bulk contributions. This treatment allows us to quantitatively evaluate both surface and bulk contributions in experimental SFG/SHG spectra. The present theory clarifies a number of qualitative features in the quadrupole contribution, and is thereby utilized to settle recent confusions about the quadrupole and/or bulk effects on the surface nonlinear spectroscopy.
Crotoxin, a rattlesnake toxin, induces a long-lasting inhibitory effect on phagocytosis by neutrophils
Authors: Lima Tatiane S , Cataneo Sálua C , Iritus Ana Caroline C , Sampaio Sandra C , Della-Casa Maisa S , Cirillo Maria Cristina
Published: October 2012

Crotalus durissus terrificus snake venom (CdtV) has long-lasting anti-inflammatory properties and inhibits the spreading and phagocytic activity of macrophages. Crotoxin (CTX), the main component of CdtV, is responsible for these effects. Considering the role of neutrophils in the inflammatory response and the lack of information about the effect of CdtV on neutrophils, the aim of this study was to investigate the effect of CdtV and CTX on two functions of neutrophils, namely phagocytosis and production of reactive oxygen species, and on the intracellular signaling involved in phagocytosis, particularly on tyrosine phosphorylation and rearrangements of the actin cytoskeleton. Our results showed that the incubation of neutrophils with CdtV or CTX, at different concentrations, or the subcutaneous injection of CdtV or CTX in rats two hours or one, four or 14 days before or one hour after the induction of inflammation inhibited the phagocytic activity of neutrophils. Furthermore, these in vitro and in vivo effects were associated with CdtV and CTX inhibition of tyrosine phosphorylation and consequently actin polymerization. Despite the inhibitory effect on phagocytosis, this study demonstrated that CdtV and CTX did not alter the production of the main reactive oxygen species. Therefore, this study characterized, for the first time, the actions of CdtV on neutrophils and demonstrated that CTX induces a long-lasting inhibition of tyrosine phosphorylation and consequently phagocytosis. We suggest that CTX represents a potential natural product in controlling inflammatory diseases, since a single dose exerts a long-lasting effect on intracellular signaling involved in phagocytosis by neutrophils.
Tracking of mouse breast cancer stem-like cells with Salmonella
Authors: Chang Wen-Wei , Kuan Yu-Diao , Chen Man-Chin , Lin Song-Tao , Lee Che-Hsin
Published: October 2012

Systemic administration of Salmonella to tumor-bearing mice leads to the preferential accumulation within tumor sites and retardation of tumor growth. The cancer stem-like cell (CSC) hypothesis suggests that CSCs are the root of cancer and induce metastasis and recurrence. The objective of this study was to examine if Salmonella could inhibit the growth of CSCs derived from mouse breast cancer. Systemically injected Salmonella preferentially accumulated within tumors for at least three weeks and the bacteria accumulated preferentially not only in subcutaneous but also in orthotopic tumors over livers and spleens at ratios ranging from 1000:1 to 10,000:1. Salmonella were capable of delaying tumor growth and enhancing survival in both subcutaneous and orthotopic tumor models. More strikingly, Salmonella acted to retard tumor growth and extensively prolong the survival time of the mice bearing CSC-induced tumors. Our results also found that Salmonella predominantly, although not exclusively, resided in the CSC regions of the tumor. These data suggest that Salmonella can inhibit the growth of breast cancer by targeting the CSC niche. In conclusion, Salmonella can be used for the management of breast cancer.
Multiplicative Utilities for Health and Consumption
Authors: Lichtendahl Kenneth C. , Bodily Samuel E.
Published: October 2012

Many challenging medical/financial decisions require a decision maker to express preferences for lifetime streams of health and consumption. To express such preferences, we develop two multiplicative utility forms from basic conditions. These forms have many advantages over the leading additive form and extend the way in which life years are adjusted in the popular quality-adjusted life-year model. Unlike additive forms, a decision maker with one of our multiplicative forms can express correlation aversion in consumption streams. In the special case of constant health and consumption streams, our forms reduce to a double exponential utility in life duration. When the decision maker is correlation averse in consumption streams, this form can express risk aversion, decreasing absolute risk aversion and increasing relative risk aversion in life duration. This reduced form under correlation aversion also has standard gamble probabilities (proportional time trade-offs) that increase (decrease) in life duration. In addition, it has standard gamble probabilities that exceed proportional time trade-offs. The properties of this reduced form under correlation seekingness are also examined and discussed in the context of the empirical evidence on attitudes toward risks in life duration, standard gamble probabilities, and proportional time trade-offs.
Dynamic Experiments for Estimating Preferences: An Adaptive Method of Eliciting Time and Risk Parameters
Authors: Toubia Olivier , Johnson Eric , Evgeniou Theodoros , Delquié Philippe
Published: October 2012

We present a method that dynamically designs elicitation questions for estimating risk and time preference parameters. Typically these parameters are elicited by presenting decision makers with a series of static choices between alternatives, gambles, or delayed payments. The proposed method dynamically (i.e., adaptively) designs such choices to optimize the information provided by each choice, while leveraging the distribution of the parameters across decision makers (heterogeneity) and capturing response error. We explore the convergence and the validity of our approach using simulations. The simulations suggest that the proposed method recovers true parameter values well under various circumstances. We then use an online experiment to compare our approach to a standard one used in the literature that requires comparable task completion time. We assess predictive accuracy in an out-of-sample task and completion time for both methods. For risk preferences, our results indicate that the proposed method predicts subjects' willingness to pay for a set of out-of-sample gambles significantly more accurately, while taking respondents about the same time to complete. For time preferences, both methods predict out-of-sample preferences equally well, while the proposed method takes significantly less completion time. For risk and time preferences, average completion time for our approach is approximately three minutes. Finally, we briefly review three applications that used the proposed methodology with various populations, and we discuss the potential benefits of the proposed methodology for research and practice.

This paper was accepted by Teck Ho, decision analysis.
Dynamic Expression Pattern of Neuro-oncological Ventral Antigen 1 (Nova1) in the Rat Brain after Focal Cerebral Ischemia/Reperfusion Insults
Authors: Li Hualing , Sun Changqing , Wang Yu , Gao Yuxiao , Liu Yichen , Gao Yan , Li Xu , Zhang Chenggang
Published: October 2012

The present study aimed to evaluate the expression of neuro-oncological ventral antigen 1 (Nova1) in cerebral ischemia/reperfusion (I/R) insults by immunohistochemistry. The focal cerebral I/R model was induced by right middle cerebral artery occlusion (MCAO) for 120 min followed by 1 day, 7 days, and 14 days of reperfusion in Sprague-Dawley (SD) rats. The results showed that Nova1 was expressed in nearly the whole brain, although with higher density in hippocampus, hypothalamus, cingulate cortex, and medial habenular nucleus. The immunoreactivity of Nova1 neurons was increased dramatically, especially on both sides of the hippocampal CA1 region, after 1 day of reperfusion. A strong response occurred at the ipsilateral CA1 region between 1 day and 7 days of reperfusion. Likewise, strong compensatory responses of Nova1 expression were observed on the contralateral side of the striate cortex, dentate gyrus, and hypothalamus. Interestingly, more Nova1 neurons were observed to translocate to the dendrites and growth cones of the axons in the hypothalamus on the ischemic side after 7 days of reperfusion. In conclusion, our data suggest that Nova1 might mediate neuronal responsiveness, and its expression might positively correlate with neural repair after I/R insults in the rat brain.
Heparan Sulfate Biosynthesis
Authors: Kreuger Johan , Kjellén Lena
Published: October 2012

Nearly all vertebrate cells have been shown to express heparan sulfate proteoglycans (HSPGs) at the cell surface. The HSPGs bind to many secreted signaling proteins, including numerous growth factors, cytokines, and morphogens, to affect their tissue distribution and signaling. The heparan sulfate (HS) chains may have variable length and may differ with regard to both degree and pattern of sulfation. As the sulfation pattern of HS chains in most cases will determine if an interaction with a potential ligand will take place, as well as the affinity of the interaction, a key to understanding the function of HSPGs is to clarify how HS biosynthesis is regulated in different biological contexts. This review provides an introduction to the current understanding of HS biosynthesis and its regulation, and identifies research areas where more knowledge is needed to better understand how the HS biosynthetic machinery works.
TMPRSS2-ERG Fusion Transcripts in Matched Urine and Needle Rinse Material after Biopsy for the Detection of Prostate Cancer
Authors: Bories Phuong-Nhi , Younes Patrick , Zerbib Marc , Denjean Lydie , Popovici Theodora , Cynober Luc , Delongchamps Nicolas Barry
Published: October 2012

BACKGROUND

Current methods for detecting TMPRSS2-ERG fusion transcript in the urine of patients with suspected prostate cancer lack diagnostic sensitivity. We combined urine and prostate biopsy rinse material (BRM) assays to improve the fusion gene detection rate.

METHODS

Eighty patients with clinical and/or prostate-specific antigen suspicion of prostate cancer were prospectively included in the study. Urine samples were collected before and after prostate biopsy, and BRM was collected from the biopsy needle. We used reverse-transcription PCR (RT-PCR) for the detection of fusion transcripts. Microfocal cancer (MFC) on biopsy was defined by a single core involved with ≤3 mm of cancer with Gleason score 3 + 3. We statistically assessed the association between RT-PCR and biopsy results.

RESULTS

Urine alone, BRM alone, and both samples were obtained in 4, 19, and 57 patients, respectively. Three patients were excluded because of insufficient material. In the remaining 77 patients, cancer was detected on biopsy in 42 (55%). The diagnostic sensitivity of the assay for cancer detection was 62% (95% CI 47%–78%), 69% (53%–85%), and 89% (73%–99%) with BRM alone, urine alone, and paired samples, respectively. The lowest values were obtained with the urine assay in patients with MFC or Gleason score >3 + 3 cancer. Assays of paired samples provided increased diagnostic sensitivity in all subgroups of patients.

CONCLUSIONS

TMPRSS2-ERG fusion gene detection may be improved by performing assays in both urine and BRM. Insufficient cell numbers in urine samples and cell lysis during centrifugation may explain the low diagnostic sensitivity of the urine assay.
Homozygous mutation of the IGF1 receptor gene in a patient with severe pre- and postnatal growth failure and congenital malformations
Authors: Gannagé-Yared Marie-Hélène , Klammt Jürgen , Chouery Eliane , Corbani Sandra , Mégarbané Hala , Abou Ghoch Joelle , Choucair Nancy , Pfäffle Roland , Mégarbané André
Published: October 2012

Background

Heterozygous mutations in the IGF1 receptor (IGF1R) gene lead to partial resistance to IGF1 and contribute to intrauterine growth retardation (IUGR) with postnatal growth failure. To date, homozygous mutations of this receptor have not been described.

Subject

A 13.5-year-old girl born from healthy first-cousin parents presented with severe IUGR and persistent short stature. Mild intellectual impairment, dysmorphic features, acanthosis nigricans, and cardiac malformations were also present.

Methods

Auxological and endocrinological profiles were measured. All coding regions of theIGF1Rgene including intron boundaries were amplified and directly sequenced. Functional characterization was performed by immunoblotting using patient's fibroblasts.

Results

IGF1 level was elevated at 950 ng/ml (+7s.d.). Fasting glucose level was normal associated with high insulin levels at baseline and during an oral glucose tolerance test. Fasting triglyceride levels were elevated. Sequencing of theIGF1Rgene led to the identification of a homozygous variation in exon 2: c.119G>T (p.Arg10Leu). As a consequence, IGF1-dependent receptor autophosphorylation and downstream signaling were reduced in patient's fibroblasts. Both parents were heterozygous for the mutation.

Conclusion

The homozygous mutation of theIGF1Ris associated with severe IUGR, dysmorphic features, and insulin resistance, while both parents were asymptomatic heterozygous carriers of the same mutation.
Quantitative, genome-wide analysis of the DNA methylome in sporadic pituitary adenomas
Authors: Duong Cuong V , Emes Richard D , Wessely Frank , Yacqub-Usman Kiren , Clayton Richard N , Farrell William E
Published: October 2012

DNA methylation is one of the several epigenetic modifications that together with genetic aberrations are hallmarks of tumorigenesis including those emanating from the pituitary gland. In this study, we examined DNA methylation across 27 578 CpG sites spanning more than 14 000 genes in the major pituitary adenoma subtypes. Genome-wide changes were first determined in a discovery cohort comprising non-functioning (NF), growth hormone (GH), prolactin (PRL)-secreting and corticotroph (CT) adenoma relative to post-mortem pituitaries. Using stringent cut-off criteria, we validated increased methylation by pyrosequencing in 12 of 16 (75%) genes. Overall, these criteria identified 40 genes in NF, 21 in GH, six in PRL and two in CT that were differentially methylated relative to controls. In a larger independent cohort of adenomas, for genes in which hypermethylation had been validated, different frequencies of hypermethylation were apparent, where the KIAA1822 (HHIPL1) and TFAP2E genes were hypermethylated in 12 of 13 NF adenomas whereas the COL1A2 gene showed an increase in two of 13 adenomas. For genes showing differential methylation across and between adenoma subtypes, pyrosequencing confirmed these findings. In three of 12 genes investigated, an inverse relationship between methylation and transcript expression was observed where increased methylation of EML2, RHOD and HOXB1 is associated with significantly reduced transcript expression. This study provides the first genome-wide survey of adenoma, subtype-specific epigenomic changes and will prove useful for identification of biomarkers that perhaps predict or characterise growth patterns. The functional characterisation of identified genes will also provide insight of tumour aetiology and identification of new therapeutic targets.
Suppression Analysis ofesa1Mutants inSaccharomyces cerevisiaeLinksNAB3to Transcriptional Silencing and Nucleolar Functions
Authors: Chang Christie S , Clarke Astrid , Pillus Lorraine
Published: October 2012

The acetyltransferase Esa1 is essential in the yeast Saccharomyces cerevisiae and plays a critical role in multiple cellular processes. The most well-defined targets for Esa1 are lysine residues on histones. However, an increasing number of nonhistone proteins have recently been identified as substrates of Esa1. In this study, four genes (LYS20, LEU2, VAP1, and NAB3) were identified in a genetic screen as high-copy suppressors of the conditional temperature-sensitive lethality of an esa1 mutant. When expressed from a high-copy plasmid, each of these suppressors rescued the temperature-sensitivity of an esa1 mutant. Only NAB3 overexpression also rescued the rDNA-silencing defects of an esa1 mutant. Strengthening the connections between NAB3 and ESA1, mutants of nab3 displayed several phenotypes similar to those of esa1 mutants, including increased sensitivity to the topoisomerase I inhibitor camptothecin and defects in rDNA silencing and cell-cycle progression. In addition, nuclear localization of Nab3 was altered in the esa1 mutant. Finally, posttranslational acetylation of Nab3 was detected in vivo and found to be influenced by ESA1.
Light-Inducible System for Tunable Protein Expression inNeurospora crassa
Authors: Hurley Jennifer M , Chen Chen-Hui , Loros Jennifer J , Dunlap Jay C
Published: October 2012

Filamentous fungi are important model systems for understanding eukaryotic cellular processes, including the study of protein expression. A salient feature of fungi is the ability of the protein-processing machinery to perform all of the extensive posttranslational modifications needed in the complex world of eukaryotic organisms, making them great hosts for production of eukaryotic proteins. In the model organism Neurospora crassa, several regulatable promoters have been used for heterologous gene expression but all suffer from leaky expression absent stimuli or an inability to induce protein expression at levels greater than those seen in vivo. To increase and better control in vivo protein expression in Neurospora, we have harnessed the light-induced vvd promoter. vvd promoter-driven mRNA expression is dependent upon light, shows a graded response, and is rapidly shut off when returned to the dark. The vvd promoter is a highly tunable and regulatable system, which could be a useful instrument for those interested in efficient and controllable gene expression.
Second-Generation Genetic Linkage Map of Catfish and Its Integration with the BAC-Based Physical Map
Authors: Ninwichian Parichart , Peatman Eric , Liu Hong , Kucuktas Huseyin , Somridhivej Benjaporn , Liu Shikai , Li Ping , Jiang Yanliang , Sha Zhenxia , Kaltenboeck Ludmilla , Abernathy Jason W , Wang Wenqi , Chen Fei , Lee Yoona , Wong Lilian , Wang Shaolin , Lu Jianguo , Liu Zhanjiang
Published: October 2012

Construction of high-density genetic linkage maps is crucially important for quantitative trait loci (QTL) studies, and they are more useful when integrated with physical maps. Such integrated maps are valuable genome resources for fine mapping of QTL, comparative genomics, and accurate and efficient whole-genome assembly. Previously, we established both linkage maps and a physical map for channel catfish, Ictalurus punctatus, the dominant aquaculture species in the United States. Here we added 2030 BAC end sequence (BES)-derived microsatellites from 1481 physical map contigs, as well as markers from singleton BES, ESTs, anonymous microsatellites, and SNPs, to construct a second-generation linkage map. Average marker density across the 29 linkage groups reached 1.4 cM/marker. The increased marker density highlighted variations in recombination rates within and among catfish chromosomes. This work effectively anchored 44.8% of the catfish BAC physical map contigs, covering ∼52.8% of the genome. The genome size was estimated to be 2546 cM on the linkage map, and the calculated physical distance per centimorgan was 393 Kb. This integrated map should enable comparative studies with teleost model species as well as provide a framework for ordering and assembling whole-genome scaffolds.
Performance Metrics After Changes in Screening Protocol for Congenital Hypothyroidism
Authors: Korzeniewski Steven J. , Grigorescu Violanda , Kleyn Mary , Young William , Birbeck Gretchen L. , Todem David , Romero Roberto , Chaiworapongsa Tinnakorn , Paneth Nigel
Published: October 2012

OBJECTIVE:

To evaluate Michigan newborn screening for congenital hypothyroidism (CH) protocol changes.

METHODS:

This population-based study includes infants born and screened in Michigan (January 1, 1994–June 30, 2010). Screening performance is compared across 4 periods defined by the dried blood spot testing method: (1) thyroxine (T4) with backup thyrotropin, (2) tandem T4 and thyrotropin, (3) primary thyrotropin testing without serial testing, and (4) primary thyrotropin plus serial testing for births weighing <1800 g. Logistic regression is used to test for differences across periods.

RESULTS:

Thyrotropin testing exhibited greater specificity overall and greater likelihood of detection with serial testing relative to primary T4 testing. Tandem T4 and thyrotropin testing appeared more sensitive relative to other protocols, yet it produced significantly more false-positives, and detection may have been affected by overdiagnosis and misclassification. Central CH was no longer detected once T4 testing ceased.

CONCLUSIONS:

Primary thyrotropin plus serial testing for infants at risk for later rising thyrotropin outperformed other newborn screening strategies for classic CH, although 2 false-negatives occurred among normal birth weight infants admitted to the NICU during this testing period. Tandem T4 and thyrotropin screening outperformed other strategies for detection of both classic and central CH combined, although it is associated with increased operating costs. Additional research is necessary to weigh the benefits of increased sensitivity against additional program operating costs.
Prevention of Invasive Cronobacter Infections in Young Infants Fed Powdered Infant Formulas
Authors: Jason Janine
Published: October 2012

BACKGROUND:

Invasive Cronobacter infection is rare, devastating, and epidemiologically/microbiologically linked to powdered infant formulas (PIFs). In 2002–2004, the US Food and Drug Administration advised health care professionals to minimize PIF and powdered human milk fortifier (HMF)’s preparation, feeding, and storage times and avoid feeding them to hospitalized premature or immunocompromised neonates. Labels for PIF used at home imply PIF is safe for healthy, term infants if label instructions are followed.

METHODS:

1) Medical, public health, Centers for Disease Control and Prevention, US Food and Drug Administration, and World Health Organization records, publications, and personal communications were used to compare 68 (1958–2003) and 30 (2004–2010) cases of invasive Cronobacter disease in children without underlying disorders. 2) The costs of PIFs and ready-to-feed formulas (RTFs) were compared.

RESULTS:

Ninety-nine percent (95/96) of all infected infants were <2 months old. In 2004–2010, 59% (17/29) were term, versus 24% (15/63) in 1958–2003; 52% (15/29) became symptomatic at home, versus 21% (13/61). Of all infected infants, 26% (22/83) had received breast milk (BM), 23% (19/82) RTF, and 90% (76/84) PIF or HMF. Eight percent received BM and not PIF/HMF; 5%, RTF without PIF/HMF. For at least 10 PIF-fed infants, label instructions were reportedly followed. Twenty-four ounces of milk-based RTF cost $0.84 more than milk-based PIF; 24 ounces of soy-based RTF cost $0.24 less than soy-based PIF.

CONCLUSIONS:

Cronobacter can infect healthy, term (not just hospitalized preterm) young infants. Invasive Cronobacter infection is extremely unusual in infants not fed PIF/HMF. RTFs are commercially sterile, require minimal preparation, and are competitively priced. The exclusive use of BM and/or RTF for infants <2 months old should be encouraged.
Drug Shortage–Associated Increase in Catheter-Related Blood Stream Infection in Children
Authors: Ralls Matthew W. , Blackwood R. Alexander , Arnold Meghan A. , Partipilo M. Luisa , Dimond James , Teitelbaum Daniel H.
Published: October 2012

BACKGROUND:

Ethanol lock therapy (ELT) has been shown to reduce the incidence of catheter-related blood stream infections (CRBSI) in intestinal failure (IF) patients. Dosing and frequency remains undefined. Scrutiny of pharmaceutical facilities by the Food and Drug Administration led to the voluntary shutdown of the sole supplier of ethanol, resulting in a nationwide shortage. To conserve supply, we reduced ELT frequency from a daily regimen. We examined the impact that reduction in ELT frequency had on CRBSI in pediatric IF patients.

METHODS:

We retrospectively reviewed our parenteral nutrition–dependent IF children. Primary outcome measure was CRBSI per 1000 catheter days after ELT frequency reduction. Data were compared (paired t test) to the same group over 1 year before ethanol shortage and to historical controls.

RESULTS:

During the shortage 13 outpatients received ELT. Eight met study criteria. Mean ± SD age was 9.1 ± 7.8 years. Mean CRBSI rate per 1000 catheter days was 0.7 ± 1.3 before ELT shortage. This increased to 6.2 ± 2.5 after frequency reduction (P < .001). This CRBSI rate was similar to historical IF children not on ELT (8.0 ± 5.4). Seven children developed CRBSI after frequency reduction, 6 requiring hospitalization, 2 to the ICU. Mean length of stay (15.5 days) averaged $104,783(± 111,034) in hospital charges. Organisms included Gram-negatives (6), methicillin-resistant Staphylococcus aureus (1), and Candida spp (1).

CONCLUSIONS:

ELT frequency reduction resulted in complete failure in CRBSI prophylaxis. The nationwide shortage of this drug has been costly both financially and in patient morbidity.
Measuring Adverse Events and Levels of Harm in Pediatric Inpatients With the Global Trigger Tool
Authors: Kirkendall Eric S. , Kloppenborg Elizabeth , Papp James , White Denise , Frese Carol , Hacker Deborah , Schoettker Pamela J. , Muething Stephen , Kotagal Uma
Published: October 2012

OBJECTIVES:

To evaluate and characterize the Global Trigger Tool’s (GTT's) utility in a pediatric population; to measure the rate of harm at our institution and compare it with previously established trigger tools and benchmark rates; and to describe the distribution of harm of the detected events.

METHODS:

Per the GTT methodology, 240 random inpatient charts were retrospectively reviewed over a 12-month pilot period for the presence of 53 predefined safety triggers. When triggers were detected, the reviewers investigated the chart more thoroughly to decide whether an adverse event occurred. Agreement with a physician reviewer was then reached, and a level of harm was assigned.

RESULTS:

A total of 404 triggers were detected (1.7 triggers per patient), and 88 adverse events were identified. Rates of 36.7 adverse events per 100 admissions and 76.3 adverse events per 1000 patient-days were calculated. Sixty-two patients (25.8%) had at least 1 adverse event during their hospitalization, and 18 (7.5%) had >1 event identified. Three-quarters of the events were category E (temporary harm). Two events required intervention to sustain life (category H). Two of the 6 trigger modules identified 95% of the adverse events.

CONCLUSIONS:

The GTT demonstrated utility in the pediatric inpatient setting. With the use of the trigger tool, we identified a rate of harm 2 to 3 times higher than previously published pediatric rates. Modifications to the trigger tool to address pediatric-specific issues could increase the test characteristics of the tool.
Computed Tomography Use Among Children Presenting to Emergency Departments With Abdominal Pain
Authors: Fahimi Jahan , Herring Andrew , Harries Aaron , Gonzales Ralph , Alter Harrison
Published: October 2012

OBJECTIVE:

To evaluate trends in and factors associated with computed tomography (CT) use among children presenting to the emergency department (ED) with abdominal pain.

METHODS:

This study was a cross-sectional, secondary analysis of the National Hospital Ambulatory Medical Care Survey data from 1998 to 2008. We identified ED patients aged <19 years with abdominal pain and collected patient demographic and hospital characteristics, and outcomes related to imaging, hospital admission, and diagnosis of appendicitis. Trend analysis was performed over the study period for the outcomes of interest, and a multivariate regression model was used to identify factors associated with CT use.

RESULTS:

Of all pediatric ED visits, 6.0% were for abdominal pain. We noted a rise in the proportion of these patients with CT use, from 0.9% in 1998 to 15.4% in 2008 (P < .001), with no change in ultrasound/radiograph use, diagnosis of appendicitis, or hospital admission. Older and male patients were more likely to have a CT scan, whereas black children were one-half as likely to undergo a CT scan compared with white children (odds ratio: 0.50 [95% confidence interval: 0.31–0.81]). Admitted children had much higher odds of undergoing a CT scan (odds ratio: 4.11 [95% confidence interval: 2.66–6.35]). There was a plateau in CT use in 2006 to 2008.

CONCLUSIONS:

There was a dramatic increase in the utilization of CT imaging in the ED evaluation of pediatric patients with abdominal pain. Some groups of children may have a differential likelihood of receiving CT scans.
Occurrence and Family Impact of Elopement in Children With Autism Spectrum Disorders
Authors: Anderson Connie , Law J. Kiely , Daniels Amy , Rice Catherine , Mandell David S. , Hagopian Louis , Law Paul A.
Published: October 2012

OBJECTIVES:

Anecdotal reports suggest that elopement behavior in children with autism spectrum disorders (ASDs) increases risk of injury or death and places a major burden on families. This study assessed parent-reported elopement occurrence and associated factors among children with ASDs.

METHODS:

Information on elopement frequency, associated characteristics, and consequences was collected via an online questionnaire. The study sample included 1218 children with ASD and 1076 of their siblings without ASD. The association among family sociodemographic and child clinical characteristics and time to first elopement was estimated by using a Cox proportional hazards model.

RESULTS:

Forty-nine percent (n = 598) of survey respondents reported their child with an ASD had attempted to elope at least once after age 4 years; 26% (n = 316) were missing long enough to cause concern. Of those who went missing, 24% were in danger of drowning and 65% were in danger of traffic injury. Elopement risk was associated with autism severity, increasing, on average, 9% for every 10-point increase in Social Responsiveness Scale T score (relative risk 1.09, 95% confidence interval: 1.02, 1.16). Unaffected siblings had significantly lower rates of elopement across all ages compared with children with ASD.

CONCLUSIONS:

Nearly half of children with ASD were reported to engage in elopement behavior, with a substantial number at risk for bodily harm. These results highlight the urgent need to develop interventions to reduce the risk of elopement, to support families coping with this issue, and to train child care professionals, educators, and first responders who are often involved when elopements occur.