bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential response of skeletal muscles to mTORC1 signaling during atrophy and hypertrophy
Authors: Bentzinger C Florian , Lin Shuo , Romanino Klaas , Castets Perrine , Guridi Maitea , Summermatter Serge , Handschin Christoph , Tintignac Lionel A , Hall Michael N , Rüegg Markus A
Published: March 2013

Background

Skeletal muscle mass is determined by the balance between protein synthesis and degradation. Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of protein translation and has been implicated in the control of muscle mass. Inactivation of mTORC1 by skeletal muscle-specific deletion of its obligatory component raptor results in smaller muscles and a lethal dystrophy. Moreover, raptor-deficient muscles are less oxidative through changes in the expression PGC-1α, a critical determinant of mitochondrial biogenesis. These results suggest that activation of mTORC1 might be beneficial to skeletal muscle by providing resistance to muscle atrophy and increasing oxidative function. Here, we tested this hypothesis by deletion of the mTORC1 inhibitor tuberous sclerosis complex (TSC) in muscle fibers.

Method

Skeletal muscles of mice with an acute or a permanent deletion of raptor or TSC1 were examined using histological, biochemical and molecular biological methods. Response of the muscles to changes in mechanical load and nerve input was investigated by ablation of synergistic muscles or by denervation .

Results

Genetic deletion or knockdown of raptor, causing inactivation of mTORC1, was sufficient to prevent muscle growth and enhance muscle atrophy. Conversely, short-term activation of mTORC1 by knockdown of TSC induced muscle fiber hypertrophy and atrophy-resistance upon denervation, in both fast tibialis anterior (TA) and slow soleus muscles. Surprisingly, however, sustained activation of mTORC1 by genetic deletion of Tsc1 caused muscle atrophy in all but soleus muscles. In contrast, oxidative capacity was increased in all muscles examined. Consistently, TSC1-deficient soleus muscle was atrophy-resistant whereas TA underwent normal atrophy upon denervation. Moreover, upon overloading, plantaris muscle did not display enhanced hypertrophy compared to controls. Biochemical analysis indicated that the atrophy response of muscles was based on the suppressed phosphorylation of PKB/Akt via feedback inhibition by mTORC1 and subsequent increased expression of the E3 ubiquitin ligases MuRF1 and atrogin-1/MAFbx. In contrast, expression of both E3 ligases was not increased in soleus muscle suggesting the presence of compensatory mechanisms in this muscle.

Conclusions

Our study shows that the mTORC1- and the PKB/Akt-FoxO pathways are tightly interconnected and differentially regulated depending on the muscle type. These results indicate that long-term activation of the mTORC1 signaling axis is not a therapeutic option to promote muscle growth because of its strong feedback induction of the E3 ubiquitin ligases involved in protein degradation.
A standardized microarray assay for the independent gene expression markers in AML: EVI1 and BAALC
Authors: Brand Jaap , van Vliet Martin H , de Best Leonie , Valk Peter JM , Viëtor Henk E , Löwenberg Bob , van Beers Erik H
Published: March 2013

High levels of BAALC, ERG, EVI1 and MN1 expression have been associated with shorter overall survival in AML but standardized and clinically validated assays are lacking. We have therefore developed and optimized an assay for standardized detection of these prognostic genes for patients with intermediate cytogenetic risk AML. In a training set of 147 intermediate cytogenetic risk cases we performed cross validations at 5 percentile steps of expression level and observed a bimodal significance profile for BAALC expression level and unimodal significance profiles for ERG and MN1 levels with no statistically significant cutoff points near the median expression level of BAALC, ERG or MN1. Of the possible cutoff points for expression levels of BAALC, ERG and MN1, just the 30th and 75th percentile of BAALC expression level and the 30th percentile of MN1 expression level cutoff points showed clinical significance. Of these only the 30th percentile of BAALC expression level reproduced in an independent verification (extended training) data set of 242 cytogenetically normal AML cases and successfully validated in an external cohort of 215 intermediate cytogenetic risk AML cases. Finally, we show independent prognostic value for high EVI1 and low BAALC in multivariate analysis with other clinically relevant molecular AML markers. We have developed a highly standardized molecular assay for the independent gene expression markers EVI1 and BAALC.
Does aid induce brain drain? A panel data analysis
Authors: Ugarte Ontiveros Darwin , Verardi Vincenzo
Published: March 2013

Recent evidence suggests that aid induces migration. This result is nevertheless not very informative from a policy perspective since what counts in terms of welfare consequences is the composition of migration. In this paper we focus on education and study which of skilled or unskilled migration is more sensitive to aid. More specifically we investigate the possible channels through which aid might affect self-selection among international emigrants and find that aid induces positive selection by easing the movement of highly qualified workers. Interestingly, we find that technical cooperation and bilateral aid have a significant influence on skilled migration but do not seem to affect unskilled migration significantly. On the other hand, aid targeted to development enhancement affects both categories but seems to have a larger effect on the former.

JEL codes

F35, F22, C23
Computational pharmacokinetics at a crossroads
Authors: Bois Frédéric Y
Published: March 2013

This first special issue of In Silico Pharmacology focuses on computational pharmacokinetics since they are an important part of integrated applications in computational pharmacology. The important topics of model structure, model parameterization, improved organ description, and modeling of drug-drug interactions are covered. They are actually at the crossroads between several emerging disciplines which will shape the future of therapeutic treatments and public health.
Zebrafish as a model for the study of neutrophil biology
Authors: Henry Katherine M , Loynes Catherine A , Whyte Moira K B , Renshaw Stephen A
Published: March 2013

To understand inflammation and immunity, we need to understand the biology of the neutrophil. Whereas these cells can readily be extracted from peripheral blood, their short lifespan makes genetic manipulations impractical. Murine knockout models have been highly informative, and new imaging techniques are allowing neutrophils to be seen during inflammation in vivo for the first time. However, there is a place for a new model of neutrophil biology, which readily permits imaging of individual neutrophils during inflammation in vivo, combined with the ease of genetic and chemical manipulation. The zebrafish has long been the model of choice for the developmental biology community, and the availability of genomic resources and tools for gene manipulation makes this an attractive model. Zebrafish innate immunity shares many features with mammalian systems, including neutrophils with morphological, biochemical, and functional features, also shared with mammalian neutrophils. Transgenic zebrafish with neutrophils specifically labeled with fluorescent proteins have been generated, and this advance has led to the adoption of zebrafish, alongside existing models, by a number of groups around the world. The use of these models has underpinned a number of key advances in the field, including the identification of a tissue gradient of hydrogen peroxide for neutrophil recruitment following tissue injury and direct evidence for reverse migration as a regulatable mechanism of inflammation resolution. In this review, we discuss the importance of zebrafish models in neutrophil biology and describe how the understanding of neutrophil biology has been advanced by the use of these models.
cAMP Response Element-Binding Protein Interacts With and Stimulates the Proteasomal Degradation of the Nuclear Receptor Coactivator GRIP1
Authors: Hoang Tuyen , Fenne Ingvild S. , Madsen Andre , Bozickovic Olivera , Johannessen Mona , Bergsvåg Mari , Lien Ernst Asbjørn , Stallcup Michael R. , Sagen Jørn V. , Moens Ugo , Mellgren Gunnar
Published: March 2013

The glucocorticoid receptor interacting protein (GRIP1) belongs to the p160 steroid receptor coactivator family that plays essential roles in nuclear receptor-dependent transcriptional regulation. Previously, we reported that the cAMP-dependent protein kinase (PKA) induces ubiquitination leading to degradation of GRIP1. Here we show that the cAMP response element-binding protein (CREB) downregulates GRIP1 and is necessary for the PKA-stimulated degradation of GRIP1, which leads to changes in the expression of a subset of genes regulated by estrogen receptor-α in MCF-7 breast cancer cells. Our data of domain-mapping and ubiquitination analyses suggest that CREB promotes the proteasomal breakdown of ubiquitinated GRIP1 through 2 functionally independent protein domains containing amino acids 347 to 758 and 1121 to 1462. We provide evidence that CREB interacts directly with GRIP1 and that CREB Ser-133 phosphorylation or transcriptional activity is not required for GRIP1 interaction and degradation. The basic leucine zipper domain (bZIP) of CREB is important for the interaction with GRIP1, and deletion of this domain led to an inability to downregulate GRIP1. We propose that CREB mediates the PKA-stimulated degradation of GRIP1 through protein-protein interaction and stimulation of proteasomal degradation of ubiquitinated GRIP1.
A truncation allele in vascular endothelial growth factor c reveals distinct modes of signaling during lymphatic and vascular development
Authors: Villefranc Jacques A. , Nicoli Stefania , Bentley Katie , Jeltsch Michael , Zarkada Georgia , Moore John C. , Gerhardt Holger , Alitalo Kari , Lawson Nathan D.
Published: March 2013

Vascular endothelial growth factor C (Vegfc) is a secreted protein that guides lymphatic development in vertebrate embryos. However, its role during developmental angiogenesis is not well characterized. Here, we identify a mutation in zebrafish vegfc that severely affects lymphatic development and leads to angiogenesis defects on sensitized genetic backgrounds. The um18 mutation prematurely truncated Vegfc, blocking its secretion and paracrine activity but not its ability to activate its receptor Flt4. When expressed in endothelial cells, vegfcum18 could not rescue lymphatic defects in mutant embryos, but induced ectopic blood vessel branching. Furthermore, vegfc-deficient endothelial cells did not efficiently contribute to tip cell positions in developing sprouts. Computational modeling together with assessment of endothelial cell dynamics by time-lapse analysis suggested that an autocrine Vegfc/Flt4 loop plays an important role in migratory persistence and filopodia stability during sprouting. Our results suggest that Vegfc acts in two distinct modes during development: as a paracrine factor secreted from arteries to guide closely associated lymphatic vasculature and as an autocrine factor to drive migratory persistence during angiogenesis.
Jun N-terminal kinase maintains tissue integrity during cell rearrangement in the gut
Authors: Dush Michael K. , Nascone-Yoder Nanette M.
Published: March 2013

Tissue elongation is a fundamental morphogenetic process that generates the proper anatomical topology of the body plan and vital organs. In many elongating embryonic structures, tissue lengthening is driven by Rho family GTPase-mediated cell rearrangement. During this dynamic process, the mechanisms that modulate intercellular adhesion to allow individual cells to change position without compromising structural integrity are not well understood. In vertebrates, Jun N-terminal kinase (JNK) is also required for tissue elongation, but the precise cellular role of JNK in this context has remained elusive. Here, we show that JNK activity is indispensable for the rearrangement of endoderm cells that underlies the elongation of the Xenopus gut tube. Whereas Rho kinase is necessary to induce cell intercalation and remodel adhesive contacts, we have found that JNK is required to maintain cell-cell adhesion and establish parallel microtubule arrays; without JNK activity, the reorganizing endoderm dissociates. Depleting polymerized microtubules phenocopies this effect of JNK inhibition on endoderm morphogenesis, consistent with a model in which JNK regulates microtubule architecture to preserve adhesive contacts between rearranging gut cells. Thus, in contrast to Rho kinase, which generates actomyosin-based tension and cell movement, JNK signaling is required to establish microtubule stability and maintain tissue cohesion; both factors are required to achieve proper cell rearrangement and gut extension. This model of gut elongation has implications not only for the etiology of digestive tract defects, but sheds new light on the means by which intra- and intercellular forces are balanced to promote topological change, while preserving structural integrity, in numerous morphogenetic contexts.
Src kinases mediate the interaction of the apical determinant Bazooka/PAR3 with STAT92E and increase signalling efficiency in Drosophila ectodermal cells
Authors: Sotillos Sol , Krahn Michael , Espinosa-Vázquez Jose Manuel , Hombría James Castelli-Gair
Published: March 2013

Intercellular communication depends on the correct organization of the signal transduction complexes. In many signalling pathways, the mechanisms controlling the overall cell polarity also localize components of these pathways to different domains of the plasma membrane. In the Drosophila ectoderm, the JAK/STAT pathway components are highly polarized with apical localization of the receptor, the associated kinase and the STAT92E protein itself. The apical localization of STAT92E is independent of the receptor complex and is due to its direct association with the apical determining protein Bazooka (Baz). Here, we find that Baz-STAT92E interaction depends on the presence of the Drosophila Src kinases. In the absence of Src, STAT92E cannot bind to Baz in cells or in whole embryos, and this correlates with an impairment of JAK/STAT signalling function. We believe that the requirement of Src proteins for STAT92E apical localization is mediated through Baz, as we can co-precipitate Src with Baz but not with STAT92E. This is the first time that a functional link between cell polarity, the JAK/STAT signalling pathway and the Src kinases has been established in a whole organism.
Characterization of Channelized Reservoir Using Ensemble Kalman Filter with Clustered Covariance
Authors: Lee Kyungbook , Jeong Hoonyoung , Jung SeungPil , Choe Jonggeun
Published: March 2013

Ensemble Kalman filter (EnKF) has the limitation of applications for multi-point geostatistics because it assumes Gaussian random field. It also uses all ensembles to get covariance matrix, even though they have different permeability field each other, resulting in filter divergence. The proposed method suggests the concept of clustered covariance by grouping initial ensembles using a distance-based method. Hausdorff distance is used for calculating similarity between permeability fields and they are separated by k-means clustering. When EnKF is applied to a 2D channel field, it shows overshooting problem and mismatches the true production data. The proposed method gives better history matching and future performance prediction without overshooting problems. Furthermore, it shows stable results for sensitivity analyses over the number of total ensembles. The more accurate covariance is calculated by clustering, the better results are obtained.
Accumulation Conditions of Upper Palaeozoic Coal-Derived Gas in Eastern Linqing Depression
Authors: Wang Mingjian , Zhang Xunhua , Zhang Yunbo , Li Wentao , He Dengfa , Sun Yanpeng
Published: March 2013

The hydrocarbon exploration is presently going on well in the Bohai Bay Basin, where several coal-derived gas fields have been found in the Upper Palaeozoic. However, no significant breakthrough has been made in the exploration of Eastern Linqing Depression, which is located in the southwest of the Bohai Bay Basin. To improve the gas exploration efficiency, this study employed the petroleum system theory to analyze the accumulation elements and processes of coal-derived gas of Upper Palaeozoic in this area, and further summarized the natural gas accumulation model. Results showed that the source rocks of Upper Palaeozoic in Eastern Linqing Depression mainly consist of coal-measure strata of Benxi-Taiyuan Formations of Carboniferous, as well as Shanxi Formation and the Lower Shihezi Formation of Permian. Reservoirs are widely distributed from the bottom to the top, mainly consisting of carbonate rocks and sandstones. The carbonate rock reservoirs include the weathering crust of Ordovician and the dolomite within Ordovician, while sandstone reservoirs include the distributary channel sand bodies of delta plain and the meandering river channel sand bodies in Upper Palaeozoic, as well as sandstones of river and lacustrine in Mesozoic and Cenozoic. The whole region is covered by the semideep-deep lacustrine mudstone of Sha 3 member (Es3) of Palaeogene, which constitutes the regional cap rock in presence of many other localized cap rocks. There are four source-reservoir-cap assemblages including Upper Palaeozoic-generating and Mesozoic-preserving assemblage, Upper Palaeozoic-generating and Cenozoic-preserving assemblage, Upper Palaeozoic-generating and Upper Palaeozoic-preserving assemblage and Upper Palaeozoic-generating and Lower Palaeozoic-preserving assemblage. The source rock, reservoir and cap rocks match well in time and space. Tectonic evolution controlled the thermal evolution of the Upper Palaeozoic coal-measure source rocks, which experienced five hydrocarbon generation stages. Hydrocarbon generated from the coal strata of Upper Palaeozoic migrated to the surrounding traps through migration pathways consisting primarily of faults, cracks and unconformities, among which faults and unconformities played a major role. Multiple types of traps, mainly structural traps, were formed by the intense tectonic movements that historically occurred in this area. The trap formation stages match well with the hydrocarbon generation stages. By analyzing the accumulation conditions of coal-derived gas of Upper Palaeozoic, we identified four accumulation models and further predicted the favorable hydrocarbon accumulation zone in the study area.
Relationships between Trace Element Abundances and Depositional Environments of Coals from the Zhangji Coal Mine, Anhui Province, China
Authors: Li Hui , Liu Guijian , Sun Ruoyu , Chen Jian , Wu Bin , Chou Chen-Lin
Published: March 2013

Coal characteristic and trace elements of 254 coal samples from Zhangji Coal Mine, Anhui Province, China were studied. Compared with average concentrations of trace elements in Chinese, U.S. and world coals, the coals from Zhangji mine contains a higher concentrations of Co, Cu, Sr and Sc and lower concentrations of Ba, Bi, Mn, Cd, Mo and Zn. The concentrations of B and the Sr/Ba ratios showed that the Permian coal-bearing sequences of the coal mine were developed from a brackish-water influenced lower delta plain (No. 6-2 coal) to a freshwater influenced fluvial upper delta plain (No. 9-1 coal) and suffered frequent marine transgression and regression, which may cause many thin and unstable coal seams. The vertical variations of trace elements in different coal seams indicate that the concentrations of most trace elements in coals are significantly related with depositional environments. Some trace elements could be utilized in coal seam correlation.
Progress in Molecular Imaging in Endoscopy and Endomicroscopy for Cancer Imaging
Authors: Khondee Supang , Wang Thomas D.
Published: March 2013

Imaging is an essential tool for effective cancer management. Endoscopes are important medical instruments for performing in vivo imaging in hollow organs. Early detection of cancer can be achieved with surveillance using endoscopy, and has been shown to reduce mortality and to improve outcomes. Recently, great advancements have been made in endoscopic instruments, including new developments in optical designs, light sources, optical fibers, miniature scanners, and multimodal systems, allowing for improved resolution, greater tissue penetration, and multispectral imaging. In addition, progress has been made in the development of highly‐specific optical probes, allowing for improved specificity for molecular targets. Integration of these new endoscopic instruments with molecular probes provides a unique opportunity for significantly improving patient outcomes and has potential to further improve early detection, image guided therapy, targeted therapy, and personalized medicine. This work summarizes current and evolving endoscopic technologies, and provides an overview of various promising optical molecular probes.
Accumulation of Phase‐Shift Nanoemulsions to Enhance MR‐Guided Ultrasound‐Mediated Tumor Ablation In Vivo
Authors: Kopechek Jonathan A. , Park Eunjoo , Mei Chang-Sheng , McDannold Nathan J. , Porter Tyrone M.
Published: March 2013

Magnetic resonance‐guided high intensity focused ultrasound (MRgHIFU) is being explored as a non‐invasive technology to treat solid tumors. However, the clinical use of HIFU for tumor ablation applications is currently limited by the long treatment times required. Phase‐shift nanoemulsions (PSNE), consisting of liquid perfluorocarbon droplets that can be vaporized into microbubbles, are being developed to accelerate HIFU‐mediated heating. The purpose of this study was to examine accumulation of PSNE in intramuscular rabbit tumors in vivo. MR images were acquired before and after intravenous injection of gadolinium‐containing PSNE. MR signal enhancement was observed in rabbit tumors up to six hours after injection, indicating that PSNE accumulated in the tumors. In addition, PSNE vaporization was detected in the tumor with B‐mode ultrasound imaging, and MR thermometry measurements indicated that PSNE accelerated the rate of HIFU‐mediated heating. These results suggest that PSNE could dramatically improve the efficiency and clinical feasibility of MRgHIFU.
The Effects of Interruptions on Oncologists′ Patient Assessment and Medication Ordering Practices
Authors: Trbovich Patricia L. , Griffin Melissa C. , White Rachel E. , Bourrier Venetia , Dhaliwal Dhali , Easty Anthony C.
Published: March 2013

Interruptions are causal factors in medication errors. Although researchers have assessed the nature and frequency of interruptions during medication administration, there has been little focus on understanding their effects during medication ordering. The goal of this research was to examine the nature, frequency, and impact of interruptions on oncologists′ ordering practices. Direct observations were conducted at a Canadian cancer treatment facility to (1) document the nature, frequency, and timing of interruptions during medication ordering, and (2) quantify the use of coping mechanisms by oncologists. On average, oncologists were interrupted 17 % of their time, and were frequently interrupted during safety‐critical stages of medication ordering. When confronted with interruptions, oncologists engaged/multitasked more often than resorting to deferring/blocking. While some interruptions are necessary forms of communication, efforts must be made to reduce unnecessary interruptions during safety‐critical tasks, and to develop interventions that increase oncologists′ resiliency to inevitable interruptions.
GumPack: A Personal Health Assistant with Reconfigurable Surface Components
Authors: Li Kejia , Warren Steve
Published: March 2013

Wearable and everyday‐carry medical devices can improve quality of life for individuals that need frequent health monitoring. Such tools can supplement ubiquitous home care environments populated with medical sensors, extending the reach of these environments and increasing the freedom of their occupants. This paper presents the concept design for an everyday‐carry medical device called a ‘GumPack’: a small cuboid‐shaped device that offers wireless connectivity and plug‐and‐play surface components, where a component can be a biomedical sensor or a wireless network coordinator that manages a body area network. This geometrical layout optimizes access to surface‐based medical hardware mounted on a small form factor. The device offers substantive computing power, supports local component reconfigurability, and promotes interoperability with medical device coordination environments. The GumPack is envisioned to be a personal health assistant carried in a pocket or handbag that can operate alone or interface to, e.g., a cell phone.
Responses of Cancer Cells Induced by Photodynamic Therapy
Authors: Kushibiki Toshihiro , Hirasawa Takeshi , Okawa Shinpei , Ishihara Miya
Published: March 2013

Photodynamic therapy (PDT) involves the administration of a photosensitizer, followed by local irradiation of tumor tissues using a laser of an appropriate wavelength to activate the photosensitizer. Since multiple cellular signaling cascades are concomitantly activated in cancer cells exposed to the photodynamic effect, understanding the responses of cancer cells to PDT will aid in the development of new interventions. This review describes the possible cell‐death signaling pathways initiated by PDT. In addition, we describe our latest findings regarding the induction of expression of miRNAs specific to apoptosis in cancer cells and the induction of antitumor immunity following PDT against cancer cells. A more detailed understanding of the molecular mechanisms related to PDT will potentially improve long‐term survival of PDT treated patients.
Alteplase for the Treatment of Catheter Occlusion in Pediatric Patients
Authors: Anderson Debra M , Pesaturo Kimberly A , Casavant Jonathan , Ramsey E Zachary
Published: March 2013

OBJECTIVE

To review the literature pertaining to the efficacy of alteplase for restoration of patency of occluded venous and dialysis catheters in pediatric patients.

DATA SOURCES

A MEDLINE search was conducted and cross-referenced with an EMBASE search through November 2012. Search terms included alteplase, tissue plasminogen activator, and catheter.

STUDY SELECTION AND DATA EXTRACTION

Search results were limited to humans, English language, and ages from neonates to 18 years. Pertinent studies discussing efficacy of alteplase for restoration of occluded venous or dialysis catheter function were included. Case reports, review articles, and studies that specified inclusion of hemophilia patients or more than 75% of children with malignancy were excluded.

DATA SYNTHESIS

Fibrinolytics are the drug class of choice for restoration of patency (defined as the ability to withdraw a blood sample) of thrombus-occluded catheters. The trials used to support Food and Drug Administration approval of alteplase for central venous catheter (CVC) occlusions generally had low pediatric enrollment; however, additional small studies are available that support use of alteplase for this indication in children. Alteplase doses of 0.5–2 mg instilled into the lumen of a CVC with dwell times ranging from 30 to more than 240 minutes plus the potential for repeat dosing were reported. Overall efficacy ranged from approximately 50% to 90%, with greater efficacy generally reported with larger doses and longer dwell times. Alteplase doses of 2–2.5 mg with dwell times of 60–120 minutes were observed in 2 studies of occluded peritoneal or hemodialysis catheters, in which efficacy was reported in 57–100% of cases. Limitations of current studies of alteplase for catheter occlusion in children include small study populations and relative lack of pediatric-specific prospective trials.

CONCLUSIONS

Alteplase appears to show efficacy for treatment of thrombus-related venous catheter occlusion in pediatric patients; however, data regarding its use in occluded dialysis catheters are limited.
Pharmacogenetics of Risperidone: A Systematic Review of the Clinical Effects of CYP2D6 Polymorphisms
Authors: Cartwright Andrea L , Wilby Kyle J , Corrigan Susan , Ensom Mary HH
Published: March 2013

OBJECTIVE

To summarize and evaluate the pharmacogenetic literature pertaining to the effects of CYP2D6 polymorphism on clinical outcomes of risperidone therapy.

DATA SOURCES

A systematic literature search was performed using the search terms risperidone, pharmacogenetics, cytochrome P-450 enzyme system, cytochrome P-450 CYP2D6, and polymorphism (genetic) in MEDLINE (1946-October 2012), EMBASE (1980-October 2012), PubMed (1947-October 2012), International Pharmaceutical Abstracts (1970-October 2012), and Google Scholar.

STUDY SELECTION AND DATA EXTRACTION

Identified articles were included if they measured the association between CYP2D6 genetic polymorphisms and clinical outcomes in at least 2 patients taking risperidone. The data elements extracted from these articles consisted of study design, number of subjects, indication for risperidone therapy, CYP2D6 phenotype status, mean daily dose of risperidone, and effects on clinical outcomes.

DATA SYNTHESIS

The identified citations consisted of 10 prospective nonrandomized, uncontrolled cohort studies, 1 retrospective cohort study, 1 prospective case-control study, and 1 retrospective case series. Studies were of variable quality and none provided high-quality evidence; they included heterogeneous patient populations with varying clinical diagnoses and drug therapy regimens. Most studies reported nonsignificant trends but were limited by power to detect statistical significance and short trial duration. However, increased risk of adverse effects (including QT interval prolongation) was observed in patients with inactive alleles.

CONCLUSIONS

While there were trends toward increased adverse effects in poor metabolizers, most outcomes were not significant. As such, routine genotyping should not be used for screening. Future usefulness cannot be ruled out, as many studies had significant limitations that preclude determination of clinical relevance. Adequately powered clinical and epidemiologic studies are warranted to clarify the role of CYP2D6 genotyping in practice.
Use of Number Needed to Treat in Cost-Effectiveness Analyses
Authors: Garg Vishvas , Shen Xian , Cheng Yan , Nawarskas James J , Raisch Dennis W
Published: March 2013

OBJECTIVE

To review the use of number needed to treat (NNT) and/or number needed to harm (NNH) values to determine their relevance in helping clinicians evaluate cost-effectiveness analyses (CEAs).

DATA SOURCES

PubMed and EconLit were searched from 1966 to September 2012.

STUDY SELECTION AND DATA EXTRACTION

Reviews, editorials, non–English-language articles, and articles that did not report NNT/NNH or cost-effectiveness ratios were excluded. CEA studies reporting cost per life-year gained, per quality-adjusted life-year (QALY), or other cost per effectiveness measure were included. Full texts of all included articles were reviewed for study information, including type of journal, impact factor of the journal, focus of study, data source, publication year, how NNT/NNH values were reported, and outcome measures.

DATA SYNTHESIS

A total of 188 studies were initially identified, with 69 meeting our inclusion criteria. Most were published in clinician-practice–focused journals (78.3%) while 5.8% were in policy-focused journals, and 15.9% in health-economics–focused journals. The majority (72.4%) of the articles were published in high-impact journals (impact factor >3.0). Many articles focused on either disease treatment (40.5%) or disease prevention (40.5%). Forty-eight percent reported NNT as a part of the CEA ratio per event. Most (53.6%) articles used data from literature reviews, while 24.6% used data from randomized clinical trials, and 20.3% used data from observational studies. In addition, 10% of the studies implemented modeling to perform CEA.

CONCLUSIONS

CEA studies sometimes include NNT ratios. Although it has several limitations, clinicians often use NNT for decision-making, so including NNT information alongside CEA findings may help clinicians better understand and apply CEA results. Further research is needed to assess how NNT/NNH might meaningfully be incorporated into CEA publications.
Longitudinal Perspectives of Child Positive Impact on Families: Relationship to Disability and Culture
Authors: Blacher Jan , Begum Gazi F. , Marcoulides George A. , Baker Bruce L.
Published: March 2013

This study examined mothers' perceptions of the positive impact of having a child with an intellectual disability. Trajectories of positive impact from 7 time points were developed using latent growth modeling and 2 predictors: culture (Anglo, Latino) and child disability status (intellectual disability, typical development). Data were from 219 mothers of children from age 3 to 9 years. Growth trajectories reflected a general decline in positive impact on Anglo mothers. On average, at age 3, Anglo mothers reported significantly lower initial values on positive impact when their children had an intellectual disability, but Latino mothers did not. Across all time points, Latino mothers had higher scores on the positive impact, regardless of whether they had a child with an intellectual disability or a typically developing child.
Prenatal and Perinatal Factors Associated with Intellectual Disability
Authors: Bilder Deborah A. , Pinborough-Zimmerman Judith , Bakian Amanda V. , Miller Judith S. , Dorius Josette T. , Nangle Barry , McMahon William M.
Published: March 2013

Prenatal and perinatal risk factors associated with intellectual disability (ID) were studied in 8-year-old Utah children from a 1994 birth cohort (N  =  26,108) using broad ascertainment methods and birth records following the most current recording guidelines. Risk factor analyses were performed inclusive and exclusive of children with a known or suspected underlying genetic disorder. Risk factors identified were poly/oligohydramnios, advanced paternal/maternal age, prematurity, fetal distress, premature rupture of membranes, primary/repeat cesarean sections, low birth weight, assisted ventilation greater than 30 min, small-for-gestational age, low Apgar scores, and congenital infection. Although several risk factors lost significance once children with underlying genetic disorders were excluded, socioeconomic variables were among those that maintained a prominent association with increased ID risk.
An Investigation of Narrative Ability in Boys with Autism and Fragile X Syndrome
Authors: Hogan-Brown Abigail L. , Losh Molly , Martin Gary E. , Mueffelmann Deborah J.
Published: March 2013

Whereas pragmatic language difficulties are characteristic of both autism and Fragile X syndrome, it is unclear whether such deficits are qualitatively similar or whether certain skills are differentially affected. This study compared narrative competence in boys with autism, Fragile X syndrome, Down syndrome, and typical development. Results revealed that an interaction between diagnosis and nonverbal mental age predicted narrative microstructure (e.g., complex syntax) but not macrostructure (e.g., thematic maintenance). Correlations with FMR1-related variation were investigated in children with Fragile X syndrome. While CGG repeat length was associated with many language characteristics, nonverbal IQ appeared to mediate these relationships. These findings are an important step toward understanding narrative abilities in boys with and without the FMR1 mutation.
Shift from Extracellular Signal-Regulated Kinase to AKT/cAMP Response Element-Binding Protein Pathway Increases Survival-Motor-Neuron Expression in Spinal-Muscular-Atrophy-Like Mice and Patient Cells
Authors: Branchu Julien , Biondi Olivier , Chali Farah , Collin Thibault , Leroy Felix , Mamchaoui Kamel , Makoukji Joelle , Pariset Claude , Lopes Philippe , Massaad Charbel , Chanoine Christophe , Charbonnier Frédéric
Published: March 2013

Spinal muscular atrophy (SMA), a recessive neurodegenerative disease, is characterized by the selective loss of spinal motor neurons. No available therapy exists for SMA, which represents one of the leading genetic causes of death in childhood. SMA is caused by a mutation of the survival-of-motor-neuron 1 (SMN1) gene, leading to a quantitative defect in the survival-motor-neuron (SMN) protein expression. All patients retain one or more copies of theSMN2 gene, which modulates the disease severity by producing a small amount of stable SMN protein. We reported recently that NMDA receptor activation, directly in the spinal cord, significantly enhanced the transcription rate of theSMN2genes in a mouse model of very severe SMA (referred as type 1) by a mechanism that involved AKT/CREB pathway activation. Here, we provide the first compelling evidence for a competition between the MEK/ERK/Elk-1 and the phosphatidylinositol 3-kinase/AKT/CREB signaling pathways forSMN2gene regulation in the spinal cord of type 1 SMA-like mice. The inhibition of the MEK/ERK/Elk-1 pathway promotes the AKT/CREB pathway activation, leading to (1) an enhanced SMN expression in the spinal cord of SMA-like mice and in human SMA myotubes and (2) a 2.8-fold lifespan extension in SMA-like mice. Furthermore, we identified a crosstalk between ERK and AKT signaling pathways that involves the calcium-dependent modulation of CaMKII activity. Together, all these data open new perspectives to the therapeutic strategy for SMA patients.
The Critical Role of Sleep Spindles in Hippocampal-Dependent Memory: A Pharmacology Study
Authors: Mednick Sara C. , McDevitt Elizabeth A. , Walsh James K. , Wamsley Erin , Paulus Martin , Kanady Jennifer C. , Drummond Sean P. A.
Published: March 2013

An important function of sleep is the consolidation of memories, and features of sleep, such as rapid eye movement (REM) or sleep spindles, have been shown to correlate with improvements in discrete memory domains. Because of the methodological difficulties in modulating sleep, however, a causal link between specific sleep features and human memory consolidation is lacking. Here, we experimentally manipulated specific sleep features during a daytime nap via direct pharmacological intervention. Using zolpidem (Ambien), a short-acting GABAAagonist hypnotic, we show increased sleep spindle density and decreased REM sleep compared with placebo and sodium oxybate (Xyrem). Naps with increased spindles produced significantly better verbal memory and significantly worse perceptual learning but did not affect motor learning. The experimental spindles were similar to control spindles in amplitude and frequency, suggesting that the experimental intervention enhanced normal sleep processes. Furthermore, using statistical methods, we demonstrate for the first time a critical role of spindles in human hippocampal memory performance. The gains in memory consolidation exceed sleep-alone or control conditions and demonstrate the potential for targeted, exceptional memory enhancement in healthy adults with pharmacologically modified sleep.
Adaptation to Speed in Macaque Middle Temporal and Medial Superior Temporal Areas
Authors: Price Nicholas S. C. , Born Richard T.
Published: March 2013

The response of a sensory neuron to an unchanging stimulus typically adapts, showing decreases in response gain that are accompanied by changes in the shape of tuning curves. It remains unclear whether these changes arise purely due to spike rate adaptation within single neurons or whether they are dependent on network interactions between neurons. Further, it is unclear how the timescales of neural and perceptual adaptation are related. To examine this issue, we compared speed tuning of middle temporal (MT) and medial superior temporal neurons in macaque visual cortex after adaptation to two different reference speeds. For 75% of speed-tuned units, adaptation caused significant changes in tuning that could be explained equally well as lateral shifts, vertical gain changes, or both. These tuning changes occurred rapidly, as both neuronal firing rate and Fano factor showed no evidence of changing beyond the first 500 ms after motion onset, and the magnitude of tuning curve changes showed no difference between trials with adaptation durations shorter or longer than 1 s. Importantly, the magnitude of tuning shifts was correlated with the transient-sustained index, which measures a well characterized form of rapid response adaptation in MT, and is likely associated with changes at the level of neuronal networks. Tuning curves changed in a manner that increased neuronal sensitivity around the adapting speed, consistent with improvements in human and macaque psychophysical performance that we observed over the first several hundred ms of adaptation.
Serotonin Facilitates Peripheral Pain Sensitivity in a Manner That Depends on the Nonproton Ligand Sensing Domain of ASIC3 Channel
Authors: Wang Xiang , Li Wei-Guang , Yu Ye , Xiao Xian , Cheng Jin , Zeng Wei-Zheng , Peng Zhong , Xi Zhu Michael , Xu Tian-Le
Published: March 2013

Tissue acidosis and inflammatory mediators play critical roles in inflammatory pain. Extracellular acidosis activates acid-sensing ion channels (ASICs), which have emerged as key sensors for extracellular protons in the central and peripheral nervous systems and play key roles in pain sensation and transmission. Additionally, inflammatory mediators, such as serotonin (5-HT), are known to enhance pain sensation. However, functional interactions among protons, inflammatory mediators, and ASICs in pain sensation are poorly understood. In the present study, we show that 5-HT, a classical pro-inflammatory mediator, specifically enhances the proton-evoked sustained, but not transient, currents mediated by homomeric ASIC3 channels and heteromeric ASIC3/1a and ASIC3/1b channels. Unexpectedly, the effect of 5-HT on ASIC3 channels does not involve activation of 5-HT receptors, but is mediated via a functional interaction between 5-HT and ASIC3 channels. We further show that the effect of 5-HT on ASIC3 channels depends on the newly identified nonproton ligand sensing domain. Finally, coapplication of 5-HT and acid significantly increased pain-related behaviors as assayed by the paw-licking test in mice, which was largely attenuated in ASIC3 knock-out mice, and inhibited by the nonselective ASIC inhibitor amiloride. Together, these data identify ASIC3 channels as an unexpected molecular target for acute actions of 5-HT in inflammatory pain sensation and reveal an important role of ASIC3 channels in regulating inflammatory pain via coincident detection of extracellular protons and inflammatory mediators.
Brain Changes Associated with Postural Training in Patients with Cerebellar Degeneration: A Voxel-Based Morphometry Study
Authors: Burciu Roxana Gabriela , Fritsche Nicole , Granert Oliver , Schmitz Lutz , Spönemann Nina , Konczak Jürgen , Theysohn Nina , Gerwig Marcus , van Eimeren Thilo , Timmann Dagmar
Published: March 2013

Recent research indicates that physiotherapy can improve motor performance of patients with cerebellar degeneration. Given the known contributions of the cerebellum to motor learning, it remains unclear whether such observable changes in performance are mediated by the cerebellum or cerebral brain areas involved in motor control and learning. The current study addressed this question by assessing the increase in gray matter volume due to sensorimotor training in cerebellar patients using voxel-based morphometry. Nineteen human subjects with pure cerebellar degeneration and matched healthy controls were trained for 2 weeks on a balance task. Postural and clinical assessments along with structural magnetic resonance imaging were performed pretraining and post-training. The main findings were as follows. First, training enhanced balance performance in cerebellar patients. Second, in contrast to controls patients revealed significantly more post-training gray matter volume in the dorsal premotor cortex. Third, training-related increase in gray matter volume was observed within the cerebellum and was more pronounced in controls than in patients. However, statistically cerebellar changes were at the trend level and thus require additional, independent confirmation. We conclude that sensorimotor training of patients with cerebellar neurodegeneration induces gray matter changes primarily within nonaffected neocortical regions of the cerebellar-cortical loop. Residual function of the cerebellum appears to be exploited suggesting either a recovery from degeneration or intact processes of cerebellar plasticity in the remaining healthy tissue.
Microglia Regulate the Number of Neural Precursor Cells in the Developing Cerebral Cortex
Authors: Cunningham Christopher L. , Martínez-Cerdeño Verónica , Noctor Stephen C.
Published: March 2013

Neurogenesis must be properly regulated to ensure that cell production does not exceed the requirements of the growing cerebral cortex, yet our understanding of mechanisms that restrain neuron production remains incomplete. We investigated the function of microglial cells in the developing cerebral cortex of prenatal and postnatal macaques and rats and show that microglia limit the production of cortical neurons by phagocytosing neural precursor cells. We show that microglia selectively colonize the cortical proliferative zones and phagocytose neural precursor cells as neurogenesis nears completion. We found that deactivating microgliain uterowith tetracyclines or eliminating microglia from the fetal cerebral cortex with liposomal clodronate significantly increased the number of neural precursor cells, while activating microgliain uterothrough maternal immune activation significantly decreased the number of neural precursor cells. These data demonstrate that microglia play a fundamental role in regulating the size of the precursor cell pool in the developing cerebral cortex, expanding our understanding of the mechanisms that regulate cortical development. Furthermore, our data suggest that any factor that alters the number or activation state of microgliain uterocan profoundly affect neural development and affect behavioral outcomes.
A Developmental Shift from Positive to Negative Connectivity in Human Amygdala–Prefrontal Circuitry
Authors: Gee Dylan G. , Humphreys Kathryn L. , Flannery Jessica , Goff Bonnie , Telzer Eva H. , Shapiro Mor , Hare Todd A. , Bookheimer Susan Y. , Tottenham Nim
Published: March 2013

Recent human imaging and animal studies highlight the importance of frontoamygdala circuitry in the regulation of emotional behavior and its disruption in anxiety-related disorders. Although tracing studies have suggested changes in amygdala–cortical connectivity through the adolescent period in rodents, less is known about the reciprocal connections within this circuitry across human development, when these circuits are being fine-tuned and substantial changes in emotional control are observed. The present study examined developmental changes in amygdala–prefrontal circuitry across the ages of 4–22 years using task-based functional magnetic resonance imaging. Results suggest positive amygdala–prefrontal connectivity in early childhood that switches to negative functional connectivity during the transition to adolescence. Amygdala–medial prefrontal cortex functional connectivity was significantly positive (greater than zero) among participants younger than 10 years, whereas functional connectivity was significantly negative (less than zero) among participants 10 years and older, over and above the effect of amygdala reactivity. The developmental switch in functional connectivity was paralleled by a steady decline in amygdala reactivity. Moreover, the valence switch might explain age-related improvement in task performance and a developmentally normative decline in anxiety. Initial positive connectivity followed by a valence shift to negative connectivity provides a neurobiological basis for regulatory development and may present novel insight into a more general process of developing regulatory connections.