bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of a Novel Approach for Dose Individualization in Pharmacotherapy Using Gabapentin in a Proof of Principles Study
Authors: Blau Gary E. , Orcun Seza , Laínez José M. , Reklaitis Gintaras V. , Suvannasankha Attaya , Fausel Chris , Anaissie Elias J. 
Published: April 2013

Study ObjectiveTo demonstrate the premise of individualized dosing charts (IDCs) as a clinical‐bedside decision‐support tool to individualize dosage regimens for drugs in which the interpatient variability is controlled by the pharmacokinetic (PK) behavior of the patient, to calculate the optimal sampling schedule (OSS), which minimizes the number of blood samples per patient. The approach is illustrated with available PK data for gabapentin.DesignRetrospective proof of principles study using gabapentin PK data from a published clinical trial.PatientsNineteen subjects in a trial designed to uncover the importance of the genetic contributions to variability in gabapentin absorption, renal elimination, and transport; subjects were monitored for 36 hours after administration of a single dose of gabapentin 400 mg, and plasma concentrations were determined at 14 time points.Measurements and Main ResultsWhen the PK profiles were different between subjects, the IDCs are dramatically different from each other and from the IDC for an “average” patient representing the patient population. The dose amount and dosing interval must be adjusted to maximize the probability of staying within the target concentration range. An optimal sampling methodology based on the assumption‐free Bayesian approach is used to distinguish the PK profile of an individual patient from the patient population. In the case of gabapentin, only two optimally selected test blood samples, at 1.5 and 6 hours after administration of a single doses, were necessary. The average sensitivity and the average specificity of the OSS was 99% and 96%, respectively.ConclusionIDCs display the risk of a patient violating the target concentration range for any dosage regimen. They can be used as a clinical‐bedside decision‐support tool in a patient–physician partnership to decide on a dose amount and dosing interval that are medically acceptable while practical and convenient to ensure compliance. By using the assumption‐free Bayesian approach and the OSS, the number of samples required from a new patient to individualize the dosage regimen can be reduced significantly while preserving high levels of sensitivity and specificity. Prospective studies are being planned to validate the encouraging results. This approach can be extended to any drug if PK data and a target concentration range are available for either therapeutic drug monitoring or target concentration intervention.
Efficacy of a First‐Grade Responsiveness‐to‐Intervention Prevention Model for Struggling Readers
Authors: Gilbert Jennifer K. , Compton Donald L. , Fuchs Douglas , Fuchs Lynn S. , Bouton Bobette , Barquero Laura A. , Cho Eunsoo 
Published: April 2013

AbstractThis randomized control trial examined the efficacy of a multitiered supplemental tutoring program within a first‐grade responsiveness‐to‐intervention prevention model. Struggling first‐grade readers (n = 649) were screened and progress monitored at the start of the school year. Those identified as unresponsive to general education Tier 1 (n = 212) were randomly assigned to receive Tier 2 small‐group supplemental tutoring (n = 134) or to continue in Tier 1 (n = 78). Progress‐monitoring data were used to identify nonresponders to Tier 2 (n = 45), who were then randomly assigned to more Tier 2 tutoring (n = 21) or one‐on‐one Tier 3 tutoring (n = 24). Tutoring in Tier 3 was the same as in Tier 2 except for the delivery format and frequency of instruction. Results from a latent change analysis indicated nonresponders to Tier 1 who received supplemental tutoring made significantly higher word reading gains compared with controls who received reading instruction only in Tier 1 (effect size = 0.19). However, no differences were detected between nonresponders to Tier 2 who were assigned to Tier 3 versus more Tier 2. This suggests more frequent 1:1 delivery of a Tier 2 standard tutoring program may be insufficient for intensifying intervention at Tier 3. Although supplemental tutoring was effective in bolstering reading performance of Tier 1 nonresponders, only 40% of all Tier 2 students and 53% of Tier 2 responders were reading in the normal range by grade 3. Results challenge the preventive intent of short‐term, standard protocol, multitiered supplemental tutoring models.
Advanced Methods for Assessing the Melt‐Specific Creep Rupture Behavior of P91 Steel for Power Plants
Authors: Frolova Olga , Maile Karl 
Published: April 2013

AbstractIn systems that operate in the creep range, such as steam power plants, the life‐time assessment of highly loaded high‐temperature components poses an important task. The main problem in this context is the reliable detection and evaluation of specific material characteristics. First of all there are the strength properties that are the result of the multidimensional interdependences between the individual elements of the chemical composition, the heat treatment parameters and the production conditions. With the current state of knowledge and technology, melt‐specific creep rupture strength can only be determined experimentally. Modeling with neural network techniques therefore represents an alternative to analytical methods since multidimensional relationships can be taken into account. This work aims to identify and assess the potential for the application of artificial neural networks to the determination of relevant properties of selected high‐temperature resistant steels. The emphasis of the study is to determinate the position of the specific melts in the scatter band of creep rupture data as well as to assess/predict time‐to‐rupture for the given steel under consideration of all relevant technical data available and to find out an optimum of the creep rupture strength.
Ermüdungsverhalten kranspezifischer Kerbdetails – Untersuchungen im Kurzzeitfestigkeitsbereich
Authors: Herion Stefan , Ummenhofer Thomas , Hrabowski Jennifer 
Published: April 2013

AbstractDie im Folgenden vorgestellten Ergebnisse experimenteller Untersuchungen sind Teil des nunmehr vierten Forschungsvorhabens, FOSTA P778 [1], das aus der Arbeitsgruppe “Krankerbdetails“ hervorgegangen ist. Die Arbeiten sind eine Fortführung der Projekte P293, P512 und LIFTHIGH sowie REFRESH ([2] bis [5]), die ausgewählte Details im Lastwechselbereich von ca. 40000 bis 5 Millionen Lastwechseln behandelten. Um die Wirtschaftlichkeit von Krankonstruktionen weiter erhöhen zu können, müssen auch stärkere Hubvorgänge nachweisbar sein, die noch höhere Beanspruchungen in der Konstruktion hervorrufen und damit zu geringeren Lebensdauern bzw. Lastwechselzahlen als in den bisherigen Untersuchungen führen. Dementsprechend wurde für die beiden typischen Kerbdetails – aufgeschweißte Längssteife und – querbelastete Stumpfnaht der Lastwechselbereich zwischen 10000 und 40000 Lastwechseln (Low Cycle Fatigue LCF) untersucht. Damit soll geklärt werden, ob und bis zu welcher Beanspruchung bzw. Lastwechselzahl die schon vorhandenen Wöhlerlinien linear in diesen LCF‐Bereich verlängert werden können. Untersuchungen wurden an Details aus den hochfesten Stahlsorten S690QL und S960QL sowie für die Stumpfnahtverbindungen zusätzlich aus S1100QL und S1300QL durchgeführt.Fatigue behaviour of crane specific notch details – Investigations on low cycle fatigue. The following experimental investigations are part of the forth research project (FOSTA P778 [1]) which is initiated by the working group “Krankerbdetails” (working group on notch details in crane structures). They are an extension of the work carried out in projects P293, P512, LIFTHIGH and REFRESH ([2] to [5]) on specific notch details in the fatigue range of 40.000 to 5 million load cycles. To raise the economic efficiency, crane structures need to be designed also for higher loads respectively for a fatigue range below the load cycles investigated so far. Therefore, the two common notch details – longitudinal stiffener and – transverse loaded butt weld have been investigated in the fatigue range between 10.000 and 40.000 load cycles (LCF low cycle fatigue). For this reason, it will be determined if it is possible to extend the existing Wöhler lines into this range, and if so, up to which load this can be done. These investigations are carried out for high strength steels S690QL and S960QL, butt welded joints of steel grades S1100QL and S1300QL are additionally investigated.
Disease-Causing Mitochondrial Heteroplasmy Segregated Within Induced Pluripotent Stem Cell Clones Derived from a Patient with MELAS
Authors: Folmes Clifford D.L. , Martinez-Fernandez Almudena , Perales-Clemente Ester , Li Xing , Mcdonald Amber , Oglesbee Devin , Hrstka Sybil C. , Perez-Terzic Carmen , Terzic Andre , Nelson Timothy J. 
Published: April 2013

Abstract
Mitochondrial diseases display pathological phenotypes according to the mixture of mutant versus wild-type mitochondrial DNA (mtDNA), known as heteroplasmy. We herein examined the impact of nuclear reprogramming and clonal isolation of induced pluripotent stem cells (iPSC) on mitochondrial heteroplasmy. Patient-derived dermal fibroblasts with a prototypical mitochondrial deficiency diagnosed as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) demonstrated mitochondrial dysfunction with reduced oxidative reserve due to heteroplasmy at position G13513A in the ND5 subunit of complex I. Bioengineered iPSC clones acquired pluripotency with multilineage differentiation capacity and demonstrated reduction in mitochondrial density and oxygen consumption distinguishing them from the somatic source. Consistent with the cellular mosaicism of the original patient-derived fibroblasts, the MELAS-iPSC clones contained a similar range of mtDNA heteroplasmy of the disease-causing mutation with identical profiles in the remaining mtDNA. High-heteroplasmy iPSC clones were used to demonstrate that extended stem cell passaging was sufficient to purge mutant mtDNA, resulting in isogenic iPSC subclones with various degrees of disease-causing genotypes. On comparative differentiation of iPSC clones, improved cardiogenic yield was associated with iPSC clones containing lower heteroplasmy compared with isogenic clones with high heteroplasmy. Thus, mtDNA heteroplasmic segregation within patient-derived stem cell lines enables direct comparison of genotype/phenotype relationships in progenitor cells and lineage-restricted progeny, and indicates that cell fate decisions are regulated as a function of mtDNA mutation load. The novel nuclear reprogramming-based model system introduces a disease-in-a-dish tool to examine the impact of mutant genotypes for MELAS patients in bioengineered tissues and a cellular probe for molecular features of individual mitochondrial diseases.
Essential Role of Sox2 for the Establishment and Maintenance of the Germ Cell Line
Authors: Campolo Federica , Gori Manuele , Favaro Rebecca , Nicolis Silvia , Pellegrini Manuela , Botti Flavia , Rossi Pellegrino , Jannini Emmanuele A. , Dolci Susanna 
Published: April 2013

Abstract
Sox2 is a pluripotency-conferring gene expressed in primordial germ cells (PGCs) and postnatal oocytes, but the role it plays during germ cell development and early embryogenesis is unknown. Since Sox2 ablation causes early embryonic lethality shortly after blastocyst implantation, we generated mice bearing Sox2-conditional deletion in germ cells at different stages of their development through the Cre/loxP recombination system. Embryos lacking Sox2 in PGCs show a dramatic decrease of germ cell numbers at the time of their specification. At later stages, we found that Sox2 is strictly required for PGC proliferation. On the contrary, Sox2 deletion in meiotic oocytes does not impair postnatal oogenesis and early embryogenesis, indicating that it is not essential for oocyte maturation or for zygotic development. We also show that Sox2 regulates Kit expression in PGCs and binds to discrete transcriptional regulatory sequences of this gene, which is known to be important for PGCs survival and proliferation. Sox2 also stimulates the expression of Zfp148, which is required for normal development of fetal germ cells, and Rif1, a potential regulator of PGC pluripotency.
PEDF promotes self-renewal of limbal stem cell and accelerates corneal epithelial wound healing
Authors: Ho Tsung-Chuan , Chen Show-Li , Wu Ju-Yun , Ho Mei-Ying , Chen Lee-Jen , Hsieh Jui-Wen , Cheng Huey-Chuan , Tsao Yeou-Ping 
Published: April 2013

Abstract
Limbal epithelial stem cell (LSC) transplantation is a prevalent therapeutic method for patients with LSC deficiency. The maintenance of stem cell characteristics in the process of culture expansion is critical for the success of ocular surface reconstruction. Pigment epithelial-derived factor (PEDF) increased the numbers of holoclone in LSC monolayer culture and preserved the stemness of LSC in suspension culture by evidence of ΔNp63α, Bmi-1, and ABCG2 expression. BrdU pulse-labeling assay also demonstrated that PEDF stimulated LSCs proliferation. In air-lift culture of limbal equivalent, PEDF was capable of increasing the numbers of ΔNp63α-positive cells. The mitogenic effect of PEDF was found to be mediated by the phosphorylations of p38 MAPK and STAT3 in LSCs. Synthetic 44-mer PEDF (residues 78–121) was as effective as the full length PEDF in LSC expansion in suspension culture and limbal equivalent formation, as well as the activation of p38 MAPK and STAT3. In mice subjecting to mechanical removal of cornea epithelium, 44-mer PEDF facilitated corneal wound healing. Microscopically, 44-mer PEDF advanced the early proliferative response in limbus, increased the proliferation of ΔNp63α-positive cells both in limbus and in epithelial healing front, and assisted the repopulation of limbus in the late phase of wound healing. In conclusion, the capability of expanding LSC in cell culture and in animal indicates the potential of PEDF and its fragment (e.g., 44-mer PEDF) in ameliorating limbal stem cell deficiency; and their uses as therapeutics for treating corneal wound.
Infiltration in soils with a saturated surface
Authors: Hogarth W. L. , Lockington D. A. , Barry D. A. , Parlange M. B. , Haverkamp R. , Parlange J.‐Y. 
Published: April 2013

Key Points
Analytic description of infiltration in soils
Comparison of constant flux and saturated surface infiltration
Linking infiltration to soil/water properties
Regulation of stress granules and P‐bodies during RNA virus infection
Authors: Lloyd Richard E. 
Published: April 2013

AbstractRNA granules are structures within cells that play major roles in gene expression and homeostasis. Two principle kinds of RNA granules are conserved from yeast to mammals: stress granules (SGs), which contain stalled translation initiation complexes, and processing bodies (P‐bodies, PBs), which are enriched with factors involved in RNA turnover. Since RNA granules are associated with silenced transcripts, viruses subvert RNA granule function for replicative advantages. This review, focusing on RNA viruses, discusses mechanisms that manipulate stress granules and P‐bodies to promote synthesis of viral proteins. Three main themes have emerged for how viruses manipulate RNA granules; (1) cleavage of key host factors, (2) control of protein kinase R (PKR) activation, and (3) redirecting RNA granule components for new or parallel roles in viral reproduction, at the same time disrupting RNA granules. Viruses utilize one or more of these routes to achieve robust and productive infection. WIREs RNA 2013, 4:317–331. doi: 10.1002/wrna.1162This article is categorized under:

RNA in Disease and Development > RNA in Disease
Genetic Counseling Training in the Philippines
Authors: Laurino Mercy Ygona , Padilla Carmencita David 
Published: April 2013

AbstractThe recently established Master of Science in Genetic Counseling (MSGC) program serves a vital role in implementing and expanding genetic counseling services in the Philippines. Currently, only eight clinical geneticists practice in the Philippines, a country of approximately 94 million people, which yields a clinical‐geneticist‐to‐population‐density ratio of 1:11,750,000. The MSGC program was created to train health care providers to become crucial members of medical genetics teams being formed to meet increasing patient and healthcare provider demands. In 2011, the Board of Regents approved our proposed curriculum at the Department of Pediatrics College of Medicine, University of the Philippines Manila. As we relate how the Philippines began its efforts to implement the program and attempted to overcome the challenges the program faced, we hope we can provide an example to those interested in creating a similar MSGC program in other low‐income and middle‐income countries.
A lower bound for topological entropy of generic non-Anosov symplectic diffeomorphisms
Authors: CATALAN THIAGO , TAHZIBI ALI 
Published: April 2013

AbstractWe prove that a${C}^{1} $generic symplectic diffeomorphism is either Anosov or its topological entropy is bounded from below by the supremum over the smallest positive Lyapunov exponent of its periodic points. We also prove that${C}^{1} $generic symplectic diffeomorphisms outside the Anosov ones do not admit symbolic extension and, finally, we give examples of volume preserving surface diffeomorphisms which are not points of upper semicontinuity of the entropy function in the${C}^{1} $topology.
On Cas A, Cassini, Comets, and King Charles
Authors: SORIA ROBERTO , BALESTRIERI RICCARDO , OHTSUKA YASUYO 
Published: April 2013

AbstractWe re-examine the long-standing problem of the date of the Cassiopeia A supernova (SN), in view of recent claims that it might be the 1630 ‘noon-star’ seen at the birth of King Charles II. We do not support this identification, based on the expected brightness of a Type-IIb SN (too faint to be seen in daylight), the extrapolated motion of the ejecta (inconsistent with a date earlier than 1650), the lack of any scientific follow-up observations, the lack of any mention of it in Asian archives. The origin of the 1630 noon-star event (if real) remains a mystery; there was a bright comet in 1630 June but no evidence to determine whether or not it was visible in daylight. Instead, we present French reports about a fourth-magnitude star discovered by Cassini in Cassiopeia in or shortly before 1671, which was not seen before or since. The brightness is consistent with what we expect for the Cas A SN; the date is consistent with the extrapolated motion of the ejecta. We argue that this source could be the long-sought SN.
Under-reporting of drug use among individuals with schizophrenia: prevalence and predictors
Authors: Bahorik A. L. , Newhill C. E. , Queen C. C. , Eack S. M. 
Published: April 2013

BackgroundIllicit drug use is common in individuals with schizophrenia, and it has been suspected that many individuals under-report their use of substances, leading to significant barriers to treatment. This study sought to examine the degree to which individuals with schizophrenia disclose their use of drugs on self-rated assessments, compared to laboratory assays, and to determine the contributors of under-reported drug use in this population.MethodA total of 1042 individuals with schizophrenia who participated in screening/baseline procedures for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) completed self-rated assessments of substance use and laboratory drug testing. Laboratory tests assayed cannabis, cocaine and methamphetamine use; the procedures included radioimmunoassay (RIA) and urine drug screens.ResultsA significant proportion of participants tested positive for drug use on laboratory measures (n = 397; 38%), and more than half (n = 229; 58%) did not report using these drugs. Logistic regression models confirmed that patients who were most likely to conceal their use tended to be older, and presented with greater neurocognitive deficits. Patients who accurately reported drug use tended to have greater involvement with the criminal justice system. Illness severity and psychopathology were not associated with whether patients disclosed drug use.ConclusionsRates of under-reported drug use are considerable among individuals with schizophrenia when compared to laboratory assays, and the exclusive reliance on self-rated assessments should be used with caution. Patients who under-report their drug use are more likely to manifest neurocognitive deficits, which could be improved by interventions attempting to optimize treatment.
Trajectories of PTSD risk and resilience in World Trade Center responders: an 8-year prospective cohort study
Authors: Pietrzak R. H. , Feder A. , Singh R. , Schechter C. B. , Bromet E. J. , Katz C. L. , Reissman D. B. , Ozbay F. , Sharma V. , Crane M. , Harrison D. , Herbert R. , Levin S. M. , Luft B. J. , Moline J. M. , Stellman J. M. , Udasin I. G. , Landrigan P. J. , Southwick S. M. 
Published: April 2013

BackgroundLongitudinal symptoms of post-traumatic stress disorder (PTSD) are often characterized by heterogeneous trajectories, which may have unique pre-, peri- and post-trauma risk and protective factors. To date, however, no study has evaluated the nature and determinants of predominant trajectories of PTSD symptoms in World Trade Center (WTC) responders.MethodA total of 10835 WTC responders, including 4035 professional police responders and 6800 non-traditional responders (e.g. construction workers) who participated in the WTC Health Program (WTC-HP), were evaluated an average of 3, 6 and 8 years after the WTC attacks.ResultsAmong police responders, longitudinal PTSD symptoms were best characterized by four classes, with the majority (77.8%) in a resistant/resilient trajectory and the remainder exhibiting chronic (5.3%), recovering (8.4%) or delayed-onset (8.5%) symptom trajectories. Among non-traditional responders, a six-class solution was optimal, with fewer responders in a resistant/resilient trajectory (58.0%) and the remainder exhibiting recovering (12.3%), severe chronic (9.5%), subsyndromal increasing (7.3%), delayed-onset (6.7%) and moderate chronic (6.2%) trajectories. Prior psychiatric history, Hispanic ethnicity, severity of WTC exposure and WTC-related medical conditions were most strongly associated with symptomatic trajectories of PTSD symptoms in both groups of responders, whereas greater education and family and work support while working at the WTC site were protective against several of these trajectories.ConclusionsTrajectories of PTSD symptoms in WTC responders are heterogeneous and associated uniquely with pre-, peri- and post-trauma risk and protective factors. Police responders were more likely than non-traditional responders to exhibit a resistant/resilient trajectory. These results underscore the importance of prevention, screening and treatment efforts that target high-risk disaster responders, particularly those with prior psychiatric history, high levels of trauma exposure and work-related medical morbidities.