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Abstract In this commentary we highlight limitations with the way nonmedical use of prescription medications has been measured in U.S. national studies. We also offer an alternative way of conceptualizing the nonmedical use of prescription medications for future study.

Removal or protection from biostratinomic agents of decomposition, such as predators and scavengers, is widely seen as a requirement for high-quality preservation of soft tissues in the fossil record. In this context, extremely rapid burial is an oft-cited mechanism for shielding remains from degradation, but not all fossils fit nicely into this paradigm. Dinosaurian mummies in particular seemingly require two mutually exclusive taphonomic processes to preserve under that framework: desiccation and rapid burial. Here we present a recently prepared Edmontosaurus mummy that reveals an alternate fossilization pathway for resistant soft tissues (e.g., skin and nails). While the skin on this specimen is well-preserved in three dimensions and contains biomarkers, it is deflated and marked by the first documented examples of injuries consistent with carnivore activity on dinosaurian soft tissue during the perimortem interval. Incomplete scavenging of the carcass provided a route for the gases, fluids, and microbes associated with decomposition to escape, allowing more durable soft tissues to persist through the weeks to months required for desiccation prior to entombment and fossilization. This pathway is consistent with actualistic observations and explains why dinosaurian skin, while rare, is more commonly preserved than expected if extreme circumstances were required for its preservation. More broadly, our assumptions guide specimen collection and research, and the presence of soft tissues and biomolecules in fossils that demonstrably were not rapidly buried, such as this mummy, suggests that such types of evidence may be substantially more common than previously assumed., Competing Interests: The authors have declared that no competing interests exist.

Ornithischians form a large clade of globally distributed Mesozoic dinosaurs, and represent one of their three major radiations. Throughout their evolutionary history, exceeding 134 million years, ornithischians evolved considerable morphological disparity, expressed especially through the cranial and osteodermal features of their most distinguishable representatives. The nearly two-century-long research history on ornithischians has resulted in the recognition of numerous diverse lineages, many of which have been named. Following the formative publications establishing the theoretical foundation of phylogenetic nomenclature throughout the 1980s and 1990s, many of the proposed names of ornithischian clades were provided with phylogenetic definitions. Some of these definitions have proven useful and have not been changed, beyond the way they were formulated, since their introduction. Some names, however, have multiple definitions, making their application ambiguous. Recent implementation of the International Code of Phylogenetic Nomenclature ( ICPN , or PhyloCode ) offers the opportunity to explore the utility of previously proposed definitions of established taxon names. Since the Articles of the ICPN are not to be applied retroactively, all phylogenetic definitions published prior to its implementation remain informal (and ineffective) in the light of the Code. Here, we revise the nomenclature of ornithischian dinosaur clades; we revisit 76 preexisting ornithischian clade names, review their recent and historical use, and formally establish their phylogenetic definitions. Additionally, we introduce five new clade names: two for robustly supported clades of later-diverging hadrosaurids and ceratopsians, one uniting heterodontosaurids and genasaurs, and two for clades of nodosaurids. Our study marks a key step towards a formal phylogenetic nomenclature of ornithischian dinosaurs., Competing Interests: Andrew A. Farke is an Academic Editor and Section Editor for PeerJ., (© 2021 Madzia et al.)

Objectives: CT angiography (CTA) is essential in acute stroke to detect emergent large vessel occlusions (ELVO) and must be interpreted by radiologists with and without subspecialized training. Additionally, grayscale inversion has been suggested to improve diagnostic accuracy in other radiology applications. This study examines diagnostic performance in ELVO detection between neuroradiologists, non-neuroradiologists, and radiology residents using standard and grayscale inversion viewing methods., Methods: A random, counterbalanced experimental design was used, where 18 radiologists with varying experiences interpreted the same patient images with and without grayscale inversion. Confirmed positive and negative ELVO cases were randomly ordered using a balanced design. Sensitivity, specificity, positive and negative predictive values as well as confidence, subjective assessment of image quality, time to ELVO detection, and overall interpretation time were examined between grayscale inversion (on/off) by experience level using generalized mixed modeling assuming a binary, negative binomial, and binomial distributions, respectively., Results: All groups of radiologists had high sensitivity and specificity for ELVO detection (all > .94). Neuroradiologists were faster than non-neuroradiologists and residents in interpretation time, with a mean of 47 s to detect ELVO, as compared with 59 and 74 s, respectively. Residents were subjectively less confident than attending physicians. With respect to grayscale inversion, no differences were observed between groups with grayscale inversion vs. standard viewing for diagnostic performance (p = 0.30), detection time (p = .45), overall interpretation time (p = .97), and confidence (p = .20)., Conclusions: Diagnostic performance in ELVO detection with CTA was high across all levels of radiologist training level. Grayscale inversion offered no significant detection advantage., Key Points: • Stroke is an acute vascular syndrome that requires acute vascular imaging. • Proximal large vessel occlusions can be identified quickly and accurately by radiologists across all training levels. • Grayscale inversion demonstrated minimal detectable benefit in the detection of proximal large vessel occlusions.

Prescription psychostimulants produce rapid changes in mood, energy, and attention. These drugs are widely used and abused. However, their effects in human neocortex on glutamate and glutamine (pooled as Glx), and key neurometabolites such as N-acetylaspartate (tNAA), creatine (tCr), choline (Cho), and myo-inositol (Ins) are poorly understood. Changes in these compounds could inform the mechanism of action of psychostimulant drugs and their abuse potential in humans. We investigated the acute impact of two FDA-approved psychostimulant drugs on neurometabolites using magnetic resonance spectroscopy ( 1 H MRS). Single clinically relevant doses of d-amphetamine (AMP, 20 mg oral), methamphetamine (MA, 20 mg oral; Desoxyn®), or placebo were administered to healthy participants (n = 26) on three separate test days in a placebo-controlled, double-blinded, within-subjects crossover design. Each participant experienced all three conditions and thus served as his/her own control. 1 H MRS was conducted in the dorsal anterior cingulate cortex (dACC), an integrative neocortical hub, during the peak period of drug responses (140-150 m post ingestion). D-amphetamine increased the level of Glu (p = .0001), Glx (p = .003), and tCr (p = .0067) in the dACC. Methamphetamine increased Glu in females, producing a significant crossover interaction pattern with gender (p = .02). Drug effects on Glu, tCr, and Glx were positively correlated with subjective drug responses, predicting both the duration of AMP liking (Glu: r = +.49, p = .02; tCr: r = +.41, p = .047) and the magnitude of peak drug high to MA (Glu: r = +.52, p = .016; Glx: r = +.42, p = .049). Neither drug affected the levels of tNAA, Cho, or Ins after correction for multiple comparisons. We conclude that d-amphetamine increased the concentration of glutamate, Glx, and tCr in the dACC in male and female volunteers 2 1 / 2 hours after drug consumption. There was evidence that methamphetamine differentially affects dACC Glu levels in women and men. These findings provide the first experimental evidence that specific psychostimulants increase the level of glutamatergic compounds in the human brain, and that glutamatergic changes predict the extent and magnitude of subjective responses to psychostimulants.

Here we present an examination of type IV pilus genes associated with competence and twitching in the bacterium Acinetobacter baylyi (strain ADP1, BD413). We used bioinformatics to identify potential competence and twitching genes and their operons. We measured the competence and twitching phenotypes of the bioinformatically-identified genes. These results demonstrate that competence and twitching in A. baylyi both rely upon a core of the same type IV pilus proteins. The core includes the inner membrane assembly platform (PilC), a periplasmic assemblage connecting the inner membrane assembly platform to the secretin (ComM), a secretin (ComQ) and its associated pilotin (PilF) that assists with secretin assembly and localization, both cytoplasmic pilus retraction ATPases (PilU, PilT), and pilins (ComP, ComB, PilX). Proteins not needed for both competence and twitching are instead found to specialize in either of the two traits. The pilins are varied in their specialization with some required for either competence (FimT) and others for twitching (ComE). The protein that transports DNA across the inner membrane (ComA) specializes in competence, while signal transduction proteins (PilG, PilS, and PilR) specialize in twitching. Taken together our results suggest that the function of accessory proteins should not be based on homology alone. In addition the results suggest that in A. baylyi the mechanisms of natural transformation and twitching are mediated by the same set of core Type IV pilus proteins with distinct specialized proteins required for each phenotype. Finally, since competence requires multiple pilins as well as both pilus retraction motors PilU and PilT, this suggests that A. baylyi employs a pilus in natural transformation.

This article describes the development process for creating a digital educational mini game prototype designed to provide practice opportunities for learning fundamental principles of arterial blood gases. Mini games generally take less than an hour to play and focus on specific subject matter. An interdisciplinary team of faculty from two universities mentored student game developers to design a digital educational mini game prototype. Sixteen accelerated bachelor of science in nursing students collaborated with game development students and playtested the game prototype during the last semester of their senior year in nursing school. Playtesting is a form of feedback that supports an iterative design process that is critical to game development. A 10-question survey was coupled with group discussions addressing five broad themes of an archetypical digital educational mini game to yield feedback on game design, play, and content. Four rounds of playtesting and incorporating feedback supported the iterative process. Accelerated bachelor of science in nursing student playtester feedback suggests that the digital educational mini game prototype has potential for offering an engaging, playful game experience that will support securing the fundamental principles of arterial blood gases. Next steps are to test the digital educational mini game for teaching and learning effectiveness., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The systematic relationships of taxa traditionally referred to as 'basal ornithopods' or 'hypsilophodontids' remain poorly resolved since it was discovered that these taxa are not a monophyletic group, but rather a paraphyletic set of neornithischian taxa. Thus, even as the known diversity of these taxa has dramatically increased over the past two decades, our knowledge of their placement relative to each other and the major ornithischian subclades remained incomplete. This study employs the largest phylogenetic dataset yet compiled to assess basal ornithischian relationships (255 characters for 65 species level terminal taxa). The resulting strict consensus tree is the most well-resolved, stratigraphically consistent hypothesis of basal ornithischian relationships yet hypothesized. The only non-iguanodontian ornithopod (=basal ornithopod) recovered in this analysis is Hypsilophodon foxii. The majority of former 'hypsilophodontid' taxa are recovered within a single clade (Parksosauridae) that is situated as the sister-taxon to Cerapoda. The Parksosauridae is divided between two subclades, the Orodrominae and the Thescelosaurinae. This study does not recover a clade consisting of the Asian taxa Changchunsaurus, Haya, and Jeholosaurus (=Jeholosauridae). Rather, the former two taxa are recovered as basal members of Thescelosaurinae, while the latter taxon is recovered in a clade with Yueosaurus near the base of Neornithischia.The endemic South American clade Elasmaria is recovered within the Thescelosaurinae as the sister taxon to Thescelosaurus. This study supports the origination of Dinosauria and the early diversification of Ornithischia within Gondwana. Neornithischia first arose in Africa by the Early Jurassic before dispersing to Asia before the late Middle Jurassic, where much of the diversification among non-cerapodan neornithischians occurred. Under the simplest scenario the Parksosauridae originated in North America, with at least two later dispersals to Asia and one to South America. However, when ghost lineages are considered, an alternate dispersal hypothesis has thescelosaurines dispersing from Asia into South America (via North America) during the Early Cretaceous, then back into North America in the latest Cretaceous. The latter hypothesis may explain the dominance of orodromine taxa prior to the Maastrichtian in North America and the sudden appearance and wide distribution of thescelosaurines in North America beginning in the early Maastrichtian. While the diversity of parksosaurids has greatly increased over the last fifteen years, a ghost lineage of over 40 myr is present between the base of Parksosauridae and Cerapoda, indicating that much of the early history and diversity of this clade is yet to be discovered. This new phylogenetic hypothesis provides a comprehensive framework for testing further hypotheses regarding evolutionary patterns and processes within Ornithischia.

Knowledge regarding the early evolution within the dinosaurian clade Ankylopollexia drastically increased over the past two decades, in part because of an increase in described taxa from the Early Cretaceous of North America. These advances motivated the recent completion of extensive preparation and conservation work on the holotype and only known specimen of Dakotadon lakotaensis, a basal ankylopollexian from the Lakota Formation of South Dakota. That specimen (SDSM 8656) preserves a partial skull, lower jaws, a single dorsal vertebra, and two caudal vertebrae. That new preparation work exposed several bones not included in the original description and revealed that other bones were previously misidentified. The presence of extensive deformation in areas of the skull is also noted that influenced inaccuracies in prior descriptions and reconstructions of this taxon. In addition to providing an extensive re-description of D. lakotaensis, this study reviews previously proposed diagnoses for this taxon, identifies two autapomorphies, and provides an extensive differential diagnosis. Dakotadon lakotaensis is distinct from the only other ankylopollexian taxon known from the Lakota Formation, Osmakasaurus depressus, in the presence of two prominent, anteroposteriorly oriented ridges on the ventral surfaces of the caudal vertebrae, the only overlapping material preserved between these taxa. The systematic relationships of D. lakotaensis are evaluated using both the parsimony and posterior probability optimality criteria, with both sets of analyses recovering D. lakotaensis as a non-hadrosauriform ankylopollexian that is more closely related to taxa from the Early Cretaceous (e.g., Iguanacolossus, Hippodraco, and Theiophytalia) than to more basally situated taxa from the Jurassic (e.g., Camptosaurus, Uteodon). This taxonomic work is supplemented by field work that relocated the type locality, confirming its provenance from unit L2 (lower Fuson Member equivalent) of the Lakota Formation. Those data, combined with recently revised ages for the members of the Lakota Formation based on charophyte and ostracod biostratigraphy, constrain the age of this taxon to the late Valanginian to early Barremian.

Approaches quantifying the relative congruence, or incongruence, of molecular divergence estimates and the fossil record have been limited. Previously proposed methods are largely node specific, assessing incongruence at particular nodes for which both fossil data and molecular divergence estimates are available. These existing metrics, and other methods that quantify incongruence across topologies including entirely extinct clades, have so far not taken into account uncertainty surrounding both the divergence estimates and the ages of fossils. They have also treated molecular divergence estimates younger than previously assessed fossil minimum estimates of clade age as if they were the same as cases in which they were older. However, these cases are not the same. Recovered divergence dates younger than compared oldest known occurrences require prior hypotheses regarding the phylogenetic position of the compared fossil record and standard assumptions about the relative timing of morphological and molecular change to be incorrect. Older molecular dates, by contrast, are consistent with an incomplete fossil record and do not require prior assessments of the fossil record to be unreliable in some way. Here, we compare previous approaches and introduce two new descriptive metrics. Both metrics explicitly incorporate information on uncertainty by utilizing the 95% confidence intervals on estimated divergence dates and data on stratigraphic uncertainty concerning the age of the compared fossils. Metric scores are maximized when these ranges are overlapping. MDI (minimum divergence incongruence) discriminates between situations where molecular estimates are younger or older than known fossils reporting both absolute fit values and a number score for incompatible nodes. DIG range (divergence implied gap range) allows quantification of the minimum increase in implied missing fossil record induced by enforcing a given set of molecular-based estimates. These metrics are used together to describe the relationship between time trees and a set of fossil data, which we recommend be phylogenetically vetted and referred on the basis of apomorphy. Differences from previously proposed metrics and the utility of MDI and DIG range are illustrated in three empirical case studies from angiosperms, ostracods, and birds. These case studies also illustrate the ways in which MDI and DIG range may be used to assess time trees resultant from analyses varying in calibration regime, divergence dating approach or molecular sequence data analyzed., (© The Author(s) 2014. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Though the dinosaur Thescelosaurus neglectus was first described in 1913 and is known from the relatively fossiliferous Lance and Hell Creek formations in the Western Interior Basin of North America, the cranial anatomy of this species remains poorly understood. The only cranial material confidently referred to this species are three fragmentary bones preserved with the paratype, hindering attempts to understand the systematic relationships of this taxon within Neornithischia. Here the cranial anatomy of T. neglectus is fully described for the first time based on two specimens that include well-preserved cranial material (NCSM 15728 and TLAM.BA.2014.027.0001). Visual inspection of exposed cranial elements of these specimens is supplemented by detailed CT data from NCSM 15728 that enabled the examination of otherwise unexposed surfaces, facilitating a complete description of the cranial anatomy of this species. The skull of T. neglectus displays a unique combination of plesiomorphic and apomorphic traits. The premaxillary and 'cheek' tooth morphologies are relatively derived, though less so than the condition seen in basal iguanodontians, suggesting that the high tooth count present in the premaxillae, maxillae, and dentaries may be related to the extreme elongation of the skull of this species rather than a retention of the plesiomorphic condition. The morphology of the braincase most closely resembles the iguanodontians Dryosaurus and Dysalotosaurus, especially with regard to the morphology of the prootic. One autapomorphic feature is recognized for the first time, along with several additional cranial features that differentiate this species from the closely related and contemporaneous Thescelosaurus assiniboiensis. Published phylogenetic hypotheses of neornithischian dinosaur relationships often differ in the placement of the North American taxon Parksosaurus, with some recovering a close relationship with Thescelosaurus and others with the South American taxon Gasparinisaura, but never both at the same time. The new morphological observations presented herein, combined with re-examination of the holotype of Parksosaurus, suggest that Parksosaurus shares a closer relationship with Thescelosaurus than with Gasparinisaura, and that many of the features previously cited to support a relationship with the latter taxon are either also present in Thescelosaurus, are artifacts of preservation, or are the result of incomplete preparation and inaccurate interpretation of specimens. Additionally, the overall morphology of the skull and lower jaws of both Thescelosaurus and Parksosaurus also closely resemble the Asian taxa Changchunsaurus and Haya, though the interrelationships of these taxa have yet to be tested in a phylogenetic analysis that includes these new morphological data for T. neglectus.

This review describes the properties and regulation of the membrane transport proteins which supply the mammary gland with aminonitrogen to support metabolism under different physiological conditions (i.e. pregnancy, lactation and involution). Early studies focussed on characterising amino acid and peptide transport pathways with respect to substrate specificity, kinetics and hormonal regulation to allow a broad picture of the systems within the gland to be established. Recent investigations have concentrated on identifying the individual transporters at the molecular level (i.e. mRNA and protein). Many of the latter studies have identified the molecular correlates of the transport systems uncovered in the earlier functional investigations but in turn have also highlighted the need for more amino acid transport studies to be performed. The transporters function as either cotransporters and exchangers (or both) and act in a coordinated and regulated fashion to support the metabolic needs of the gland. However, it is apparent that a physiological role for a number of the transport proteins has yet to be elucidated. This article highlights the many gaps in our knowledge regarding the precise cellular location of a number of amino acid transporters within the gland. We also describe the role of amino acid transport in mammary cell volume regulation. Finally, the important role that individual mammary transport proteins may have in the growth and proliferation of mammary tumours is discussed.

The primary purpose of this qualitative study was to explore the knowledge, attitudes, and behaviors of low-income women considered high priority for receiving the novel influenza A (H1N1) vaccine to improve communication in emergency preparedness and response. Researchers sought to identify the factors that affect this high priority population's ability to successfully comply with vaccination recommendations. By utilizing an existing communication framework through the special supplemental nutrition program for women, infants, and children (WIC) they were able to document the systems and infrastructure needed to foster constructive responses in a sustainable manner in the future. Six focus group discussions with WIC clients (n = 56) and 10 individual interviews with staff members were conducted at two WIC clinics in Georgia (1 urban and 1 rural). Data were collected after the 2009-2010 influenza season and analyzed using thematic analysis. Knowledge and attitudes regarding H1N1 differed among participants with regard to perceived severity and perceived risk of influenza illness. Participants identified several barriers and motivators to receiving the vaccination, as well as information needs, sources, and information-seeking behaviors. Similarities emerged among both WIC clients and staff members regarding impressions of H1N1 and the vaccine's use, suggesting that while the information may be provided, it is not effectively understood or accepted. Comprehensive education, policy and planning development regarding pandemic influenza and vaccine acceptance among low-income women is necessary, including improvements in risk communication messages and identifying effective methods to disseminate trusted information to these high priority groups.

Background: Long-term adhesion-related complications and incisional hernias after abdominal surgery are common and costly. There are few data on the risk of these complications after different abdominal operations., Study Design: We identified Medicare beneficiaries who underwent endovascular repair of an abdominal aortic aneurysm from 2001-2008 who presumably are not at risk for laparotomy-related complications. We identified all laparoscopic and open operations involving the abdomen, pelvis, or retroperitoneum and categorized them into 5 groups according to invasiveness. We then identified laparotomy-related complications for up to 5 years after the index operation and compared these with the baseline rate of complications in a control group of patients who did not undergo an abdominal operation., Results: We studied 85,663 patients, 7,513 (8.8%) of which underwent a laparotomy, including 2,783 major abdominal operations, 709 minor abdominal operations, 963 ventral hernia repairs, 493 retroperitoneal/pelvic operations, and 2,565 laparoscopic operations. Mean age was 76.7 years and 82.0% were male. Major abdominal operations carried the highest risk for adhesion-related complications (14.3% and 25.0% at 2 and 5 years compared with 4.0% and 7.8% for the control group; p < 0.001) and incisional hernias (7.8% and 12.0% compared with 0.6% and 1.2% for the control group; p < 0.001). Laparoscopic operations (4.6% and 10.7% for adhesions, 1.9% and 3.2% for incisional hernias) carried the lowest risk., Conclusions: Late-onset laparotomy-related complications are frequent and their risk extends through 5 years beyond the perioperative period. With the advancement and expansion of laparoscopic techniques and its attendant lower risk for long-term complications, these results can alter the risk-to-benefit profile of various types of abdominal operations and can also strengthen the rationale for additional development of laparoscopic approaches to abdominal operations., (Copyright © 2013 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

The placenta must act as a surrogate lung, gastrointestinal tract and kidney for the fetus as well as acting as an endocrine gland necessary for the maintenance of a successful pregnancy: to achieve this, to what extent does the trophoblast necessarily share a similar epithelial phenotype? Here I review from a historical and a contemporary perspective some relevant studies with an emphasis on the similarities and differences between small intestinal and trophoblast biology. Certain physiological, structural and cell biological similarities are striking., (Copyright © 2012. Published by Elsevier Ltd.)

Objective: To determine the frequency and predictors of cardiac stress testing before elective noncardiac surgery in Medicare patients with no indications for cardiovascular evaluation., Background: The American College of Cardiology/American Heart Association guidelines indicate that patients without class I (American Heart Association high risk) or class II cardiac conditions (clinical risk factors) should not undergo cardiac stress testing before elective noncardiac, nonvascular surgery., Methods: We used 5% Medicare inpatient claims data (1996-2008) to identify patients aged ≥ 66 years who underwent elective general surgical, urological, or orthopedic procedures (N = 211,202). We examined the use of preoperative stress testing in the subset of patients with no diagnoses consistent with cardiac disease (N = 74,785). Bivariate and multivariate analyses were used to identify predictors of preoperative cardiac stress testing., Results: Of the patients with no cardiac indications for preoperative stress testing, 3.75% (N = 2803) received stress testing in the 2 months before surgery. The rate of preoperative stress testing increased from 1.72% in 1996 to 6.44% in 2007 (P < 0.0001). A multivariate analysis adjusting for patient and hospital characteristics showed a significant increase in preoperative stress testing over time. Female sex [odds ratio (OR) 1.11; 95% CI: 1.02-1.21], presence of other comorbidities [OR 1.22; 95% confidence interval (CI): 1.09-1.35], high-risk procedure (OR 2.42; 95% CI: 2.04-2.89), and larger hospital size (OR 1.17; 95% CI: 1.03-1.32) were positive predictors of stress testing. Patients living in regions with greater Medicare expenditures (OR 1.24; 95% CI: 1.05-1.45) were also more likely to receive stress tests., Conclusions: In a 5% sample of Medicare claims data, 2803 patients underwent preoperative stress testing without any indications. When these results were applied to the entire Medicare population, we estimated that there are over 56,000 patients who underwent unnecessary preoperative stress testing. The rate of testing in patients without cardiac indications has increased significantly over time.

Crocodyliforms serve as important taphonomic agents, accumulating and modifying vertebrate remains. Previous discussions of Mesozoic crocodyliform feeding in terrestrial and riverine ecosystems have often focused on larger taxa and their interactions with equally large dinosaurian prey. However, recent evidence suggests that the impact of smaller crocodyliforms on their environments should not be discounted. Here we present direct evidence of feeding by a small crocodyliform on juvenile specimens of a 'hypsilophodontid' dinosaur from the Upper Cretaceous (Campanian) Kaiparowits Formation of southern Utah. Diagnostic crocodyliform bite marks present on a left scapula and a right femur, as well as a partial probable crocodyliform tooth crown (ovoid in cross-section) preserved within a puncture on the right femur, comprise the bulk of the feeding evidence. Computed tomography scans of the femoral puncture reveal impact damage to the surrounding bone and that the distal tip of the embedded tooth was missing prior to the biting event. This is only the second reported incidence of a fossil crocodyliform tooth being found embedded directly into prey bone. These bite marks provide insight into the trophic interactions of the ecosystem preserved in the Kaiparowits Formation. The high diversity of crocodyliforms within this formation may have led to accentuated niche partitioning, which seems to have included juvenile dinosaurian prey.

Background: Venous thromboembolic events after saphenous vein ablation procedures for varicose veins have been reported. Current knowledge of these events is based on single-institution studies or studies with small numbers of patients., Methods: The National Surgical Quality Improvement Program (NSQIP) database (2005-2009) was used to identify 3874 patients who underwent radiofrequency ablation (RFA) or endovenous laser ablation (EVLA) of the saphenous veins with or without stab phlebectomy. Outcome variables included documented postoperative deep vein thrombosis (DVT) or pulmonary embolism (PE). Bivariate and multivariate logistic regression analyses were performed to identify factors associated with venous thromboembolic events after ablation procedures., Results: Procedures for lower extremity varicose veins included RFA in 2897 patients (74.8%) and EVLA in 977 (25.2%). Patients who underwent RFA were more likely to be older, obese, diabetic, hypertensive, and to have undergone procedures involving more than one vein (24% vs 4%; P < .0001). Patients who underwent EVLA were more likely to have received general anesthesia (56.9% vs 40.8%; P < .0001) and to have undergone concomitant stab phlebectomy (44.9% vs 31.7%; P < .0001). The incidences of DVT (1.74% vs 1.52%; P = .63) and pulmonary embolus (0.07% vs 0%; P >.99) were similar between EVLA and RFA. No significant predictors of DVT in the postoperative period were identified on bivariate or multivariate analyses. In the subgroup of 2514 patients who underwent ablation procedures without stab phlebectomy, those undergoing EVLA showed a trend toward a higher incidence of DVT (2.6% vs 1.4%; P = .057). After adjusting for patient demographics, DVT was 2.4 times more likely to develop in patients presenting with lower extremity ulcers than in those without ulcers (odds ratio, 2.4; 95% confidence interval, 1.01-6.11; P = .04). Although not statistically significant, the multivariate model found that when only ablation procedures were performed, EVLA was associated with an 83% increase in odds of DVT compared with RFA (odds ratio, 1.83; 95% confidence interval, 0.95-3.52; P = .06)., Conclusions: The incidence of venous thromboembolic events after saphenous ablation is low. However, given that patients with lower extremity ulcers experienced an increased risk of DVT, care should be taken to ensure that the ablation catheter is positioned an appropriate distance from the saphenofemoral or sapheno-popliteal junction and that periprocedural preventative measures, such as anticoagulation prophylaxis, early ambulation, and lower extremity compression, are emphasized. The finding of a trend toward increased venous thromboembolic events in patients undergoing EVLA warrants further investigation in a large patient population., (Published by Elsevier Inc.)

Background: Depression has been associated with delayed presentation, inadequate treatment, and poor survival in patients with cancer., Methods: Using Surveillance, Epidemiology and End Results and Medicare linked data (1992-2005), we identified patients with pancreatic adenocarcinoma (N = 23,745). International classification of diseases, 9th edition, clinical modification codes were used to evaluate depression during the 3 to 27 months before the diagnosis of cancer. The effect of depression on receipt of therapy and survival was evaluated in univariate and multivariate models., Results: Of patients with pancreatic cancer in our study, 7.9% had a diagnosis of depression (N = 1,868). Depression was associated with increased age, female sex, white race, single or widowed status, and advanced stage disease (P < .0001). In an adjusted model, patients with locoregional disease and depression had 37% lower odds of undergoing surgical resection (odds ratio, 0.63; 95% confidence interval, 0.52-0.76). In patients with locoregional disease, depression was associated with lower 2-year survival (hazard ratio, 1.20; 95% confidence interval, 1.09-1.32). After adjusting for surgical resection, this association was attenuated (hazard ratio, 1.14; 95% confidence interval, 1.04-1.26). In patients who underwent surgical resection, depression was a significant predictor of survival (hazard ratio, 1.34; 95% confidence interval, 1.04-1.73). Patients with distant disease and depression had 21% lower odds of receiving chemotherapy (odds ratio, 0.79; 95% confidence interval, 0.70-0.90). After adjusting for chemotherapy for distant disease, depression was no longer a significant predictor of survival (hazard ratio, 1.03; 95% confidence interval, 0.97-1.09)., Conclusion: The decreased survival associated with depression appears to be mediated by a lower likelihood of appropriate treatment in depressed patients. Accurate recognition and treatment of pancreatic cancer patients with depression may improve treatment rates and survival., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Background: Controversy exists regarding the use of concurrent cholecystectomy during Roux-en-Y gastric bypass performed for morbid obesity., Methods: A decision model was developed to evaluate the cost-effectiveness of current strategies: routine concurrent cholecystectomy, Roux-en-Y gastric bypass alone with or without postoperative ursodiol therapy, and selective cholecystectomy based on preoperative findings on ultrasonography. Probabilities were obtained from a comprehensive literature review. Costs and hospital days were obtained from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample. One-way sensitivity analyses were performed., Results: The least expensive strategy was to perform RYGB alone without preoperative ultrasonography, with an average cost (over RYGB costs) of $537 per patient. RYGB with concurrent cholecystectomy had a cost of $631. Selective cholecystectomy based on preoperative ultrasonography was dominated by the other 2 strategies. Our model was most sensitive to the probability of developing gallbladder-related symptoms after RYGB alone. When the incidence of gallbladder-related symptoms was <4.6%, the dominant strategy was to perform a RYGB alone without preoperative ultrasonography. For values >6.9%, performing concurrent cholecystectomy at the time of the RYGB was superior to other strategies. When ursodiol was used, the least expensive strategy was to perform a concurrent cholecystectomy during RYGB., Conclusion: The main factor determining the most cost-effective strategy is the incidence of gallbladder-related symptoms after RYGB. The use of ursodiol was associated with an increase in cost that does not justify its use after RYGB. Finally, selective cholecystectomy based on preoperative ultrasonography was dominated by the other strategies in the scenarios evaluated., (Published by Mosby, Inc.)

Background: Little is known about resource utilization (number of days in the hospital or medical care) between diagnosis and death in patients with pancreatic cancer., Methods: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data, we identified 25,476 patients with pancreatic cancer (1992-2005). Hospital and medical care days per person-month from the time of diagnosis were described, stratified by stage, treatment, and survival duration., Results: Hospital/medical care days vary by length of survival and treatment strategy in patients with pancreatic cancer. For all stages, patients were in the hospital a mean of 6.4 days and received medical care a total of 9.0 days in the first month after diagnosis, decreasing to 1.7 and 3.7 days per month, respectively, by the end of the first year. Hospital/medical care days per month of life were higher in patients with shorter survival but increased sharply at the end of life in all patients, regardless of duration of survival. In patients with locoregional disease, resection was associated with a higher number of hospital/medical care days during the first 4 months after diagnosis, but fewer at the end of the first year. For distant disease, hospital days were similar but days in medical care were higher for patients receiving chemotherapy, increasing especially at the end of life., Conclusions: This study is the first to quantify hospital/medical care days in patients with pancreatic cancer by stage, treatment, and survival. This information will provide realistic expectations and allow for treatment decisions based on patient preferences.

Background: Neoplasms of the pancreas during pregnancy are rare, with less than 25 cases of benign and malignant tumors reported in the literature., Methods: We present three unique cases of pancreatic tumors occurring during pregnancy--one mucinous cystic neoplasm and two adenocarcinomas. We review the literature regarding pancreatic neoplasms during pregnancy and discuss the diagnosis, complications, and management of these tumors., Results: Magnetic resonance imaging and ultrasound are the imaging modalities of choice in pregnancy. In patients with benign or premalignant tumors, surgical resection may be postponed until the second trimester. In symptomatic patients, or if there is a concern for intrauterine growth restriction, urgent surgical intervention should be performed. With malignant tumors, the benefit of delaying surgery must be balanced with the risk of maternal disease progression. Termination of the pregnancy should be discussed when a malignant tumor is diagnosed during the first trimester. Pancreatic tumors diagnosed during the third trimester may be resected after delivery. If malignant, early delivery of the fetus and subsequent maternal operation can be considered at appropriate fetal maturity., Conclusion: When these tumors occur during pregnancy, they present a diagnostic and treatment dilemma, with variation in treatment based on gestational age and patient preference.

Background: Adenosquamous carcinoma of the pancreas is rare. Our understanding of the disease and its prognosis comes mainly from small retrospective studies., Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database (1988 to 2007), we identified patients with adenosquamous carcinoma (n = 415) or adenocarcinoma (n = 45,693) of the pancreas. The demographics, tumor characteristics, resection status, and survival were compared between the groups., Results: Compared with patients with adenocarcinoma, patients with adenosquamous carcinoma were more likely to have disease located in the pancreatic body and tail (44.6% versus 53.5%, P < 0.0001). While the stage distribution was similar between the two groups, adenosquamous carcinomas were more likely to be poorly differentiated (71% versus 45%, P < 0.0001), node positive (53% versus 47%, P < 0.0001), and larger (5.7 versus 4.3 cm, P < 0.0001). For locoregional disease, resection increased over time from 26% in 1988 to 56% in 2007. The overall 2-y survival was 11% in both groups. Following resection, patients with adenosquamous carcinoma had worse 2-y survival (29% versus 36%, P < 0.0001). Resection was the strongest independent predictor of survival for patients with locoregional pancreatic adenosquamous carcinoma (HR 2.35, 95% CI = 1.47-3.76)., Conclusions: This is the first population-based study to evaluate outcomes in adenosquamous carcinoma of the pancreas. Compared with pancreatic adenocarcinoma, adenosquamous carcinoma was more likely to occur in the pancreatic tail, be poorly differentiated, larger, and node positive. The long-term survival following surgical resection is significantly worse for adenosquamous cancers; however, patients with adenosquamous carcinoma can still benefit from surgical resection, which is the strongest predictor of survival., (Copyright © 2012 Elsevier Inc. All rights reserved.)

This study aimed to test an interactive model of perceived parental expectations and the meaning of those expectations in relation to bulimic symptoms in Black (n=97) and White (n=179) college women. Black young women reported higher parental expectations and attached more positive meanings to high parental expectations, in comparison to their White peers. There was an interactive effect for Black young women such that, in the context of perceived high parental expectations, interpreting high parental expectations as negative was associated with higher levels of bulimic symptoms whereas interpreting high expectations as positive was associated with lower levels of bulimic symptoms. However, no interactive effect emerged for White young women. The role of differences in cultural contexts is discussed., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: The authors' goal was to characterize hospice enrollment and aggressiveness of care for pancreatic cancer patients at the end of life., Methods: Surveillance, Epidemiology, and End Results and linked Medicare claims data (1992-2006) were used to identify patients with pancreatic cancer who had died (n = 22,818). The authors evaluated hospice use, hospice enrollment ≥ 4 weeks before death, and aggressiveness of care as measured by receipt of chemotherapy, acute care hospitalization, and intensive care unit (ICU) admission in the last month of life., Results: Overall, 56.9% of patients enrolled in hospice, and 35.9% of hospice users enrolled for 4 weeks or more. Hospice use increased from 36.2% in 1992-1994 to 67.2% in 2004-2006 (P < .0001). Admission to the ICU and receipt of chemotherapy in the last month of life increased from 15.5% to 19.6% (P < .0001) and from 8.1% to 16.4% (P < .0001), respectively. Among patients with locoregional disease, those who underwent resection were less likely to enroll in hospice before death and much less likely to enroll early. They were also more likely to receive chemotherapy (14% vs 9%, P < .0001), be admitted to an acute care hospital (61% vs 53%, P < .0001), and be admitted to an ICU (27% vs 15%, P < .0001) in the last month of life., Conclusions: Although hospice use increased over time, there was a simultaneous decrease in early enrollment and increase in aggressive care at the end of life for patients with pancreatic cancer., (Copyright © 2011 American Cancer Society.)

Background: When compared with ultrasound, CT scans are more expensive, have substantial radiation exposure and lower sensitivity, specificity, positive, and negative predictive values for patients with gallstone disease., Study Design: We reviewed data on patients emergently admitted with complicated gallstone disease between January 2005 and May 2010. Use of CT and ultrasound imaging on admission was described. Multivariate logistic regression was used to evaluate factors predicting receipt of CT., Results: Five hundred and sixty-two consecutive patients presented emergently with complicated gallstone disease. Mean age was 45 years. Seventy-two percent of patients were female, 46% were white, and 41% were Hispanic. Seventy-two percent of patients had an ultrasound during the initial evaluation and 41% had a CT. Both studies were performed in 25% of patients (n = 141), 16% (n = 93) had CT only, and 47% (n = 259) had ultrasound only. CT was performed first in 67% of those who underwent both studies. Evening imaging (7 PM-7 AM, odds ratio [OR] = 4.44; 95% CI, 2.88-6.85), increased age (OR = 1.14 per 5-year increase; 95% CI, 1.07-1.21), leukocytosis (OR = 1.67; 95% CI, 1.10-2.53), and hyperamylasemia (OR = 2.02; 95% CI, 1.16-3.51) predicted use of CT., Conclusions: Our study demonstrates the overuse of CT in evaluation of complicated gallstone disease. Evening imaging was the biggest predictor of CT use, suggesting that CT is performed not to clarify the diagnosis, but rather a surrogate for the indicated study. Surgeons and emergency physicians should be trained to perform right upper quadrant ultrasound to avoid unnecessary studies in the appropriate clinical setting., (Published by Elsevier Inc.)

Background: The recommended therapy for mild gallstone pancreatitis is cholecystectomy on initial hospitalization., Methods: Using a 5% national Medicare sample (1996-2005), we evaluated adherence to current recommendations for gallstone pancreatitis (cholecystectomy rates on initial hospitalization and the use of endoscopic retrograde cholangiopancreatography [ERCP]/sphincterotomy). We evaluated predictors of cholecystectomy, gallstone-related readmissions, and 2-year mortality., Results: Adherence to current guidelines was low. Only 57% of 8,452 Medicare beneficiaries presenting to an acute care hospital with a first episode of mild gallstone pancreatitis underwent cholecystectomy on initial hospitalization. Of the patients who did not undergo cholecystectomy, 55% were never evaluated by a surgeon. Likewise, only 28% of patients who did not undergo cholecystectomy had a sphincterotomy. The 2-year readmission rates were higher among patients who did not undergo cholecystectomy (44% vs 4%; P < .0001), and 33% of these patients required cholecystectomy after discharge. In the no cholecystectomy group, ERCP prevented readmissions (hazard ratio, 0.53; 95% confidence interval, 0.47-0.61) and when readmissions occurred they were less likely to be for gallstone pancreatitis in patients who had an ERCP (27.8% vs 53.2%; P < .0001). On multivariate analysis, patients who were older, black, admitted to a nonsurgical service, lived in certain US regions, and had specific comorbidities were less likely to undergo cholecystectomy., Conclusion: Adherence to current recommendations for the management of mild gallstone pancreatitis is low in older patients. Our data suggest that >40% of patients who did not undergo cholecystectomy would have benefited from early definitive therapy. Implementation of policies to increase adherence to guidelines would prevent gallstone-related morbidity and mortality in older patients., (Copyright © 2011 Mosby, Inc. All rights reserved.)

IDO is the rate-limiting enzyme in the kynurenine pathway, catabolizing tryptophan to kynurenine. Tryptophan depletion by IDO-expressing tumors is a common mechanism of immune evasion inducing regulatory T cells and inhibiting effector T cells. Because mammalian cells cannot synthesize tryptophan, it remains unclear how IDO(+) tumor cells overcome the detrimental effects of local tryptophan depletion. We demonstrate that IDO(+) tumor cells express a novel amino acid transporter, which accounts for ∼50% of the tryptophan uptake. The induced transporter is biochemically distinguished from the constitutively expressed tryptophan transporter System L by increased resistance to inhibitors of System L, resistance to inhibition by high concentrations of most amino acids tested, and high substrate specificity for tryptophan. Under conditions of low extracellular tryptophan, expression of this novel transporter significantly increases tryptophan entry into IDO(+) tumors relative to tryptophan uptake through the low-affinity System L alone, and further decreases tryptophan levels in the microenvironment. Targeting this additional tryptophan transporter could be a way of pharmacological inhibition of IDO-mediated tumor escape. These findings highlight the ability of IDO-expressing tumor cells to thrive in a tryptophan-depleted microenvironment by expressing a novel, highly tryptophan-specific transporter, which is resistant to inhibition by most other amino acids. The additional transporter allows tumor cells to strike the ideal balance between supply of tryptophan essential for their own proliferation and survival, and depleting the extracellular milieu of tryptophan to inhibit T cell proliferation.

The stratigraphic record of first appearances provides an independent source of data for evaluating and comparing phylogenetic hypotheses that include taxa with fossil histories. However, no standardized method exists for calculating these metrics for polytomous phylogenies, restricting their applicability. Previously proposed methods insufficiently deal with this problem because they skew or restrict the resulting scores. To resolve this issue, we propose a standardized method for treating polytomies when calculating these metrics: the Comprehensive Polytomy approach (ComPoly). This approach accurately describes how phylogenetic uncertainty, indicated by polytomies, affects stratigraphic consistency scores. We also present a new program suite (Assistance with Stratigraphic Consistency Calculations) that incorporates the ComPoly approach and simplifies the calculation of absolute temporal stratigraphic consistency metrics. This study also demonstrates that stratigraphic consistency scores calculated from strict consensus trees can be overly inclusive and those calculated from less-than-strict consensus trees inaccurately describe the phylogenetic signal present in the source most-parsimonious trees (MPTs). Therefore, stratigraphic consistency scores should be calculated directly from the source MPTs whenever possible to ensure their accuracy. Finally, we offer recommendations for standardizing comparisons between molecular divergence dates and the stratigraphic record of first appearances, a promising new application of these methods. © The Willi Hennig Society 2010., (© The Willi Hennig Society 2010.)

The phosphoinositide3-kinase (PI3K)/Akt and downstream mammalian target of rapamycin complex 1 (mTORC1) signalling cascades promote normal growth and are frequently hyperactivated in tumour cells. mTORC1 is also regulated by local nutrients, particularly amino acids, but the mechanisms involved are poorly understood. Unexpectedly, members of the proton-assisted amino-acid transporter (PAT or SLC36) family emerged from in vivo genetic screens in Drosophila as transporters with uniquely potent effects on mTORC1-mediated growth. In this study, we show the two human PATs that are widely expressed in normal tissues and cancer cell lines, namely PAT1 and PAT4, behave similarly to fly PATs when expressed in Drosophila. Small interfering RNA knockdown shows that these molecules are required for the activation of mTORC1 targets and for proliferation in human MCF-7 breast cancer and HEK-293 embryonic kidney cell lines. Furthermore, activation of mTORC1 in starved HEK-293 cells stimulated by amino acids requires PAT1 and PAT4, and is elevated in PAT1-overexpressing cells. Importantly, in HEK-293 cells, PAT1 is highly concentrated in intracellular compartments, including endosomes, wherein mTOR shuttles upon amino-acid stimulation. Therefore our data are consistent with a model in which PATs modulate the activity of mTORC1 not by transporting amino acids into the cell but by modulating the intracellular response to amino acids.

The effect of 5-aminoimidazole-4-carboxamide-ribonucleoside (AICAR) activation of the AMP-activated protein kinase (AMPK) on the transport of the model radiolabeled dipeptide [(3)H]-D-Phe-L-Gln was investigated in the human epithelial colon cancer cell line Caco-2. Uptake and transepithelial fluxes of [(3)H]-D-Phe-L-Gln were carried out in differentiated Caco-2 cell monolayers, and hPepT1 and glucose transporter 2 (GLUT2) protein levels were quantified by immunogold electron microscopy. AICAR treatment of Caco-2 cells significantly inhibited apical [(3)H]-D-Phe-L-Gln uptake, matched by a decrease in brush-border membrane hPepT1 protein but with a concomitant increase in the facilitated glucose transporter GLUT2. A restructuring of the apical brush-border membrane was seen by electron microscopy. The hPepT1-mediated transepithelial (A-to-B) peptide flux across the Caco-2 monolayers showed no significant alteration in AICAR-treated cells. The electrical resistance in the AICAR-treated monolayers was significantly higher compared with control cells. Inhibition of the sodium/hydrogen exchanger 3 (NHE3) had an additive effect to AICAR, suggesting that the AMPK effect is not via NHE3. Fluorescence measurement of intracellular pH showed no reduction in the proton gradient driving PepT1-mediated apical uptake. The reduction in apical hPepT1 protein and dipeptide uptake after AICAR treatment in Caco-2 cells demonstrates a regulatory effect of AMPK on hPepT1, along with an influence on both the microvilli and tight junction structures. The absence of an associated reduction in transepithelial peptide movement implies an additional stimulatory effect of AICAR on the basolateral peptide transport system in these cells. These results provide a link between the hPepT1 transporter and the metabolic state of this model enterocyte.

Generating challenging and meaningful academic assignments for nursing students in which the student manages the technology used to deliver information is needed for accelerated second-degree nursing students. Developing those assignments is critical for keeping accelerated second-degree students engaged in the learning process. They are highly motivated, self-directed learners who have been found to have a preference for teaching-learning experiences that incorporate the use of technology. This paper describes the development of a mock webpage assignment to meet the learning needs of accelerated second-degree nursing students.

New clinical and employment information, together with over-looked previously published information, on a patient (H.C.) is reviewed. H.C., who died at the age of 76 in 1939, was found, by chance during anatomical dissection, to lack a cerebellum. This synthesis challenges an unusual and interesting account of cerebellar agenesis published in Brain in 1994 by Glickstein (see also Glickstein, 2006), in which the allegedly 'bogus' oral history of this individual's motor skills was held to have led to 'medical myth making'. Part of the burden of the 1994 paper was to show that 'cerebellar agenesis is always associated with profound motor deficits'. Glickstein therefore focussed on an apparent 'exception' to this conclusion, concerning the brain of a single case, H.C., who died 70 years ago, who 'had given rise to an oral tradition alleging that normal movement is possible despite total cerebellar agenesis'. Glickstein (1994) concludes 'despite an oral tradition to the contrary there is absolutely no evidence about the motor capacities of this man during his life'. Rather remarkably, an extensive history of this individual has become available, its significance becoming noted only this year; this complements and adds to a previous brief history published on H.C. (and not mentioned in the 1994 paper; see below). The new evidence includes the death certificate stating the man's occupation to have been 'manual labourer' with all the implications relevant to his supposed incapacity. The written historical record thus confronts the alleged 'myth'. It is interesting to note how medical records on an undoubtedly very ordinary citizen were recorded in London in the 1930s (before the NHS was set up in 1949) and how they could be made accessible to clinical colleagues in east London in the middle of World War II blitz bombing of the capital.

The nature of Cambridge (UK) placental and fetal research in the middle third of the twentieth century is reviewed on the basis of published literature and personal recollection. Joseph Barcroft is a central figure who came to fetal research late in an extremely productive career which is briefly sketched. Contemporaneous Cambridge academics in the field included J.D. Boyd (the authors father), J. Hammond, F.H.A. Marshall, R.A. McCance, J. Needham, A.S. Parkes and Elsie Widdowson. The then current Cambridge academic geography is explained and features of its scientific life such as funding, institutional structure and ethos, teaching and clinical duties, domestic and gender roles, and political context, including war and empire, are briefly considered. The testing of research findings against general principles and use of quantitative thinking are identified as important features. Intergenerational connections, often within individual families, are identified as a striking feature. The long-term impact of Cambridge work of this period; locally, in current trophoblast and feto-placental genetic research, in Oxford in probably influencing G.S. Dawes research leadership, and internationally, especially through D.H. Barron, and through him to the Denver School, is considered. That human placental and embryological specimens collected by J.D. Boyd have received a new lease of life as the "Boyd Collection", including use by Allen Enders is noted. Mechanisms for the maintenance of scientific quality and productivity during the period, mainly through the scientist himself relying on an internalised sense of "obligation", are contrasted with those current in the UK and more widely; formal peer-review at frequent intervals, with subsequent allocation of short-term funding. The strengths and weaknesses of each are considered.

Bisphosphoglycerate mutase (BPGM) catalyses the formation of 2,3 bisphosphoglycerate (BPG) a ligand of haemoglobin. BPG facilitates liberation of oxygen from haemoglobin at low oxygen tension enabling efficient delivery of oxygen to tissues. We describe expression of BPGM in mouse labyrinthine trophoblasts, located at the maternal-placental interface. Expression is lower in placentae of igf2(+/-) knockout mice, a widely used model of growth restriction, compared to wild type placentae. Circulating maternal BPG increased throughout gestation but this increase was less in wt mothers carrying igf2(+/-) pups than in those carrying exclusively wt pups. This reduction was observed well before term and may contribute to the low birth weight of igf2(+/-) pups. Strikingly, we also measured reductions of fetal and placental weight in wt littermates of igf2(+/-) pups compared to pups developing in an exclusively wt environment. These data suggest that placental expression of BPGM can influence maternal BPG concentrations and supports a hypothesis under which BPG synthesized in the placenta may act on maternal haemoglobin to enhance delivery of oxygen to the developing fetus.

Mammalian CD98 heterodimeric amino acid transporters consist of a promiscuous single-pass transmembrane glycoprotein, CD98hc (CD98 heavy chain), and one of six multipass transmembrane proteins or 'light chains'. The heterodimeric complexes of CD98hc and the light chains LAT1 (L-type amino acid transporter 1) or LAT2 specifically promote sodium-independent System L exchange of neutral amino acids, including leucine. CD98hc is also implicated in other processes, including cell fusion, cell adhesion and activation of TOR (target of rapamycin) signalling. Surprisingly, recent reports suggested that insects lack a membrane-bound CD98hc, but in the present study we show that Drosophila CG2791 encodes a functional CD98hc orthologue with conservation in intracellular, transmembrane and extracellular domains. We demonstrate by RNA-interference knockdown in Drosophila Schneider cells that CG2791 and two Drosophila homologues of the mammalian CD98 light chains, Mnd (Minidiscs) and JhI-21, are required for normal levels of System L transport. Furthermore, we show that System L activity is increased by methoprene, an analogue of the developmentally regulated endocrine hormone juvenile hormone, an effect that is potentially mediated by elevated Mnd expression. Co-expression of CG2791 and JhI-21, but not CG2791 and Mnd, in Xenopus oocytes mediates System L transport. Finally, mapping of conserved sequences on to the recently determined crystal structure of the human CD98hc extracellular domain highlights two conserved exposed hydrophobic patches at either end of the domain that are potential protein-protein-interaction surfaces. Therefore our results not only show that there is functional conservation of CD98hc System L transporters in flies, but also provide new insights into the structure, functions and regulation of heterodimeric amino acid transporters.

mTOR (mammalian target of rapamycin) is a highly conserved serine/threonine protein kinase that has roles in cell metabolism, cell growth and cell survival. Although it has been known for some years that mTOR acts as a hub for inputs from growth factors (in particular insulin and insulin-like growth factors), nutrients and cellular stresses, some of the mechanisms involved are still poorly understood. Recent work has implicated mTOR in a variety of important human pathologies, including cancer, Type 2 diabetes and neurodegenerative disorders, heightening interest and accelerating progress in dissecting out the control and functions of mTOR.

mTOR (mammalian target of rapamycin) plays a key role in determining how growth factor, nutrient and oxygen levels modulate intracellular events critical for the viability and growth of the cell. This is reflected in the impact of aberrant mTOR signalling on a number of major human diseases and has helped to drive research to understand how TOR (target of rapamycin) is itself regulated. While it is clear that amino acids can affect TOR signalling, how these molecules are sensed by TOR remains controversial, perhaps because cells use different mechanisms as environmental conditions change. Even the question of whether they have an effect inside the cell or at its surface remains unresolved. The present review summarizes current ideas and suggests ways in which some of the models proposed might be unified to produce an amino acid detection system that can adapt to environmental change.

The IIS (insulin/IGF (insulin-like growth factor) signalling) cascade has an important role in regulating normal development and physiology, as evidenced by its effects in a host of major human diseases including cancer, Type 2 diabetes and neurodegeneration. Recently, it has become clear that multiple types of local nutrient-sensing mechanisms have an impact on cellular insulin-sensitivity through the downstream kinase TOR (target of rapamycin). In vivo analysis in flies has surprisingly highlighted PATs (proton-assisted amino acid transporters) as having a uniquely potent role in regulating IIS/TOR activity and growth, potentially via a novel signalling mechanism. Other molecules such as the heterodimeric amino acid transporter, CD98, which provides the principal route for cellular uptake of leucine, an amino acid implicated in regulating TOR, also appear to have important effects. As our understanding of how nutrient sensing has an impact on IIS/TOR increases, novel targets to modulate aberrant IIS in disease are likely to emerge, which could complement current strategies designed to block kinases in this pathway.