bluuebunny/crossref_metadata_2025 huggingface dataset:
Unintended Consequences of Health Information Technology: Evidence From Veterans Affairs Colorectal Cancer Oncology Watch Intervention
Authors: Bian John , Bennett Charles L. , Fisher Deborah A. , Ribeiro Maria , Lipscomb Joseph
Published: October 2012

Purpose

We evaluated the Colorectal Cancer (CRC) Oncology Watch intervention, a clinical reminder implemented in Veterans Integrated Service Network 7 (including eight hospitals) to improve CRC screening rates in 2008.

Patients and Methods

Veterans Affairs (VA) administrative data were used to construct four cross-sectional groups of veterans at average risk, age 50 to 64 years; one group was created for each of the following years: 2006, 2007, 2009, and 2010. We applied hospital fixed effects for estimation, using a difference-in-differences model in which the eight hospitals served as the intervention sites, and the other 121 hospitals served as controls, with 2006 to 2007 as the preintervention period and 2009 to 2010 as the postintervention period.

Results

The sample included 4,352,082 veteran-years in the 4 years. The adherence rates were 37.6%, 31.6%, 34.4%, and 33.2% in the intervention sites in 2006, 2007, 2009, and 2010, respectively, and the corresponding rates in the controls were 31.0%, 30.3%, 32.3%, and 30.9%. Regression analysis showed that among those eligible for screening, the intervention was associated with a 2.2–percentage point decrease in likelihood of adherence (P < .001). Additional analyses showed that the intervention was associated with a 5.6–percentage point decrease in likelihood of screening colonoscopy among the adherent, but with increased total colonoscopies (all indicators) of 3.6 per 100 veterans age 50 to 64 years.

Conclusion

The intervention had little impact on CRC screening rates for the studied population. This absence of favorable impact may have been caused by an unintentional shift of limited VA colonoscopy capacity from average-risk screening to higher-risk screening and to CRC surveillance, or by physician fatigue resulting from the large number of clinical reminders implemented in the VA.
Stage-Adapted Treatment of HIV-Associated Hodgkin Lymphoma: Results of a Prospective Multicenter Study
Authors: Hentrich Marcus , Berger Marcel , Wyen Christoph , Siehl Jan , Rockstroh Jürgen K. , Müller Markus , Fätkenheuer Gerd , Seidel Elisabeth , Nickelsen Maike , Wolf Timo , Rieke Ansgar , Schürmann Dirk , Schmidmaier Ralf , Planker Manfred , Alt Jürgen , Mosthaf Franz , Engert Andreas , Arasteh Keikawus , Hoffmann Christian
Published: October 2012

Purpose

Although the outcome of patients with HIV-related Hodgkin lymphoma (HIV-HL) has markedly improved since the introduction of combined antiretroviral therapy, standard therapy is still poorly defined. This prospective study investigates a stage- and risk-adapted treatment strategy in patients with HIV-HL.

Patients and Methods

Patients with early favorable HIV-HL received two to four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of involved-field (IF) radiation. In patients with early unfavorable HIV-HL, four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP baseline) or four cycles of ABVD + 30 Gy of IF radiation were administered. Six to eight cycles of BEACOPP baseline were given in patients with advanced-stage HIV-HL. In patients with advanced HIV infection, BEACOPP was replaced with ABVD.

Results

Of 108 patients (including eight female patients) included in the study, 23 (21%) had early favorable HL, 14 (13%) had early unfavorable HL, and 71 (66%) had advanced-stage HL. The median CD4 count at HL diagnosis was 240/μL. The complete remission rates for patients with early favorable, early unfavorable, and advanced-stage HL were 96%, 100%, and 86%, respectively. The 2-year progression-free survival of the entire study population was 91.7%. Eleven patients (11%) have died, and treatment-related mortality was 5.6%. The 2-year overall survival rate was 90.7% with no significant difference between early favorable (95.7%), early unfavorable (100%), and advanced-stage HL (86.8%).

Conclusion

In patients with HIV-HL, stage- and risk-adapted treatment is feasible and effective. The prognosis for patients with HIV-HL may approach that of HIV-negative patients with HL.
Fetal and Neonatal Iron Deficiency Reduces Thyroid Hormone-Responsive Gene mRNA Levels in the Neonatal Rat Hippocampus and Cerebral Cortex
Authors: Bastian Thomas W. , Anderson Jeremy A. , Fretham Stephanie J. , Prohaska Joseph R. , Georgieff Michael K. , Anderson Grant W.
Published: October 2012

Copper (Cu), iron (Fe), and thyroid hormone (TH) deficiencies produce similar defects in late brain development including hypomyelination of axons and impaired synapse formation and function, suggesting that these micronutrient deficiencies share a common mechanism contributing to these derangements. We previously demonstrated that fetal/neonatal Cu and Fe deficiencies lower circulating TH concentrations in neonatal rats. Fe deficiency also reduces whole-brain T3 content, suggesting impaired TH action in the developing Fe-deficient brain. We hypothesized that fetal/neonatal Cu and Fe deficiencies will produce mild or moderate TH deficiencies and will impair TH-responsive gene expression in the neonatal cerebral cortex and hippocampus. To test this hypothesis, we rendered pregnant Sprague Dawley rats Cu-, Fe-, or TH-deficient from early gestation through postnatal d 10 (P10). Mild and moderate TH deficiencies were induced by 1 and 3 ppm propylthiouracil treatment, respectively. Cu deficiency did not significantly alter serum or tissue TH concentrations or TH-responsive brain mRNA expression. Fe deficiency significantly lowered P10 serum total T3 (45%), serum total T4 (52%), whole brain T3 (14%), and hippocampal T3 (18%) concentrations, producing a mild TH deficiency similar to 1 ppm propylthiouracil treatment. Fe deficiency lowered Pvalb, Enpp6, and Mbp mRNA levels in the P10 hippocampus. Fe deficiency also altered Hairless, Dbm, and Dio2 mRNA levels in the P10 cerebral cortex. These results suggest that some of the brain defects associated with Fe deficiency may be mediated through altered thyroidal status and the concomitant alterations in TH-responsive gene transcription.
Doing Time: Mimetic Labor and Human Capital Accumulation in Chinese Vocational Schools
Authors: Woronov T. E.
Published: October 2012

Working-class youth enrolled in China’s urban vocational schools spend years hanging out and sleeping through their classes. Rather than condemning this as a failure of the students’ ability or the schools’ pedagogy, this essay argues that attending vocational school is a form of mimetic labor in China today. Based on a year of ethnographic research in two vocational schools and theorized using Diane Elson’s value theory of labor, this essay analyzes China’s current regimes of human capital accumulation. I argue that these regimes structure nonelite education such that working-class youth generate value by laboring at the mimetic production of a school-like environment.
Broad relays hormone signals to regulate stem cell differentiation in Drosophila midgut during metamorphosis
Authors: Zeng Xiankun , Hou Steven X.
Published: October 2012

Like the mammalian intestine, the Drosophila adult midgut is constantly replenished by multipotent intestinal stem cells (ISCs). Although it is well known that adult ISCs arise from adult midgut progenitors (AMPs), relatively little is known about the mechanisms that regulate AMP specification. Here, we demonstrate that Broad (Br)-mediated hormone signaling regulates AMP specification. Br is highly expressed in AMPs temporally during the larva-pupa transition stage, and br loss of function blocks AMP differentiation. Furthermore, Br is required for AMPs to develop into functional ISCs. Conversely, br overexpression drives AMPs toward premature differentiation. In addition, we found that Br and Notch (N) signaling function in parallel pathways to regulate AMP differentiation. Our results reveal a molecular mechanism whereby Br-mediated hormone signaling directly regulates stem cells to generate adult cells during metamorphosis.
Torso RTK controls Capicua degradation by changing its subcellular localization
Authors: Grimm Oliver , Zini Victoria Sanchez , Kim Yoosik , Casanova Jordi , Shvartsman Stanislav Y. , Wieschaus Eric
Published: October 2012

The transcriptional repressor Capicua (Cic) controls multiple aspects of Drosophila embryogenesis and has been implicated in vertebrate development and human diseases. Receptor tyrosine kinases (RTKs) can antagonize Cic-dependent gene repression, but the mechanisms responsible for this effect are not fully understood. Based on genetic and imaging studies in the early Drosophila embryo, we found that Torso RTK signaling can increase the rate of Cic degradation by changing its subcellular localization. We propose that Cic is degraded predominantly in the cytoplasm and show that Torso reduces the stability of Cic by controlling the rates of its nucleocytoplasmic transport. This model accounts for the experimentally observed spatiotemporal dynamics of Cic in the early embryo and might explain RTK-dependent control of Cic in other developmental contexts.
Epigenetic memory and parliamentary privilege combine to evoke discussions on inheritance
Authors: Fisher Amanda G. , Brockdorff Neil
Published: October 2012

Understanding the basis of epigenetic memory is a fast-moving challenge in modern biology. At a recent Company of Biologists Workshop held at Steyning's historic Wiston House, thirty researchers led by John Gurdon interrogated three central questions: how are cell type-specific programs generated, what mechanisms duplicate this programmatic information as cells divide, and how does epigenetics contribute to trans-generational inheritance? We report some of the emerging themes arising from this debate.
Mixing Properties of Binary Liquid Mixtures of Cyclopentane with Branched Alcohols at Different Temperatures
Authors: Kumar Harsh , Chadha Chanda
Published: October 2012

Densities, ρ, and speeds of sound, u, of cyclopentane with 2-methyl-1-propanol, 3-methyl-1-butanol, and 2-methyl-2-butanol binary liquid mixtures have been measured over the whole composition range at atmospheric pressure at temperatures: 288.15, 298.15, and 308.15 K. Excess molar volumes VmE, isentropic compressibility κS, and their excess counterpart excess isentropic compressibility KS,mE have been calculated from experimental densities and speeds of sound. Apparent molar volume, Vφ,i partial molar volume, Vi, and apparent molar compressibilities have been calculated from the experimental density and speeds of measurements.
The expression of leucine-rich repeat gene family members in colorectal cancer
Authors: Piepoli Ada , Palmieri Orazio , Maglietta Rosalia , Panza Anna , Cattaneo Elisa , Latiano Anna , Laczko Endre , Gentile Annamaria , Carella Massimo , Mazzoccoli Gianluigi , Ancona Nicola , Marra Giancarlo , Andriulli Angelo
Published: October 2012

This study was conducted to evaluate the association of the leucine-rich repeat (LRR) gene family with colorectal cancer (CRC). The expression of members of the LRR gene family were analyzed in 17 CRC specimens and in 59 healthy colorectal tissues by using Human Exon1.0ST microarray, and in 25 CRC specimens and 32 healthy colorectal tissues by U133Plus2.0 microarray. An association was found for 25 genes belonging to the plant-specific (PS) class of LRR genes ( P = 0.05 for Exon1.0 ST and P = 0.04 for U133Plus2.0). In both data-sets, in CRC, we found down-regulation of SHOC2 ( P < 0.00003) and LRRC28 ( P < 0.01) and up-regulation of LRSAM1 ( P < 0.000001), while up-regulation of MFHAS1 ( P = 0.0005) and down-regulation of WDFY3 ( P = 0.026) were found only in the Exon1.0 ST data-set. The PS LLR gene class encodes proteins that activate immune cells and might play a key role in programmed cell death and autophagy. SHOC2 and LRRC28 genes involved in RAS-mediated signaling, which hinders nutrient deprivation-induced autophagy, might be a possible link between the negative control of autophagy and tumorigenesis.
A novel CaV2.2 channel inhibition by piracetam in peripheral and central neurons
Authors: Bravo-Martínez Jorge , Arenas Isabel , Vivas Oscar , Rebolledo-Antúnez Santiago , Vázquez-García Mario , Larrazolo Arturo , García David E
Published: October 2012

No mechanistic actions for piracetam have been documented to support its nootropic effects. Voltage-gated calcium channels have been proposed as a promising pharmacological target of nootropic drugs. In this study, we investigated the effect of piracetam on CaV2.2 channels in peripheral neurons, using patch-clamp recordings from cultured superior cervical ganglion neurons. In addition, we tested if CaV2.2 channel inhibition could be related with the effects of piracetam on central neurons. We found that piracetam inhibited native CaV2.2 channels in superior cervical ganglion neurons in a dose-dependent manner, with an IC50 of 3.4 μmol/L and a Hill coefficient of 1.1. GDP βS dialysis did not prevent piracetam-induced inhibition of CaV2.2 channels and G-protein-coupled receptor activation by noradrenaline did not occlude the piracetam effect. Piracetam altered the biophysical characteristics of CaV2.2 channel such as facilitation ratio. In hippocampal slices, piracetam and ω-conotoxin GVIA diminished the frequency of excitatory postsynaptic potentials and action potentials. Our results provide evidence of piracetam's actions on CaV2.2 channels in peripheral neurons, which might explain some of its nootropic effects in central neurons.
Gestational naltrexone ameliorates fetal ethanol exposures enhancing effect on the postnatal behavioral and neural response to ethanol
Authors: Youngentob Steven L , Kent Paul F , Youngentob Lisa M
Published: October 2012

The association between gestational exposure to ethanol and adolescent ethanol abuse is well established. Recent animal studies support the role of fetal ethanol experience-induced chemosensory plasticity as contributing to this observation. Previously, we established that fetal ethanol exposure, delivered through a dam's diet throughout gestation, tuned the neural response of the peripheral olfactory system of early postnatal rats to the odor of ethanol. This occurred in conjunction with a loss of responsiveness to other odorants. The instinctive behavioral response to the odor of ethanol was also enhanced. Importantly, there was a significant contributory link between the altered response to the odor of ethanol and increased ethanol avidity when assessed in the same animals. Here, we tested whether the neural and behavioral olfactory plasticity, and their relationship to enhanced ethanol intake, is a result of the mere exposure to ethanol or whether it requires the animal to associate ethanol's reinforcing properties with its odor attributes. In this later respect, the opioid system is important in the mediation (or modulation) of the reinforcing aspects of ethanol. To block endogenous opiates during prenatal life, pregnant rats received daily intraperitoneal administration of the opiate antagonist naltrexone from gestational day 6–21 jointly with ethanol delivered via diet. Relative to control progeny, we found that gestational exposure to naltrexone ameliorated the enhanced postnatal behavioral response to the odor of ethanol and postnatal drug avidity. Our findings support the proposition that in utero ethanol-induced olfactory plasticity (and its relationship to postnatal intake) requires, at least in part, the associative pairing between ethanol's odor quality and its reinforcing aspects. We also found suggestive evidence that fetal naltrexone ameliorated the untoward effects of gestational ethanol exposure on the neural response to non-fetal-exposure odorants. Thus, gestational naltrexone may also have a neuroprotective and/or neuroproliferative impact on olfactory development.
Value-Focused Brainstorming
Authors: Keeney Ralph L.
Published: October 2012

Brainstorming can be a useful technique to create alternatives for complex decisions. To enhance the quality and innovativeness of the created alternatives, value-focused brainstorming incorporates two features of value-focused thinking into the traditional brainstorming procedures. First, it explicitly identifies the valued aspects of potential alternatives, specified as distinct objectives, to guide brainstormers to create alternatives of greater value. Second, all participants in a brainstorm individually create alternatives prior to any anchoring on group discussions, which will enhance getting the full range of each individual's thoughts articulated. Concepts and procedures of the approach are discussed. A public policy application, done to address recommendations following the World Trade Center disaster, illustrates the approach by creating alternatives to improve emergency evacuation of individuals from large buildings.
Effects of Piracy on Quality of Information Goods
Authors: Lahiri Atanu , Dey Debabrata
Published: October 2012

It is commonly believed that piracy of information goods leads to lower profits, which translate to lower incentives to invest in innovation and eventually to lower-quality products. Manufacturers, policy makers, and researchers all claim that inadequate piracy enforcement efforts translate to lower investments in product development. However, we find many practical examples that contradict this claim. Therefore, to examine this claim more carefully, we develop a rigorous economic model of the manufacturer's quality decision problem in the presence of piracy. We consider a monopolist who does not have any marginal costs but has a product development cost quadratic in the quality level produced. The monopolist faces a consumer market heterogeneous in its preference for quality and offers a quality level that maximizes its profit. We also allow for the possibility that the manufacturer may use versioning to counter piracy. We unexpectedly find that in certain situations, lower piracy enforcement increases the monopolist's incentive to invest in quality. We explain the reasons and welfare implications of our findings.

This paper was accepted by Lorin Hitt, information systems.
Industry or Academia, Basic or Applied? Career Choices and Earnings Trajectories of Scientists
Authors: Agarwal Rajshree , Ohyama Atsushi
Published: October 2012

We extend life cycle models of human capital investments by incorporating matching theory to examine the sorting pattern of heterogeneous scientists into different career trajectories. We link differences in physical capital investments and complementarities between basic and applied scientists across industry and academic settings to individual differences in scientist ability and preferences to predict an equilibrium matching of scientists to careers and to their earnings evolution. Our empirical analysis, using the National Science Foundation's Scientists and Engineers Statistical Data System database, is consistent with theoretical predictions of (i) sorting by ability into basic versus applied science among academic scientists, but not among industry scientists; and (ii) sorting by higher taste for nonmonetary returns into academia over industry. The evolution of an earnings profile is consistent with these sorting patterns: the earnings trajectories of basic and applied scientists are distinct from each other in academia but are similar in industry.

This paper was accepted by Lee Fleming, entrepreneurship and innovation.
Worst-Case Value at Risk of Nonlinear Portfolios
Authors: Zymler Steve , Kuhn Daniel , Rustem Berç
Published: October 2012

Portfolio optimization problems involving value at risk (VaR) are often computationally intractable and require complete information about the return distribution of the portfolio constituents, which is rarely available in practice. These difficulties are compounded when the portfolio contains derivatives. We develop two tractable conservative approximations for the VaR of a derivative portfolio by evaluating the worst-case VaR over all return distributions of the derivative underliers with given first- and second-order moments. The derivative returns are modelled as convex piecewise linear or—by using a delta–gamma approximation—as (possibly nonconvex) quadratic functions of the returns of the derivative underliers. These models lead to new worst-case polyhedral VaR (WPVaR) and worst-case quadratic VaR (WQVaR) approximations, respectively. WPVaR serves as a VaR approximation for portfolios containing long positions in European options expiring at the end of the investment horizon, whereas WQVaR is suitable for portfolios containing long and/or short positions in European and/or exotic options expiring beyond the investment horizon. We prove that—unlike VaR that may discourage diversification—WPVaR and WQVaR are in fact coherent risk measures. We also reveal connections to robust portfolio optimization.

This paper was accepted by Dimitris Bertsimas, optimization.
Performance Guarantees for Empirical Markov Decision Processes with Applications to Multiperiod Inventory Models
Authors: Cooper William L. , Rangarajan Bharath
Published: October 2012

We consider Markov decision processes with unknown transition probabilities and unknown single-period expected cost functions, and we study a method for estimating these quantities from historical or simulated data. The method requires knowledge of the system equations that govern state transitions as well as the single-period cost functions (but not the single-period expected cost functions). The estimation procedure is based upon taking expectations with respect to the empirical distribution functions of such data. Once the estimates are in place, the method computes a policy by solving the obtained “empirical” Markov decision process as if the estimates were correct. For MDPs that satisfy some conditions, we provide explicit, easily computed expressions for the probability that the procedure will produce a policy whose true expected cost is within any specified absolute distance of the actual optimal expected cost of the true Markov decision process. We also provide expressions for the number of historical or simulated data values that is sufficient for the procedure to produce a policy whose true expected cost is, with a prescribed probability, within a prescribed absolute distance of the actual optimal expected cost of the true Markov decision process. We apply our results to multiperiod inventory models. In addition, we provide a specialized analysis of such inventory models that also yields relative, rather than absolute, accuracy guarantees. We make comparisons with related results that have recently appeared, and we provide numerical examples.
Patient Streaming as a Mechanism for Improving Responsiveness in Emergency Departments
Authors: Saghafian Soroush , Hopp Wallace J. , Van Oyen Mark P. , Desmond Jeffrey S. , Kronick Steven L.
Published: October 2012

Crisis-level overcrowding conditions in emergency departments (EDs) have led hospitals to seek out new patient-flow designs to improve both responsiveness and safety. One approach that has attracted attention and experimentation in the emergency medicine community is a system in which ED beds and care teams are segregated and patients are “streamed” based on predictions of whether they will be discharged or admitted to the hospital. In this paper, we use a combination of analytic and simulation models to determine whether such a streaming policy can improve ED performance, where it is most likely to be effective, and how it should be implemented for maximum performance. Our results suggest that the concept of streaming can indeed improve patient flow, but only in some situations. First, ED resources must be shared across streams rather than physically separated. This leads us to propose a new “virtual-streaming” patient flow design for EDs. Second, this type of streaming is most effective in EDs with (1) a high percentage of admitted patients, (2) longer care times for admitted patients than discharged patients, (3) a high day-to-day variation in the percentage of admitted patients, (4) long patient boarding times (e.g., caused by hospital “bed-block”), and (5) high average physician utilization. Finally, to take full advantage of streaming, physicians assigned to admit patients should prioritize upstream (new) patients, whereas physicians assigned to discharge patients should prioritize downstream (old) patients.
Reviews Books
Authors: Chatham Hugh , Hillier David , Labuza Peter , O’Reilly Erin
Published: October 2012

Directory of World Cinema: American Independent, John Berra (ed.), (2010) Chicago: Intellect, 327pp., ISBN: 9781841503684 (pbk), $25.00

Film England: Culturally English Film-making since the 1990s, Andrew Higson, (2011) New York: I.B. Taurus, 296pp., ISBN: 9781848854536 (pbk),
$34.00

Steven Soderbergh, Aaron Baker, (2011) Chicago: University of Illinois press, 132pp., ISBN: 9780252077968 (pbk), $22.00

Hedy Lamarr: The Most Beautiful Woman in Film, Ruth Barton, (2010) Lexington: University Press of Kentucky, 281pp., ISBN: 9780813126043 (hbk),
$29.95
Reviews DVD and Blu-ray
Authors: Shaw Jake , Warne Jude
Published: October 2012

House (Hausu, 1977) Japan Director Nobuhiko Obayashi Runtime 88 minutes DVD UK, 2010

Fanny and Alexander (1982) Box Set Sweden Director Ingmar Bergman Runtime 618 minutes (Box Set total) Blu-ray USA, 2011
Raf Kinase Inhibitory Protein is Required for Cerebellar Long-Term Synaptic Depression by Mediating PKC-Dependent MAPK Activation
Authors: Yamamoto Yukio , Lee Dongwon , Kim Yoonhee , Lee Bokyoung , Seo Changwoo , Kawasaki Hiroshi , Kuroda Shinya , Tanaka-Yamamoto Keiko
Published: October 2012

It was demonstrated previously that a positive feedback loop, including protein kinase C (PKC) and mitogen-activated protein kinase (MAPK), is required for the gradual expression of cerebellar long-term depression (LTD). PKC and MAPK are mutually activated in this loop. MAPK-dependent PKC activation is likely to be mediated by phospholipase A2. On the other hand, it is not clear how PKC activates MAPK. Therefore, the entire picture of this loop was not fully understood. We here test the hypothesis that this loop is completed by the PKC substrate, Raf kinase inhibitory protein (RKIP). To test this hypothesis, we used a mutant form of RKIP that is not phosphorylated by PKC and thus constitutively inhibits Raf-1 and MEK, upstream kinases of MAPK. When this RKIP mutant was introduced into Purkinje cells of mouse cerebellar slices through patch-clamp electrodes, LTD was blocked, while wild-type (WT) RKIP had no effect on LTD. Physiological epistasis experiments demonstrated that RKIP works downstream of PKC and upstream of MAPK during LTD induction. Furthermore, biochemical analyses demonstrated that endogenous RKIP dissociates from Raf-1 and MEK during LTD induction in a PKC-dependent manner, suggesting that RKIP binding-dependent inhibition of Raf-1 and MEK is removed upon LTD induction. We therefore conclude that PKC-dependent regulation of RKIP leads to MAPK activation, with RKIP completing the positive feedback loop that is required for LTD.
Vps10 Family Proteins and the Retromer Complex in Aging-Related Neurodegeneration and Diabetes
Authors: Lane Rachel F. , St George-Hyslop Peter , Hempstead Barbara L. , Small Scott A. , Strittmatter Stephen M. , Gandy Sam
Published: October 2012

Members of the vacuolar protein sorting 10 (Vps10) family of receptors (including sortilin, SorL1, SorCS1, SorCS2, and SorCS3) play pleiotropic functions in protein trafficking and intracellular and intercellular signaling in neuronal and non-neuronal cells. Interactions have been documented between Vps10 family members and the retromer coat complex, a key component of the intracellular trafficking apparatus that sorts cargo from the early endosome to thetrans-Golgi network. In recent years, genes encoding several members of the Vps10 family of proteins, as well as components of the retromer coat complex, have been implicated as genetic risk factors for sporadic and autosomal dominant forms of neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease, with risk for type 2 diabetes mellitus and atherosclerosis. In addition to their functions in protein trafficking, the Vps10 family proteins modulate neurotrophic signaling pathways. Sortilin can impact the intracellular response to brain-derived neurotrophic factor (BDNF) by regulating anterograde trafficking of Trk receptors to the synapse and direct control of BDNF levels, while both sortilin and SorCS2 function as cell surface receptors to mediate acute responses to proneurotrophins. This mini-review and symposium will highlight the emerging data from this rapidly growing area of research implicating the Vps10 family of receptors and the retromer in physiological intracellular trafficking signaling by neurotrophins and in the pathogenesis of neurodegeneration.
Mary Shelley's Malthusian Objections in The Last Man
Authors: Cameron Lauren
Published: October 2012

This essay considers Mary Shelley's The Last Man (1826) as intervening in the ongoing debate between Thomas Malthus and William Godwin. Malthus published An Essay on the Principle of Population (1798) in large part as a response to Godwin's Enquiry Concerning Political Justice (1793) and “Of Avarice and Profusion” (1797); Godwin later wrote an extended refutation of Malthus in Of Population (1820). Mary Shelley uses The Last Man, a story of the end of the human species, in part as a meditation on the merits of Malthus's philosophical positions in the Essay on the Principle of Population, but she seems to disagree with a number of the mechanisms he identifies: in contrast to Malthus, Shelley identifies a blind and random nature rather than any divine plan as controlling population change, and disease rather than food scarcity as the primary cause of population reduction, but insists upon the importance of individuating and empathizing with the suffering.
Authors, Speakers, Readers in a Trio of Sea-Pieces in Herman Melville's John Marr and Other Sailors
Authors: Ford Sean
Published: October 2012

Much recent interest in Herman Melville's poetry involves reassessing its position both within the Melville canon and within or against various literary traditions. This essay considers the range of stances, speakers, and personae in John Marr and Other Sailors With Some Sea-Pieces (1888) and its resonances of past works as evidence that Melville is more committed to a public audience and less oppositional or adversarial to established traditions than a number of scholars have proposed. A study of topical and rhetorical interdependencies in a sequence of poems in the volume uncovers dynamic affinities, whether by direct influence or otherwise, with William Shakespeare, Samuel Taylor Coleridge, Alfred Tennyson, and Walt Whitman, participants in Melville's own recurring urge to tell of things that cannot be told. Through a communion of voices, “The Æolian Harp,” “To the Master of the ‘Meteor,’” and “Far Off-Shore” display varying and alternating expressions of this urge as part of a rhetorical project that invites readers to interact and ultimately acquiesce in essential limits of accessing and telling the truth.
Exploration of the Genetic Organization of Morphological Modularity on the Mouse Mandible Using a Set of Interspecific Recombinant Congenic Strains Between C57BL/6 and Mice of theMus spretusSpecies
Authors: Burgio Gaëtan , Baylac Michel , Heyer Evelyne , Montagutelli Xavier
Published: October 2012

Morphological integration and modularity within semi-autonomous modules are essential mechanisms for the evolution of morphological traits. However, the genetic makeup responsible for the control of variational modularity is still relatively unknown. In our study, we tested the hypothesis that the genetic variation for mandible shape clustered into two morphogenetic components: the alveolar group and the ascending ramus. We used the mouse as a model system to investigate genetics determinants of mandible shape. To do this, we used a combination of geometric morphometric tools and a set of 18 interspecific recombinant congenic strains (IRCS) derived from the distantly related species, Mus spretus SEG/Pas and Mus musculus C57BL/6. Quantitative trait loci (QTL) analysis comparing mandible morphometry between the C57BL/6 and the IRCSs identified 42 putative SEG/Pas segments responsible for the genetic variation. The magnitude of the QTL effects was dependent on the proportion of SEG/Pas genome inherited. Using a multivariate correlation coefficient adapted for modularity assessment and a two-block partial least squares analysis to explore the morphological integration, we found that these QTL clustered into two well-integrated morphogenetic groups, corresponding to the ascending ramus and the alveolar region. Together, these results provide evidence that the mouse mandible is subjected to genetic coordination in a modular manner.
Functional Analysis With a Barcoder Yeast Gene Overexpression System
Authors: Douglas Alison C , Smith Andrew M , Sharifpoor Sara , Yan Zhun , Durbic Tanja , Heisler Lawrence E , Lee Anna Y , Ryan Owen , Göttert Hendrikje , Surendra Anu , van Dyk Dewald , Giaever Guri , Boone Charles , Nislow Corey , Andrews Brenda J
Published: October 2012

Systematic analysis of gene overexpression phenotypes provides an insight into gene function, enzyme targets, and biological pathways. Here, we describe a novel functional genomics platform that enables a highly parallel and systematic assessment of overexpression phenotypes in pooled cultures. First, we constructed a genome-level collection of ~5100 yeast barcoder strains, each of which carries a unique barcode, enabling pooled fitness assays with a barcode microarray or sequencing readout. Second, we constructed a yeast open reading frame (ORF) galactose-induced overexpression array by generating a genome-wide set of yeast transformants, each of which carries an individual plasmid-born and sequence-verified ORF derived from the Saccharomyces cerevisiae full-length EXpression-ready (FLEX) collection. We combined these collections genetically using synthetic genetic array methodology, generating ~5100 strains, each of which is barcoded and overexpresses a specific ORF, a set we termed “barFLEX.” Additional synthetic genetic array allows the barFLEX collection to be moved into different genetic backgrounds. As a proof-of-principle, we describe the properties of the barFLEX overexpression collection and its application in synthetic dosage lethality studies under different environmental conditions.
Fractionation, Stability, and Isolate-Specificity of QTL for Resistance toPhytophthora infestansin Cultivated Tomato (Solanum lycopersicum)
Authors: Johnson Emily B , Haggard J Erron , St.Clair Dina A
Published: October 2012

Cultivated tomato (Solanum lycopersicum) is susceptible to late blight, a major disease caused by Phytophthora infestans, but quantitative resistance exists in the wild tomato species S. habrochaites. Previously, we mapped several quantitative trait loci (QTL) from S. habrochaites and then introgressed each individually into S. lycopersicum. Near-isogenic lines (NILs) were developed, each containing a single introgressed QTL on chromosome 5 or 11. NILs were used to create two recombinant sub-NIL populations, one for each target chromosome region, for higher-resolution mapping. The sub-NIL populations were evaluated for foliar and stem resistance to P. infestans in replicated field experiments over two years, and in replicated growth chamber experiments for resistance to three California isolates. Each of the original single QTL on chromosomes 5 and 11 fractionated into between two and six QTL for both foliar and stem resistance, indicating a complex genetic architecture. The majority of QTL from the field experiments were detected in multiple locations or years, and two of the seven QTL detected in growth chambers were co-located with QTL detected in field experiments, indicating stability of some QTL across environments. QTL that confer foliar and stem resistance frequently co-localized, suggesting that pleiotropy and/or tightly linked genes control the trait phenotypes. Other QTL exhibited isolate-specificity and QTL × environment interactions. Map-based comparisons between QTL mapped in this study and Solanaceae resistance genes/QTL detected in other published studies revealed multiple cases of co-location, suggesting conservation of gene function.
Multiple Pathways Regulate Minisatellite Stability During Stationary Phase in Yeast
Authors: Kelly Maire K , Brosnan Laura , Jauert Peter A , Dunham Maitreya J , Kirkpatrick David T
Published: October 2012

Alterations in minisatellite DNA repeat tracts in humans have been correlated with a number of serious disorders, including cancer. Despite their importance for human health, the genetic factors that influence minisatellite stability are not well understood. Previously, we identified mutations in the Saccharomyces cerevisiae zinc homeostasis genes ZRT1 and ZAP1 that significantly increase the frequency of minisatellite alteration specifically during stationary phase. In this work, we identified mutants of END3, PKC1, and RAD27 that increase minisatellite instability during stationary phase. Genetic analysis reveals that these genes, along with ZRT1 and ZAP1, comprise multiple pathways regulating minisatellite stability during stationary phase. Minisatellite alterations generated by perturbation of any of these pathways occur via homologous recombination. We present evidence that suggests formation of ssDNA or ssDNA breaks may play a primary role in stationary phase instability. Finally, we examined the roles of these pathways in the stability of a human minisatellite tract associated with the HRAS1 oncogene and found that loss of RAD27, but not END3 or PKC1, destabilizes the HRAS1 minisatellite in stationary phase yeast. This result indicates that the genetic control of stationary phase minisatellite stability is dependent on the sequence composition of the minisatellite itself.
Identification of Genes Underlying Hypoxia Tolerance inDrosophilaby a P-element Screen
Authors: Azad Priti , Zhou Dan , Zarndt Rachel , Haddad Gabriel G
Published: October 2012

Hypoxia occurs in physiologic conditions (e.g. high altitude) or during pathologic states (e.g. ischemia). Our research is focused on understanding the molecular mechanisms that lead to adaptation and survival or injury to hypoxic stress using Drosophila as a model system. To identify genes involved in hypoxia tolerance, we screened the P-SUP P-element insertion lines available for all the chromosomes of Drosophila. We screened for the eclosion rates of embryos developing under 5% O2 condition and the number of adult flies surviving one week after eclosion in the same hypoxic environment. Out of 2187 lines (covering ∼1870 genes) screened, 44 P-element lines representing 44 individual genes had significantly higher eclosion rates (i.e. >70%) than those of the controls (i.e. ∼7–8%) under hypoxia. The molecular function of these candidate genes ranged from cell cycle regulation, DNA or protein binding, GTP binding activity, and transcriptional regulators. In addition, based on pathway analysis, we found these genes are involved in multiple pathways, such as Notch, Wnt, Jnk, and Hedgehog. Particularly, we found that 20 out of the 44 candidate genes are linked to Notch signaling pathway, strongly suggesting that this pathway is essential for hypoxia tolerance in flies. By employing the UAS/RNAi-Gal4 system, we discovered that genes such as osa (linked to Wnt and Notch pathways) and lqf (Notch regulator) play an important role in survival and development under hypoxia in Drosophila. Based on these results and our previous studies, we conclude that hypoxia tolerance is a polygenic trait including the Notch pathway.
Decreased Incidence of Pneumothorax in VLBW Infants After Increased Monitoring of Tidal Volumes
Authors: Vellanki Haritha , Antunes Michael , Locke Robert G. , McGreevy Theresa , Mackley Amy , Eubanks Jacquline J. , Western Mike , Emberger John , Paul David A.
Published: October 2012

BACKGROUND AND OBJECTIVE:

Pneumothorax is common in very low birth weight (VLBW) infants. In our NICU, we noted an above average incidence of pneumothorax compared with similar NICUs based on Vermont Oxford Network benchmarking. The quality improvement project was designed to decrease the incidence of pneumothorax in VLBW infants in a tertiary care NICU.

METHODS:

The project was divided into 2 periods. During period 1, all VLBW infants were followed for 6 months for the presence of pneumothorax. A multidisciplinary team met regularly to review cases of pneumothorax and identify potential causes. High tidal volumes (VT) (>6 mL/kg) were noted around the time of occurrence of pneumothorax. Guidelines were developed for improved monitoring and rapid feedback of VT and peak inspiratory pressure between nursing staff and clinicians. During period 2, these guidelines were implemented and VLBW infants were again followed for 6 months. The incidence of pneumothorax was tracked. Run charts were used to monitor changes.

RESULTS:

The incidence of pneumothorax in VLBW infants decreased from 10.4% to 2.6% after the intervention (P = .04). By using process control, a reduction in pneumothorax was achieved in period 2.

CONCLUSIONS:

Increased vigilance and real-time monitoring of VT and peak inspiratory pressure decreased the incidence of pneumothorax in our population of VLBW infants. These interventions can be considered in other NICUs with an above-average risk adjusted incidence of pneumothorax in VLBW infants. Our data illustrate the benefits of comparative benchmarking and organized quality improve-ment in advancing patient care outcomes.
Gastric Ulcers Due to Varicella-Zoster Reactivation
Authors: Milligan Ki Lee , Jain Ajay Kumar , Garrett Jeremy S. , Knutsen Alan P.
Published: October 2012

We report on an 18-year-old man with common variable immunodeficiency presenting with abdominal pain and vomiting due to gastric ulcers caused by reactivation of varicella-zoster virus (VZV). Endoscopy revealed multiple ulcers in the gastric antrum. Fever and rash developed the next day. Skin biopsy showed multinucleated cells with intranuclear inclusions highly suggestive of VZV infection, and high-dose intravenous acyclovir was started. VZV was detected on direct immunofluorescence from skin biopsy and polymerase chain reaction from endoscopic biopsy. His course was complicated by encephalopathy, pancreatitis, hepatitis, renal impairment, and hyponatremia. After 3 weeks of antiviral therapy, he gradually improved. Skin lesions cleared within a week. He remained well on follow-up 1 year later. Disseminated zoster presenting as gastric ulcers in the absence of the classic rash is unusual but has been reported in immunosuppressed patients with a history of bone marrow and stem cell transplant. We report this rare presentation in a patient with common variable immunodeficiency and highlight the importance of considering zoster as a cause for severe abdominal pain and of seeking endoscopic diagnosis to facilitate early therapy and reduced mortality risk.
Factors Influencing Participation in a Population-based Biorepository for Childhood Heart Disease
Authors: Papaz Tanya , Safi Mina , Manickaraj Ashok-Kumar , Ogaki Carly , Breaton Kyryliuk Jennifer , Burrill Liz , Dodge Christine , Chant-Gambacort Catherine , Walter Laura-Lee , Rosenberg Herschel , Mondal Tapas , Smythe John , Lougheed Jane , Bergin Lynn , Gordon Elaine , Chitayat David , Oechslin Erwin , Mital Seema
Published: October 2012

BACKGROUND:

Consenting minors for genetics research and biobanking involves ethical and social challenges. We examined factors influencing participation rates in a population-based biorepository for childhood heart disease.

METHODS:

Individuals were prospectively enrolled across 7 centers in Ontario by using a standardized consent form. Individuals were approached for consent for the donation of blood/saliva (DNA), tissue, and skin from the affected individual for future genomics and stem cell research. Consent rates were compared between pediatric and adult patients and factors affecting consent were analyzed by using multiple logistic regression analysis.

RESULTS:

From 2008 to 2011, 3637 patients were approached. A total of 2717 pediatric patients consented (90% consent rate); mean age was 8.5 ± 5.8 years (57% male; 76% white). A total of 561 adult patients consented (92% consent rate, P = .071 versus pediatric). Factors associated with lower pediatric consent rates included younger age, race, absence of complex defects, and location of consent; these were not associated with adult consent rates. Leading causes for refusal of consent were lack of interest in research (43%), overwhelmed clinically (14%), and discomfort with genetics (11%). Concerns related to privacy, insurability, indefinite storage, and ongoing access to medical records were not the leading causes for refusal.

CONCLUSIONS:

The high pediatric consent rate (90%) was comparable with that of adults. Ethical, social, or legal issues were not the leading reasons for refusal of consent.
Mental Health Services Use by Children Investigated by Child Welfare Agencies
Authors: Horwitz Sarah McCue , Hurlburt Michael S. , Goldhaber-Fiebert Jeremy D. , Heneghan Amy M. , Zhang Jinjin , Rolls-Reutz Jennifer , Fisher Emily , Landsverk John , Stein Ruth E.K.
Published: October 2012

OBJECTIVE:

To examine the rates and predictors of mental health services use for a nationally representative cohort of youths who had been investigated for alleged maltreatment.

METHODS:

Data came from caregiver and caseworker baseline and 18-month interviews in the second National Survey of Child and Adolescent Well-being. These interviews took place from March 2008 to September 2008 and September 2010 to March 2011. Data on family and child characteristics and service use were gathered and examined by using weighted univariate and multivariate analyses.

RESULTS:

Children had numerous challenges: 61.8% had a previous report of maltreatment, 46.3% had poor socialization skills, and 23.9% had a mental health problem measured by the Child Behavior Checklist (CBCL). At baseline, 33.3% received some mental health service and this varied by age, with younger children receiving fewer services. This percentage decreased to 30.9% at the 18-month follow-up, although the youngest children had increases in services use. For younger children, race/ethnicity, out-of-home placement, chronic physical health problems, low adaptive behaviors, and CBCL scores in the clinical range were related to use. For children ≥11, out-of-home placement, high CBCL scores, and family risk factors predicted services use at 18 months.

CONCLUSIONS:

Mental health services utilization increases as young children come into contact with schools and medical providers or have more intensive involvement with child welfare. Minority children receive fewer services adjusting for need. Over the 18-month follow-up, there was a decrease in service use that may be a result of the tremendous financial challenges taking place in the United States.