bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of the role of distinct plasma cell‐free DNA species in age‐associated inflammation and frailty
Authors: Jylhävä Juulia , Nevalainen Tapio , Marttila Saara , Jylhä Marja , Hervonen Antti , Hurme Mikko 
Published: February 2013

SummaryPlasma cell‐free DNA (cf‐DNA) has recently emerged as a potential biomarker of aging, reflecting systemic inflammation, and cell death. In addition, it has been suggested that cf‐DNA could promote autoinflammation. Because the total cf‐DNA pool comprises different cf‐DNA species, we quantified the plasma levels of gene‐coding cf‐DNA, Alu repeat cf‐DNA, mitochondrial DNA (mtDNA) copy number, and the amounts of unmethylated and total cf‐DNAs. We identified the relationships between these cf‐DNA species and age‐associated inflammation, immunosenescence, and frailty. Additionally, we determined the cf‐DNA species‐specific transcriptomic signatures in blood mononuclear cells to elucidate the age‐linked leukocyte responses to cf‐DNA. The study population consisted of n = 144 nonagenarian participants of the Vitality 90+ Study and n = 30 young controls. In the nonagenarians, higher levels of total and unmethylated cf‐DNAs were associated with systemic inflammation and increased frailty. The mtDNA copy number was also directly correlated with increased frailty but not with inflammation. None of the cf‐DNA species were associated with immunosenescence. The transcriptomic pathway analysis revealed that higher levels of total and unmethylated cf‐DNAs were associated with immunoinflammatory activation in the nonagenarians but not in the young controls. The plasma mtDNA appeared to be inert in terms of inflammatory activation in both the nonagenarians and young controls. These data demonstrate that the plasma levels of total and unmethylated cf‐DNA and the mtDNA copy number could serve as biomarkers of frailty. In addition, we suggest that circulating self‐DNA, assessed as total or unmethylated cf‐DNA, might aggravate immunoinflammatory reactivity in very old individuals.
Dietary restriction of rodents decreases aging rate without affecting initial mortality rate – a meta‐analysis
Authors: Simons Mirre J. P. , Koch Wouter , Verhulst Simon 
Published: February 2013

SummaryDietary restriction (DR) extends lifespan in multiple species from various taxa. This effect can arise via two distinct but not mutually exclusive ways: a change in aging rate and/or vulnerability to the aging process (i.e. initial mortality rate). When DR affects vulnerability, this lowers mortality instantly, whereas a change in aging rate will gradually lower mortality risk over time. Unraveling how DR extends lifespan is of interest because it may guide toward understanding the mechanism(s) mediating lifespan extension and also has practical implications for the application of DR. We reanalyzed published survival data from 82 pairs of survival curves from DR experiments in rats and mice by fitting Gompertz and also Gompertz–Makeham models. The addition of the Makeham parameter has been reported to improve the estimation of Gompertz parameters. Both models separate initial mortality rate (vulnerability) from an age‐dependent increase in mortality (aging rate). We subjected the obtained Gompertz parameters to a meta‐analysis. We find that DR reduced aging rate without affecting vulnerability. The latter contrasts with the conclusion of a recent analysis of a largely overlapping data set, and we show how the earlier finding is due to a statistical artifact. Our analysis indicates that the biology underlying the life‐extending effect of DR in rodents likely involves attenuated accumulation of damage, which contrasts with the acute effect of DR on mortality reported for Drosophila. Moreover, our findings show that the often‐reported correlation between aging rate and vulnerability does not constrain changing aging rate without affecting vulnerability simultaneously.
Characterizing the longitudinal patterns of substance use among individuals diagnosed with serious mental illness after psychiatric hospitalization
Authors: Bahorik Amber L. , Newhill Christina E. , Eack Shaun M. 
Published: February 2013

AbstractAimTo characterize longitudinal patterns of substance use across a large sample of psychiatric patients discharged from inpatient admission, followed for 1‐year post‐hospitalization.DesignProspective cohort study.SettingKansas City, MO, USA; Pittsburgh, PA, USA; Worcester, MA, USA.ParticipantsEight hundred and one schizophrenia‐spectrum (n = 204), bipolar (n = 137) and depressive disorder (n = 460) patients from the MacArthur Violence Risk Assessment Study.MeasurementsSymptoms, functioning, drug/alcohol use assessed by the Brief Psychiatric Rating Scale, the Global Assessment of Functioning, and substance use interviews.FindingsPatients used alcohol (67.0%;n = 540) and cannabis (30.0%;n = 237) more frequently than other substances up to 30 days before admission, and those with depressive and schizophrenia‐spectrum used heroin more than individuals with bipolar (P = 0.023). Post‐hospitalization, patients using alcohol (B = −0.15,P < 0.001) and cannabis (B = −0.27,P < 0.001) decreased, but patterns varied across diagnosis and genders. Patients using cannabis decreased at greater rates in depressive and schizophrenia‐spectrum compared with bipolar (allP < 0.05), and more men used alcohol (B = 0.76,P < 0.001) and cannabis (B = 1.56,P < 0.001) than women. Cannabis (B = 1.65,P < 0.001) and alcohol (B = 1.04,P = 0.002) were associated with higher symptomatology; cannabis (B = −2.33,P < 0.001) and alcohol (B = −1.45,P = 0.012) were associated with lower functioning.ConclusionsSubstance use is frequent and associated with poor recovery in patients with serious mental illness recently discharged from psychiatric hospitalization. Addiction treatments personalized by diagnosis and gender may be effective for improving outcomes in people with serious mental illness.
Citizenship and Belonging in the Rural Fringe: A Case Study of a Hindu Temple in Sydney, Australia
Authors: Bugg Laura Beth 
Published: February 2013

AbstractDespite Australian multicultural policy that asserts the right of all citizens to maintain and practice their religion, formal citizenship has not guaranteed the welcome or belonging of migrant religious groups at the neighbourhood scale. This is most starkly reflected in contests over the inclusion of minority religious spaces in the Australian landscape, which increasingly take place in the rural–urban fringe of metropolitan areas. This work examines the controversy over a proposed Hindu temple in metropolitan Sydney and reveals insights into the way that rural–urban fringe space is imagined, understood and experienced by land use planners, residents and temple members. Critical discourse analysis of policy documentation along with interviews reveals that land use planners circumscribe belonging in the landscape through the use of zoning ordinances and design controls, local residents mark the boundaries of white privilege through narratives of heritage and cultural difference and temple members claim rights to citizenship based on assertions of sameness.
DNA polymorphism in the FKBP5 gene affects impulsivity in intertemporal choice
Authors: Kawamura Yoshiya , Takahashi Taiki , Liu Xiaoxi , Nishida Nao , Tokunaga Katsushi , Ukawa Ko , Noda Yoshihiro , Yoshikawa Akane , Shimada Takafumi , Umekage Tadashi , Sasak Tsukasa 
Published: February 2013

AbstractIntroductionImpulsivity in intertemporal choice has been operationalized as “delay discounting”, referring to the preference for a sooner, smaller reward. FK506 binding protein 5 (FKBP5) is a co‐chaperone of the glucocorticoid receptor (GR). FKBP5 overexpression causes GR resistance, resulting in increased plasma cortisol levels. High cortisol levels are associated with low impulsivity in intertemporal choice. The aim of this study was to explore the effect of single nucleotide polymorphisms (SNPs) in FKBP5 on delay discounting.MethodsThe participants consisted of 91 healthy Japanese people (66 males and 25 females with a mean age of 40.9 ± 6.9 years). Each participant completed Kirby's monetary choice questionnaire (MCQ) and donated a whole blood sample. Five SNPs in FKBP5 were genotyped using the DigiTag2. SNP linear regression analyses with 100,000 permutations were conducted for the hyperbolic time‐discount rate (k).ResultsTwo SNPs were excluded from analysis because of their low minor allelic frequencies. The SNP rs1360780 showed a significant association; participants with more minor alleles (T) were less impulsive in intertemporal choice for delayed gain (multiplicity‐corrected P = 0.047).DiscussionThe significant SNP rs1360780 is located in the region adjacent to the hormone response element (HRE)‐binding sequence where transcription factors bind and alter the transcription of FKBP5. A minor allele (T) of rs1360780, which causes FKBP5 overexpression, may reduce impulsivity in intertemporal choice (i.e. delay discounting) via GR resistance and the subsequent high cortisol levels. This is the first study to demonstrate an association between FKBP5 and impulsivity in intertemporal choice.
Aripiprazole for the treatment of pediatric bipolar I disorder: a 30‐week, randomized, placebo‐controlled study
Authors: Findling Robert L , Correll Christoph U , Nyilas Margaretta , Forbes Robert A , McQuade Robert D , Jin Na , Ivanova Svetlana , Mankoski Raymond , Carson William H , Carlson Gabrielle A 
Published: February 2013

Objective:  To evaluate the long‐term efficacy, safety, and tolerability of aripiprazole in pediatric subjects with bipolar I disorder.Methods:  A randomized, double‐blind, 30‐week, placebo‐controlled study of aripiprazole (10 or 30 mg/day) in youths (10–17 years) with bipolar I disorder (manic or mixed) ± psychotic features (n = 296) was performed. After four weeks, acute treatment completers continued receiving ≤26 weeks of double‐blind treatment (n = 210). The primary outcome was Young Mania Rating Scale (YMRS) total score change.Results:  Of the 210 subjects who entered the 26‐week extension phase, 32.4% completed the study (45.3% for aripiprazole 10 mg/day, 31.0% for aripiprazole 30 mg/day, and 18.8% for placebo). Both aripiprazole doses demonstrated significantly (p < 0.001) greater improvements in YMRS total score at endpoint compared with placebo in protocol‐specified last observation carried forward analyses, but not in observed case or mixed‐model repeated measures at week 30. Overall time to all‐cause discontinuation was longer for aripiprazole 10 mg/day (15.6 weeks) and aripiprazole 30 mg/day (9.5 weeks) compared with placebo (5.3 weeks; both p < 0.05 versus placebo). Both aripiprazole doses were significantly superior to placebo regarding response rates, Children’s Global Assessment of Functioning and Clinical Global Impressions‐Bipolar severity of overall and mania scores at endpoint in all analyses. Commonly reported adverse events included headache, somnolence, and extrapyramidal disorder.Conclusions:  Aripiprazole 10 mg/day and 30 mg/day were superior to placebo and generally well tolerated in pediatric subjects with bipolar I disorder up to 30 weeks. Despite the benefits of treatment, completion rates were low in all treatment arms.
A phase 2 multicentre study of siltuximab, an anti‐interleukin‐6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma
Authors: Voorhees Peter M. , Manges Robert F. , Sonneveld Pieter , Jagannath Sundar , Somlo George , Krishnan Amrita , Lentzsch Suzanne , Frank Richard C. , Zweegman Sonja , Wijermans Pierre W. , Orlowski Robert Z. , Kranenburg Britte , Hall Brett , Casneuf Tineke , Qin Xiang , van de Velde Helgi , Xie Hong , Thomas Sheeba K. 
Published: February 2013

SummaryInterleukin‐6 (IL6) plays a central role in multiple myeloma pathogenesis and confers resistance to corticosteroid‐induced apoptosis. We therefore evaluated the efficacy and safety of siltuximab, an anti‐IL6 monoclonal antibody, alone and in combination with dexamethasone, for patients with relapsed or refractory multiple myeloma who had ≥2 prior lines of therapy, one of which had to be bortezomib‐based. Fourteen initial patients received siltuximab alone, 10 of whom had dexamethasone added for suboptimal response; 39 subsequent patients were treated with concurrent siltuximab and dexamethasone. Patients received a median of four prior lines of therapy, 83% were relapsed and refractory, and 70% refractory to their last dexamethasone‐containing regimen. Suppression of serum C‐reactive protein levels, a surrogate marker of IL6 inhibition, was demonstrated. There were no responses to siltuximab but combination therapy yielded a partial (17%) + minimal (6%) response rate of 23%, with responses seen in dexamethasone‐refractory disease. The median time to progression, progression‐free survival and overall survival for combination therapy was 4·4, 3·7 and 20·4 months respectively. Haematological toxicity was common but manageable. Infections occurred in 57% of combination‐treated patients, including ≥grade 3 infections in 18%. Further study of siltuximab in modern corticosteroid‐containing myeloma regimens is warranted, with special attention to infection‐related toxicity.
The Role of Chromatin Remodeling in Medulloblastoma
Authors: Jones David T. W. , Northcott Paul A. , Kool Marcel , Pfister Stefan M. 
Published: February 2013

AbstractThe unexpectedly high frequency and universality of alterations to the chromatin machinery is one of the most striking themes emerging from the current deluge of cancer genomics data. Medulloblastoma (MB), a malignant pediatric brain tumor, is no exception to this trend, with a wealth of recent studies indicating multiple alterations at all levels of chromatin processing. MB is typically now regarded as being composed of four major molecular entities (WNT, SHH, Group 3 and Group 4), which vary in their clinical and biological characteristics. Similarities and differences across these subgroups are also reflected in the specific chromatin modifiers that are found to be altered in each group, and each new cancer genome sequence or microarray profile is adding to this important knowledge base. These data are fundamentally changing our understanding of tumor developmental pathways, not just for MB but also for cancer as a whole. They also provide a new class of targets for the development of rational, personalized therapeutic approaches. The mechanisms by which these chromatin remodelers are dysregulated in MB, and the consequences both for future basic research and for translation to the clinic, will be examined here.
Emerging Insights into the Ependymoma Epigenome
Authors: Mack Stephen C. , Witt Hendrik , Wang Xin , Milde Till , Yao Yuan , Bertrand Kelsey C. , Korshunov Andrey , Pfister Stefan M. , Taylor Michael D. 
Published: February 2013

AbstractEpendymoma is the third most common pediatric brain tumor, yet because of the paucity of effective therapeutic interventions, 45% of patients remain incurable. Recent transcriptional and copy number profiling of the disease has identified few driver genes and in fact points to a balanced genomic profile. Candidate gene approaches looking at hypermethylated promoters and genome‐wide epigenetic arrays suggest that DNA methylation may be critical to ependymoma pathogenesis. This review attempts to highlight existing and emerging evidence implicating the ependymoma epigenome as a key player and that epigenetic modifiers may offer new targeted therapeutic avenues for patients.
Chromatin Remodeling Defects in Pediatric and Young Adult Glioblastoma: A Tale of a Variant Histone 3 Tail
Authors: Fontebasso Adam M. , Liu Xiao‐Yang , Sturm Dominik , Jabado Nada 
Published: February 2013

AbstractPrimary brain tumors occur in 8 out of 100 000 people and are the leading cause of cancer‐related death in children. Among brain tumors, high‐grade astrocytomas (HGAs) including glioblastoma multiforme (GBM) are aggressive and are lethal human cancers. Despite decades of concerted therapeutic efforts, HGAs remain essentially incurable in adults and children. Recent discoveries have revolutionized our understanding of these tumors in children and young adults. Recurrent somatic driver mutations in the tail of histone 3 variant 3 (H3.3), leading to amino acid substitutions at key residues, namely lysine (K) 27 (K27M) and glycine 34 (G34R/G34V), were identified as a new molecular mechanism in pediatric GBM. These mutations represent the pediatric counterpart of the recurrent mutations in isocitrate dehydrogenases (IDH) identified in young adult gliomas and provide a much‐needed new pathway that can be targeted for therapeutic development. This review will provide an overview of the potential role of these mutations in altering chromatin structure and affecting specific molecular pathways ultimately leading to gliomagenesis. The distinct changes in chromatin structure and the specific downstream events induced by each mutation need characterizing independently if progress is to be made in tackling this devastating cancer.
PDGFRA Amplification is Common in Pediatric and Adult High‐Grade Astrocytomas and Identifies a Poor Prognostic Group in IDH1 Mutant Glioblastoma
Authors: Phillips Joanna J. , Aranda Derick , Ellison David W. , Judkins Alexander R. , Croul Sidney E. , Brat Daniel J. , Ligon Keith L. , Horbinski Craig , Venneti Sriram , Zadeh Gelareh , Santi Mariarita , Zhou Shengmei , Appin Christina L. , Sioletic Stefano , Sullivan Lisa M. , Martinez‐Lage Maria , Robinson Aaron E. , Yong William H. , Cloughesy Timothy , Lai Albert , Phillips Heidi S. , Marshall Roxanne , Mueller Sabine , Haas‐Kogan Daphne A. , Molinaro Annette M. , Perry Arie 
Published: February 2013

AbstractHigh‐grade astrocytomas (HGAs), corresponding to World Health Organization grades III (anaplastic astrocytoma) and IV (glioblastoma; GBM), are biologically aggressive, and their molecular classification is increasingly relevant to clinical management. PDGFRA amplification is common in HGAs, although its prognostic significance remains unclear. Using fluorescence in situ hybridization (FISH), the most sensitive technique for detecting PDGFRA copy number gains, we determined PDGFRA amplification status in 123 pediatric and 263 adult HGAs. A range of PDGFRA FISH patterns were identified and cases were scored as non‐amplified (normal and polysomy) or amplified (low‐level and high‐level). PDGFRA amplification was frequent in pediatric (29.3%) and adult (20.9%) tumors. Amplification was not prognostic in pediatric HGAs. In adult tumors diagnosed initially as GBM, the presence of combined PDGFRA amplification and isocitrate dehydrogenase 1 (IDH1)R132H mutation was a significant independent prognostic factor (P = 0.01). In HGAs, PDGFRA amplification is common and can manifest as high‐level and focal or low‐level amplifications. Our data indicate that the latter is more prevalent than previously reported with copy number averaging techniques. To our knowledge, this is the largest survey of PDGFRA status in adult and pediatric HGAs and suggests PDGFRA amplification increases with grade and is associated with a less favorable prognosis in IDH1 mutant de novo GBMs.
Online Lexical Competition During Spoken Word Recognition and Word Learning in Children and Adults
Authors: Henderson Lisa , Weighall Anna , Brown Helen , Gaskell Gareth 
Published: February 2013

Lexical competition that occurs as speech unfolds is a hallmark of adult oral language comprehension crucial to rapid incremental speech processing. This study used pause detection to examine whether lexical competition operates similarly at 7–8 years and tested variables that influence “online” lexical activity in adults. Children (n = 20) and adults (n = 17) were slower to detect pauses in familiar words with later uniqueness points. Faster latencies were obtained for words with late uniqueness points in constraining compared with neutral sentences; no such effect was observed for early unique words. Following exposure to novel competitors (“biscal”), children (n = 18) and adults (n = 18) showed competition for existing words with early uniqueness points (“biscuit”) after 24 hr. Thus, online lexical competition effects are remarkably similar across development.
Preschoolers Use Emotion in Speech to Learn New Words
Authors: Berman Jared M. J. , Graham Susan A. , Callaway Dallas , Chambers Craig G. 
Published: February 2013

Two experiments examined 4‐ and 5‐year‐olds' use of vocal affect to learn new words. In Experiment 1 (n = 48), children were presented with two unfamiliar objects, first in their original state and then in an altered state (broken or enhanced). An instruction produced with negative, neutral, or positive affect, directed children to find the referent of a novel word. During the novel noun, eye gaze measures indicated that both 4‐ and 5‐year‐olds were more likely to consider an object congruent with vocal affect cues. In Experiment 2, 5‐year‐olds (n = 15) were asked to extend and generalize their initial mapping to new exemplars. Here, 5‐year‐olds generalized these newly mapped labels but only when presented with negative vocal affect.
A community-based study on determinants of circulating markers of cellular immune activation and kynurenines: the Hordaland Health Study
Authors: Theofylaktopoulou D , Midttun Ø , Ulvik A , Ueland P M , Tell G S , Vollset S E , Nygård O , Eussen S J P M 
Published: February 2013

Summary
Circulating neopterin and kynurenine/tryptophan ratio (KTR) increase during inflammation and serve as markers of cellular immune activation, but data are sparse on other determinants of these markers and metabolites of the kynurenine pathway. We measured neopterin, tryptophan, kynurenine, anthranilic acid, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and xanthurenic acid in plasma in two age groups, 45–46 years (n = 3723) and 70–72 years (n = 3329). Differences across categories of the potential determinants, including age, gender, renal function, body mass index (BMI), smoking and physical activity, were tested by Mann–Whitney U-test and multiple linear regression including age group, gender, renal function and lifestyle factors. In this multivariate model, neopterin, KTR and most kynurenines were 20–30% higher in the older group, whereas tryptophan was 7% lower. Men had 6–19% higher concentrations of tryptophan and most kynurenines than women of the same age. Compared to the fourth age-specific estimated glomerular filtration rate (eGFR) quartile, the first quartile was associated with higher concentrations of neopterin (25%) and KTR (24%) and 18–36% higher concentrations of kynurenines, except 3-hydroxyanthranilic acid. Additionally, KTR, tryptophan and all kynurenines, except anthranilic acid, were 2–8% higher in overweight and 3–17% higher in obese, than in normal-weight individuals. Heavy smokers had 4–14% lower levels of tryptophan and most kynurenines than non-smokers. Age and renal function were the strongest determinants of plasma neopterin, KTR and most kynurenines. These findings are relevant for the design and interpretation of studies investigating the role of plasma neopterin, KTR and kynurenines in chronic diseases.