bluuebunny/crossref_metadata_2025 huggingface dataset:
Obsessive‐Compulsive Disorder in Adults with High‐Functioning Autism Spectrum Disorder: What Does Self‐Report with the OCI‐R Tell Us?
Authors: Cadman Tim , Spain Debbie , Johnston Patrick , Russell Ailsa , Mataix‐Cols David , Craig Michael , Deeley Quinton , Robertson Dene , Murphy Clodagh , Gillan Nicola , Wilson C. Ellie , Mendez Maria , Ecker Christine , Daly Eileen , Findon James , Glaser Karen ,   MRC AIMS Consortium, Happé Francesca , Murphy Declan
Published: February 2015

Little is known about the symptom profile of obsessive‐compulsive disorder (OCD) in individuals who have autism spectrum disorders (ASD). It is also unknown whether self‐report questionnaires are useful in measuring OCD in ASD. We sought to describe the symptom profiles of adults with ASD, OCD, and ASD + OCD using the Obsessive Compulsive Inventory‐Revised (OCI‐R), and to assess the utility of the OCI‐R as a screening measure in a high‐functioning adult ASD sample. Individuals with ASD (n = 171), OCD (n = 108), ASD + OCD (n = 54) and control participants (n = 92) completed the OCI‐R. Individuals with ASD + OCD reported significantly higher levels of obsessive‐compulsive symptoms than those with ASD alone. OCD symptoms were not significantly correlated with core ASD repetitive behaviors as measured on the ADI‐R or ADOS‐G. The OCI‐R showed good psychometric properties and corresponded well with clinician diagnosis of OCD. Receiver operating characteristic analysis suggested cut‐offs for OCI‐R Total and Checking scores that discriminated well between ASD + versus –OCD, and fairly well between ASD‐alone and OCD‐alone. OCD manifests separately from ASD and is characterized by a different profile of repetitive thoughts and behaviors. The OCI‐R appears to be useful as a screening tool in the ASD adult population. Autism Res 2015, 8: 477–485. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
16p11.2 Deletion Syndrome Mice Display Sensory and Ultrasonic Vocalization Deficits During Social Interactions
Authors: Yang Mu , Mahrt Elena J. , Lewis Freeman , Foley Gillian , Portmann Thomas , Dolmetsch Ricardo E. , Portfors Christine V. , Crawley Jacqueline N.
Published: February 2015

Recurrent deletions and duplications at chromosomal region 16p11.2 are variably associated with speech delay, autism spectrum disorder, developmental delay, schizophrenia, and cognitive impairments. Social communication deficits are a primary diagnostic symptom of autism. Here we investigated ultrasonic vocalizations (USVs) in young adult male 16p11.2 deletion mice during a novel three‐phase male–female social interaction test that detects vocalizations emitted by a male in the presence of an estrous female, how the male changes its calling when the female is suddenly absent, and the extent to which calls resume when the female returns. Strikingly fewer vocalizations were detected in two independent cohorts of 16p11.2 heterozygous deletion males (+/−) during the first exposure to an unfamiliar estrous female, as compared to wildtype littermates (+/+). When the female was removed, +/+ emitted calls, but at a much lower level, whereas +/− males called minimally. Sensory and motor abnormalities were detected in +/−, including higher nociceptive thresholds, a complete absence of acoustic startle responses, and hearing loss in all +/− as confirmed by lack of auditory brainstem responses to frequencies between 8 and 100 kHz. Stereotyped circling and backflipping appeared in a small percentage of individuals, as previously reported. However, these sensory and motor phenotypes could not directly explain the low vocalizations in 16p11.2 deletion mice, since (a) +/− males displayed normal abilities to emit vocalizations when the female was subsequently reintroduced, and (b) +/− vocalized less than +/+ to social odor cues delivered on an inanimate cotton swab. Our findings support the concept that mouse USVs in social settings represent a response to social cues, and that 16p11.2 deletion mice are deficient in their initial USVs responses to novel social cues. Autism Res 2015, 8: 507–521. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
Involvement of GPR50 polymorphisms in depression: independent replication in a prospective elderly cohort
Authors: Ryan Joanne , Carrière Isabelle , Ritchie Karen , Ancelin Marie‐Laure
Published: February 2015

Introduction

Despite the explosion in genetic association studies over the last decade, clearly identified genetic risk factors for depression remain scarce and replication studies are becoming increasingly important. G‐protein‐coupled receptor 50 (GPR50) has been implicated in psychiatric disorders in a small number of studies, although not consistently.

Methods

Data were obtained from 1010 elderly men and women from the prospective population‐based ESPRIT study. Logistic regression and survival models were used to determine whether three common GPR50 polymorphisms were associated with depression prevalence or the incidence of depression over 12‐years. The analyses were adjusted for a range of covariates such as comorbidity and cholesterol levels, to determine independent associations.

Results

All three variants showed some evidence of an association with late‐life depression in women, although these were not consistent across outcomes, the overall effect sizes were relatively small, and most would not remain significant after correction for multiple testing. Women heterozygous for rs13440581, had a 1.6‐fold increased risk of baseline depression, while the odds of depression comorbid with anxiety were increased fourfold for women homozygous for the minor allele of rs2072621. When depressed women at baseline were excluded from the analysis, however, neither variant was associated with the 12‐year incidence of depression. In contrast, rs561077 was associated with a 1.8‐fold increased risk of incident depression specifically. No significant associations were observed in men.

Discussion

Our results thus provide only weak support for the involvement of GPR50 variants in late‐life depression, which appear specific to certain subgroups of depressed individuals (i.e., women and those with more severe forms of depression).
Prevalence of renal impairment and use of nephrotoxic agents among patients with bone metastases from solid tumors in the United States
Authors: Arellano Jorge , Hernandez Rohini K. , Wade Sally W. , Chen Kristina , Pirolli Melissa , Quach David , Quigley Jane , Liede Alexander , Shahinian Vahakn B.
Published: February 2015

The renal status of patients with bone metastases secondary to solid tumors and their treatment with nephrotoxic agents is not well characterized. This retrospective study analyzed electronic medical records data from US‐based oncology clinics to identify adult (age ≥18) solid tumor patients with first bone metastasis diagnosis and ≥1 serum creatinine recorded between January 1, 2009 and December 31, 2013. Patients with multiple myeloma, multiple primary tumor types, acute renal failure, and/or end‐stage renal disease were excluded. Using the Chronic Kidney Disease Epidemiology Collaboration formula, we determined the prevalence of renal impairment (RI: single estimated glomerular filtration rate [eGFR] value <60 mL/min per 1.73 m2) and chronic kidney disease (CKD: ≥2 eGFR values <60, at least 90 days apart). We also examined the use of intravenous bisphosphonates (IV BP) and other nephrotoxic agents. Approximately half of the 11,809 patients were female. Breast (34%) and lung (28%) tumors were the most common. At bone metastasis diagnosis, mean age was 67 years and 24% of patients exhibited RI. The 5‐year prevalence was 43% for RI and 71% for CKD among RI patients. Nearly half (46%) of CKD patients received IV BP in the 12 months following their confirming eGFR and 13% of these patients received at least one other nephrotoxic agent during that period. This is the first US‐based study to examine the prevalence of RI among patients with bone metastases from solid tumors. RI is common at bone metastases diagnosis, and a substantial proportion of patients develop RI or CKD as their disease progresses. Whenever possible, treatments that are potentially less damaging for the kidney should be considered for patients with or predisposed to RI.
RARβ regulates neuronal cell death and differentiation in the avian ciliary ganglion
Authors: Koszinowski Sophie , Boerries Melanie , Busch Hauke , Krieglstein Kerstin
Published: February 2015

Programmed cell death during chicken ciliary ganglion (CG) development is mostly discussed as an extrinsically regulated process, guided either by the establishment of a functional balance between preganglionic and postganglionic activity or the availability of target‐derived neurotrophic factors. We found that the expression of the gene coding for the nuclear retinoic acid receptor β (RARB) is transiently upregulated prior to and during the execution phase of cell death in the CG. Using retroviral vectors, the expression of RARB was knocked down during embryonic development in ovo. The knockdown led to a significant increase in CG neuron number after the cell death phase. BrdU injections and active caspase‐3 staining revealed that this increase in neuron number was due to an inhibition of apoptosis during the normal cell death phase. Furthermore, apoptotic neuron numbers were significantly increased at a stage when cell death is normally completed. While the cholinergic phenotype of the neurons remained unchanged after RARB knockdown, the expression of the proneural gene Cash1 was increased, but somatostatin‐like immunoreactivity, a hallmark of the mature choroid neuron population, was decreased. Taken together, these results point toward a delay in neuronal differentiation as well as cell death. The availability of nuclear retinoic acid receptor β (RARβ) and RARβ‐induced transcription of genes could therefore be a new intrinsic cue for the maturation of CG neurons and their predisposition to undergo cell death. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1204–1218, 2015
Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss
Authors: Locher Heiko , de Groot John C.M.J. , van Iperen Liesbeth , Huisman Margriet A. , Frijns Johan H.M. , Chuva de Sousa Lopes Susana M.
Published: February 2015

Sensorineural hearing loss (SNHL) is one of the most common congenital disorders in humans, afflicting one in every thousand newborns. The majority is of heritable origin and can be divided in syndromic and nonsyndromic forms. Knowledge of the expression profile of affected genes in the human fetal cochlea is limited, and as many of the gene mutations causing SNHL likely affect the stria vascularis or cochlear potassium homeostasis (both essential to hearing), a better insight into the embryological development of this organ is needed to understand SNHL etiologies. We present an investigation on the development of the stria vascularis in the human fetal cochlea between 9 and 18 weeks of gestation (W9–W18) and show the cochlear expression dynamics of key potassium‐regulating proteins. At W12, MITF+/SOX10+/KIT+ neural‐crest‐derived melanocytes migrated into the cochlea and penetrated the basement membrane of the lateral wall epithelium, developing into the intermediate cells of the stria vascularis. These melanocytes tightly integrated with Na+/K+‐ATPase‐positive marginal cells, which started to express KCNQ1 in their apical membrane at W16. At W18, KCNJ10 and gap junction proteins GJB2/CX26 and GJB6/CX30 were expressed in the cells in the outer sulcus, but not in the spiral ligament. Finally, we investigated GJA1/CX43 and GJE1/CX23 expression, and suggest that GJE1 presents a potential new SNHL associated locus. Our study helps to better understand human cochlear development, provides more insight into multiple forms of hereditary SNHL, and suggests that human hearing does not commence before the third trimester of pregnancy. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1219–1240, 2015
Synaptic localization of α5 GABA (A) receptors via gephyrin interaction regulates dendritic outgrowth and spine maturation
Authors: Brady Megan L. , Jacob Tija C.
Published: February 2015

GABAAreceptor subunit composition is a critical determinant of receptor localization and physiology, with synaptic receptors generating phasic inhibition and extrasynaptic receptors producing tonic inhibition. Extrasynaptically localized α5 GABAAreceptors are largely responsible for tonic inhibition in hippocampal neurons. However, we show here that inhibitory synapses also contain a constant level of α5 GABAAreceptors throughout neuronal development, as measured by its colocalization with gephyrin, the inhibitory postsynaptic scaffolding protein. Immunoprecipitation of the α5 subunit from both cultured neurons and adult rat brain coimmunoprecipitated gephyrin, confirming this interactionin vivo. Furthermore, the α5 subunit can interact with gephyrin independent of other synaptically localized alpha subunits, as shown by immunoprecipitation experiments in HEK cells. By replacing the α5 predicted gephyrin binding domain (Residues 370–385) with either the high affinity gephyrin binding domain of the α2 subunit or homologous residues from the extrasynaptic α4 subunit that does not interact with gephyrin, α5 GABAAreceptor localization shifted into or out of the synapse, respectively. These shifts in the ratio of synaptic/extrasynaptic α5 localization disrupted dendritic outgrowth and spine maturation. In contrast to the predominant view of α5 GABAAreceptors being extrasynaptic and modulating tonic inhibition, we identify an intimate association of the α5 subunit with gephyrin, resulting in constant synaptic levels of α5 GABAAR throughout circuit formation that regulates neuronal development. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1241–1251, 2015
High temperature intensifies negative density dependence of fitness in red flour beetles
Authors: Halliday William D. , Thomas Alison S. , Blouin‐Demers Gabriel
Published: February 2015

Competition for food, space, or other depletable resources has strong impacts on the fitness of organisms and can lead to a pattern known as negative density dependence, where fitness decreases as population density increases. Yet, many resources that have strong impacts on fitness are nondepletable (e.g., moisture or temperature). How do these nondepletable resources interact with depletable resources to modify negative density dependence? We tested the hypothesis that negative density dependence is modulated by temperature in red flour beetles and tested the prediction that the strength of negative density dependence should decrease as temperature decreases. We measured the number of eggs laid, offspring development time, and the number of offspring that reached maturity at three temperatures and two food treatment combinations as we simultaneously manipulated adult population density. We demonstrated that low temperatures weaken negative density dependence in the number of eggs laid; this pattern was most evident when food was abundant. Density had no effect on development time, but low temperatures increased development time. The percent of eggs that emerged as adults decreased with both density and temperature and increased with food. Temperature, an abiotic driver, can thus modulate density‐dependent processes in ectotherms. Therefore, models of population growth for ectotherms should incorporate the effects of temperature.
Policosanol variation in olive oil as a result of variety, ripening, and storage
Authors: Lukić Marina , Lukić Igor , Sladonja Barbara , Piližota Vlasta
Published: February 2015

Despite their importance as bioactive compounds and authentication parameters in olive oil, the response of policosanol aliphatic alcohols to even the most influential sources of variability is practically unknown. To investigate policosanol variation in olive oil as a result of variety, ripening, and oil storage temperature, 36 samples were subjected to gas chromatographic (GC‐FID) and mass spectrometric (GC‐MS) analysis, and results were processed by univariate (ANOVA) and multivariate (SLDA) statistics. The concentration (mg/100 g) and relative amount (%) of pentacosanol accounted for the most variation due to variety. The largest influence of ripening was observed for pentacosanol (%) and docosanol (%). Docosanol, tricosanol, and tetracosanol amounts mostly increased during ripening, whereas those of pentacosanol, hexacosanol, heptacosanol, and octacosanol decreased in Črna and Rosinjola oils, whereas Buža showed different patterns in some cases. Variations as a result of storage were lower and inconsistent. Results suggest that the investigated olive oils retained the bulk of their health beneficial features of policosanol origin throughout shelf‐life. Relatively successful differentiation of oils achieved by multivariate models pointed to the potential use of policosanol alcohols as chemical indicators of varietal origin which are independent on ripening degree, and vice versa, applicable both for fresh and stored oils.

Practical applications

The results obtained may serve producers to assess and optimize the suitability of individual steps in production, and develop strategies aimed at producing olive oils with targeted policosanol composition. More generally, the indicators of variety and ripening degree among policosanol aliphatic alcohols proposed may contribute to the scientific work on the authenticity and quality of olive oil which is an ever‐growing area, and be used for characterization, differentiation, authentication, and certification of olive oils of specific origin and attributes. The approach tested in this work could be utilized for developing more robust olive oil chemical composition specifications for European Union's Protected Designations of Origin (PDO) and other designations, because it considers the inter‐relationship between three factors of variability and extracts only the most useful and stable indicators or markers.

Policosanol alcohol variation as a result of variety, ripening degree, and storage temperature was investigated. The use of policosanol variation as a chemical indicator and discriminator according to these factors was tested.
Proof of concept for the use of macroinvertebrates as indicators of polychlorinated biphenyls (PCB) contamination in Lake Hartwell
Authors: Lazorchak James M. , Griffith Michael B. , Mills Marc , Schubauer-Berigan Joseph , McCormick Frank , Brenner Richard , Zeller Craig
Published: February 2015

The US Environmental Protection Agency (USEPA) develops methods and tools for evaluating risk management strategies for sediments contaminated with polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), and other legacy pollutants. Monitored natural recovery is a risk management alternative that relies on existing physical, chemical, and biological processes to contain, destroy, and/or reduce the bioavailability or toxicity of in-place contaminants. These naturally occurring processes are monitored to ensure that management and recovery are progressing as expected. One approach frequently used to evaluate the recovery of contaminated sediments and associated biota is the assessment of contaminant tissue levels, or body burden concentrations, in top trophic level fish. In the present study, aquatic invertebrates were examined as an indicator of recent exposure to PCBs. The approach aimed to determine whether invertebrates collected using artificial substrates (i.e., Hester–Dendy samplers) could be used to discriminate among contaminated sites through the analyses of PCBs in whole homogenates of macroinvertebrates. Macroinvertebrates were sorted, preserved, and analyzed for total PCBs (t-PCBs), by summing 107 PCB congeners. Macroinvertebrate body burden concentrations showed similar trends to sediment t-PCB concentrations at the sites sampled. The results indicate that macroinvertebrates can be used to assess sediment contamination among sites that have different PCB contamination levels. Environ Toxicol Chem 2015;34:1277–1282. Published 2015 SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.
Benzoylurea pesticides used as veterinary medicines in aquaculture: Risks and developmental effects on nontarget crustaceans
Authors: Macken Ailbhe , Lillicrap Adam , Langford Katherine
Published: February 2015

Diflubenzuron and teflubenzuron are benzoylureas that are used in aquaculture to control sea lice. Flubenzurons have low toxicity to many marine species such as fish and algae but by their nature are likely to have significant adverse effects on nontarget species such as crustaceans and amphipods. Although the exact mechanism of toxicity is not known, these compounds are thought to inhibit the production of the enzyme chitin synthase during molting of immature stages of arthropods. These chitin synthesis inhibitors are effective against the larval and pre-adult life stages of sea lice. Due to their low solubility and results of recent monitoring studies conducted in Norway, the sediment compartment is considered the most likely reservoir for these compounds and possible remobilization from the sediment to benthic crustaceans could be of importance. For this reason, the epibenthic copepod Tisbe battagliai was selected for investigations into the acute and developmental effects of these compounds. For comparative purposes, azamethiphos was investigated to identify differences in sensitivity and act as a negative control for developmental effects at environmentally relevant concentrations. Standard acute studies with adult copepods showed little or no acute toxicity at milligrams per liter levels with the flubenzurons, whereas a naupliar developmental test demonstrated that environmentally relevant concentrations (e.g., nanograms per liter) caused a complete cessation of molting and finally death in the exposed copepods. Environ Toxicol Chem 2015;34:1533–1542. © 2015 SETAC
On-site, serial exposure of female fathead minnows to the Elkhorn River, Nebraska, USA, spring agrichemical pulse
Authors: Ali Jonathan M. , Kolok Alan S.
Published: February 2015

In the Midwestern United States, waterways such as the Elkhorn River experience an annual spring pulse of runoff that carries sediments, nutrients, and organic compounds downstream. The objective of the present study was to elucidate relationships between contaminant load in Elkhorn River water and biological impacts on female fathead minnows throughout the entire spring agrichemical pulse. Fish were maintained in on-site outdoor microcosms at the Elkhorn River Research Station. The start of the spring pulse was determined using commercially available atrazine strips that detected atrazine when concentrations exceeded 3 ppb. Once the pulse began, 5 serial 7-d exposures were conducted. Concentrations of atrazine, its metabolites, and 5 other herbicides were quantified using gas chromatography–mass spectrometry. Agrichemicals peaked during the first and second weeks of the pulse, with a smaller peak occurring during week 4, but the peaks were not directly associated with runoff events (as estimated from river discharge). Elevated agrichemical concentrations were associated with biological impacts, but not solely responsible. In the present study, differences in the abiotic environment were found to play a significant role in the defeminization of exposed female fathead minnows. Environ Toxicol Chem 2015;34:1354–1361. © 2015 SETAC
The impact of stratifying by family history in colorectal cancer screening programs
Authors: Goede Simon Lucas , Rabeneck Linda , Lansdorp‐Vogelaar Iris , Zauber Ann G. , Paszat Lawrence F. , Hoch Jeffrey S. , Yong Jean H.E. , van Hees Frank , Tinmouth Jill , van Ballegooijen Marjolein
Published: February 2015

In the province‐wide colorectal cancer (CRC) screening program in Ontario, Canada, individuals with a family history of CRC are offered colonoscopy screening and those without are offered guaiac fecal occult blood testing (gFOBT, Hemoccult II). We used microsimulation modeling to estimate the cumulative number of CRC deaths prevented and colonoscopies performed between 2008 and 2038 with this family history‐based screening program, compared to a regular gFOBT program. In both programs, we assumed screening uptake increased from 30% (participation level in 2008 before the program was launched) to 60%. We assumed that 11% of the population had a family history, defined as having at least one first‐degree relative diagnosed with CRC. The programs offered screening between age 50 and 74 years, every two years for gFOBT, and every ten years for colonoscopy. Compared to opportunistic screening (2008 participation level kept constant at 30%), the gFOBT program cumulatively prevented 6,700 more CRC deaths and required 570,000 additional colonoscopies by 2038. The family history‐based screening program increased these numbers to 9,300 and 1,100,000, a 40% and 93% increase, respectively. If biennial gFOBT was replaced with biennial fecal immunochemical test (FIT), annual Hemoccult Sensa or five‐yearly sigmoidoscopy screening, both the added benefits and colonoscopies required would decrease. A biennial gFOBT screening program that identifies individuals with a family history of CRC and recommends them to undergo colonoscopy screening would prevent 40% (range in sensitivity analyses: 20–51%) additional deaths while requiring 93% (range: 43–116%) additional colonoscopies, compared to a regular gFOBT screening program.
Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates?
Authors: Mesens Natalie , Crawford Alexander D. , Menke Aswin , Hung Pham Duc , Van Goethem Freddy , Nuyts Rik , Hansen Erik , Wolterbeek Andre , Van Gompel Jacky , De Witte Peter , Esguerra Camila V.
Published: February 2015

Drug‐induced liver injury (DILI) is poorly predicted by single‐cell‐based assays, probably because of the lack of physiological interactions with other cells within the liver. An intact whole liver system such as one present in zebrafish larvae could provide added value in a screening strategy for DILI; however, the possible occurrence of other organ toxicities and the immature larval stage of the zebrafish might complicate accurate and fast analysis. We investigated whether expression analysis of liver‐specific fatty acid binding protein 10a (lfabp10a) was an appropriate endpoint for assessing hepatotoxic effects in zebrafish larvae. It was found that expression analysis of lfabp10a was a valid marker, as after treatment with hepatotoxicants, dose–response curves could be obtained and statistically significant abnormal lfabp10 expression levels correlated with hepatocellular histopathological changes in the liver. However, toxicity in other vital organs such as the heart could impact liver outgrowth and thus had to be assessed concurrently. Whether zebrafish larvae were suitable for assessing human relevant drug‐induced hepatotoxicity was assessed with hepatotoxicants and non‐hepatotoxicants that have been marketed for human use and classified according to their mechanism of toxicity. The zebrafish larva showed promising predictivity towards a number of mechanisms and was capable of distinguishing between hepatotoxic and non‐hepatotoxic chemical analogues, thus implying its applicability as a potential screening model for DILI. Copyright © 2015 John Wiley & Sons, Ltd.
Safety assessment of aditoprim acute, subchronic toxicity and mutagenicity studies
Authors: Wang Xu , Tan Ziqiang , Pan Yuanhu , Ihsan Awais , Liu Qianying , Huang Lingli , Cheng Guyue , Chen Dongmei , Tao Yanfei , Liu Zhenli , Yuan Zonghui
Published: February 2015

Aditoprim (ADP), a new developed dihydrofolate reductase (DHFR) inhibitor, has great potential in clinical veterinary medicine because of its greater pharmacokinetic properties than structural analogs. Preclinical toxicology studies were performed to assess the safety of ADP including an acute oral toxicity test, a subchronic toxicity test and five mutagenicity tests. In the acute oral toxicity test, ADP was administered singly by oral gavage to Wistar rats and Kunming mice. The LD50calculated was 1400 mg kg–1body weight (BW) day–1in rats and 1130 mg kg–1BW day–1in mice. In a subchronic study, Wistar rats were administered ADP at dose levels of 0, 20, 100 and 1000 mg kg–1diet for 90 days. Significant decreases were observed on body weight and food efficiency in the high‐dose group. Treatment‐related changes in clinical serum biochemistry were found in the medium‐ and high‐dose groups. Significant increases in the relative weights of livers and kidneys in females and testis in males in the 1000 mg kg–1diet, and significant decrease in relative weights of livers in males in the 100 mg kg–1diet were noted. Histopathological observations revealed that the 1000 mg kg–1ADP diet could induce lymphocytic infiltration and hepatocytic necrosis near the hepatic portal area. The genotoxicity of ADP was negative in tests, such as the bacterial reverse mutation assay, mice bone marrow erythrocyte micronucleus assay,in vitrochromosomal aberration test,in vitrocho/hgprt mammalian cell mutagenesis assay and mice testicle cells chromosome aberration. Based on the subchronic study, the no‐observed‐adverse‐effect level for ADP was a 20 mg kg–1diet, which is about 1.44‐1.53 mg kg–1BW day–1in rats. Copyright © 2015 John Wiley & Sons, Ltd.
Human bone morphogenetic protein‐7 does not counteract aristolochic acid‐induced renal toxicity
Authors: Antoine Marie‐Hélène , Debelle Frédéric , Piccirilli Julie , El Kaddouri Fadoua , Declèves Anne‐Emilie , De Prez Eric , Husson Cécile , Mies Frédérique , Bourgeade Marie‐Françoise , Nortier Joëlle L.
Published: February 2015

Aristolochic acids (AA) are nephrotoxic and profibrotic agents, leading to chronic kidney disease. As some controversial studies have reported a nephroprotective effect of exogenous recombinant human bone morphogenetic protein (rhBMP)‐7 in several models of renal fibrosis, we investigated the putative effect of rhBMP‐7 to prevent progressive tubulointerstitial damage after AA intoxication in vitro and in vivo. In vitro, the toxicity of AA on renal tubular cells was demonstrated by an increase in vimentin as well as a decrease in β‐catenin expressions, reflecting a dedifferentiation process. Increased fibronectin and interleukin‐6 levels were measured in the supernatants. Enhanced α‐SMA mRNA levels associated to decreased E‐cadherin mRNA levels were also measured. Incubation with rhBMP‐7 only prevented the increase in vimentin and the decrease in β‐catenin expressions. In vivo, in a rat model of AA nephropathy, severe tubulointerstitial lesions induced by AA after 10 and 35 days (collagen IV deposition and tubular atrophy), were not prevented by the rhBMP‐7 treatment. Similarly, rhBMP‐7 did not ameliorate the significant increase in urinary concentrations of transforming growth factor‐β. In summary, our in vitro data demonstrated a poor beneficial effect of rhBMP‐7 to reverse cell toxicity while, in vivo, there was no beneficial effect of rhBMP‐7. Therefore, further investigations are needed to confirm the exact role of BMP‐7 in progressive chronic kidney disease. Copyright © 2015 John Wiley & Sons, Ltd.
Origin‐independent sum over states simulations of magnetic and electronic circular dichroism spectra via the localized orbital/local origin method
Authors: Štěpánek Petr , Bouř Petr
Published: February 2015

Although electronic and magnetic circular dichroism (ECD, MCD) spectra reveal valuable details about molecular geometry and electronic structure, quantum‐chemical simulations significantly facilitate their interpretation. However, the simulated results may depend on the choice of coordinate origin. Previously (Štěpánek and Bouř, J. Comput. Chem. 2013, 34, 1531), the sum‐over‐states (SOS) methodology was found useful for efficient MCD computations. Approximate wave functions were “resolved” using time‐dependent density functional theory, and the origin‐dependence was avoided by placing the origin to the center of mass of the investigated molecule. In this study, a more elegant way is proposed, based on the localized orbital/local origin (LORG) formalism, and a similar approach is also applied to generate ECD intensities. The LORG‐like approach yields fully origin‐independent ECD and MCD spectra. The results thus indicate that the computationally relatively cheap SOS simulations open a new way of modeling molecular properties, including those involving the origin‐dependent magnetic dipole moment operator. © 2015 Wiley Periodicals, Inc.
Comparison of the effects of human dental pulp stem cells and human bone marrow‐derived mesenchymal stem cells on ischemic human astrocytes in vitro
Authors: Song Miyeoun , Jue Seong‐Suk , Cho Young‐Ah , Kim Eun‐Cheol
Published: February 2015

This study assesses the cytoprotective effects of human dental pulp stem cells (hDPSCs) and conditioned medium from hDPSCs (CM‐hDPSCs) on ischemic human astrocytes (hAs) in vitro compared with human bone marrow‐derived mesenchymal stem cells (hMSCs). Ischemia of hAs was induced by oxygen–glucose deprivation (OGD). CM‐hDPSCs and hMSCs were collected after 48 hr of culture. Cell death was determined by 3‐[4,5‐dimethylthialzol‐2‐yl]‐2,5‐diphenyltetrazolium bromide and cellular ATP assays. The expression of glial fibrillary acidic protein (GFAP) and musashi‐1 as markers of reactive astrogliosis was examined with immunochemical staining. mRNA expression and reactive oxygen species (ROS) were analyzed by RT‐PCR and flow cytometry, respectively. OGD increased cytotoxicity in a time‐dependent manner and decreased cellular ATP content concomitantly in hAs. Pretreatment and posttreatment with hDPSCs were associated with greater recovery from OGD‐induced cytotoxicity in hAs compared with hMSCs. Similarly, CM‐hDPSCs had a greater effect on OGD‐induced cytotoxicity in a dose‐dependent manner. Pre‐ and posttreatment with CM‐hDPSCs or CM‐hMSCs attenuated OGD‐induced GFAP, nestin, and musashi‐1 expression in hAs. Furthermore, treatment of cells with CM‐hDPSCs and hMSCs blocked OGD‐induced ROS production and interleukin‐1ß upregulation. This study demonstrates for the first time that hDPSCs and CM‐hDPSCs confer superior cytoprotection against cell death in an in vitro OGD model compared with hMSCs as shown by cell viability assay. Reactive gliosis, ROS production, and inflammatory mediators might contribute to this protective effect. Therefore, hDPSCs could represent an alternative source of cell therapy for ischemic stroke. © 2015 Wiley Periodicals, Inc.
The Style Troika Model: A Structural Model of the Thinking and Creating Styles Scale
Authors: Ibérico Nogueira Sara , Almeida Leonor , Garcês Soraia , Pocinho Margarida , Wechsler Solange
Published: February 2015

Individuals express their creativity through a variety of thinking and creating styles (Wechsler, 2006, 2007). These constructs underlie the Thinking and Creating Styles Scale (TCSS), which is used to identify individuals' creating styles. The aim of this research is to assess the factorial structure of the Portuguese version of the TCSS. Two studies were performed using 414 and 369 Portuguese participants with mean ages of 29.25 and 29.35 years, respectively. Study 1 consisted of an exploratory factor analysis that yielded a three‐factor solution. Study 2 consisted of a confirmatory factor analysis used to test the fit and compare the suitability of several factorial solutions. The three‐factor model (Non‐Conforming/Transformer, Cautious/Reflexive, and Logical/Objective) with the best statistical fit was called the Troika Model. In this model, each factor had five items and showed good and acceptable indices of fit. This new three‐factor structure results in a more efficient and attractive version of the TCSS: the Creating and Thinking Styles‐Troika Scale (CTS‐TS). Future studies should use the CTS‐TS and other creativity assessment instruments to explore the creativity level and style dichotomy.
Larger femoral periprosthetic bone mineral density decrease following total hip arthroplasty for femoral neck fracture than for osteoarthritis: A prospective, observational cohort study
Authors: Mann Tobias , Eisler Thomas , Bodén Henrik , Muren Olle , Stark André , Salemyr Mats , Sköldenberg Olof
Published: February 2015

Studies on patients with degenerative joint disease of the hip show that femoral periprosthetic bone mineral decreases following total hip arthroplasty. Scarcely any osteodensitometric data exist on femoral neck fracture (FNF) patients and periprosthetic bone remodelling. In two parallel cohorts we enrolled 87 patients (mean age, 72 ± 12 years; male:female ratio, 30:57) undergoing total hip arthroplasty for either primary osteoarthritis (OA) of the hip (n = 37) or for an acute FNF (n = 50) and followed them for a mean of 5.4 years. Outcomes were bone mineral density (BMD) changes in the periprosthetic Gruen zones 1–7, the incidence of periprosthetic fractures and clinical outcome. The bone mineral loss in the fracture group was more than twice that of the osteoarthritis group, −16.9% versus −6.8% (p = 0.004). The incidence of periprosthetic fractures was 12% (6/50) in the fracture cohort compared with none (0%) in the OA cohort (p = 0.03). Periprosthetic bone mineral loss following total hip arthroplasty is significantly greater in patients who are treated for acute FNF than in OA patients. This decrease of BMD follows a different pattern with the FNF patients losing larger proportions of bone in Gruen zones 1, 2, 6, and 7 while the OA patients tend to have larger losses only in zones 1 and 7. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:504–512, 2015.
Prognostic significance of tumor mitotic rate in T2 melanoma staged with sentinel lymphadenectomy
Authors: Baker Justin J. , Meyers Michael O. , Deal Allison M. , Frank Jill F. , Stitzenberg Karyn B. , Ollila David W.
Published: February 2015

Background and Objectives

Tumor mitotic rate (TMR) is an important prognostic variable for patients with thin melanoma. However it remains unclear what the significance of TMR is for more deeply invasive melanoma pathologically staged with a sentinel lymph node biopsy. We sought to determine the prognostic value of TMR in clinically node‐negative T2 melanoma patients staged with sentinel lymphadenectomy.

Methods

A prospective IRB‐approved database of cutaneous melanoma patients treated from 09/01/1997–03/01/2011 was used to identify patients with T2 melanoma staged with a SLN. Associations were evaluated using Fisher's Exact test, and Kaplan–Meier analysis.

Results

Three hundred thirteen T2 patients were included. 19% had ulceration, 11% a positive sentinel node (SLN), and 10% recurred. 44% of patients had TMR ≥1/mm2. TMR ≥1/mm2 did not predict SLN status. TMR ≥1/mm2 was significantly associated with recurrence in SLN negative patients; only 3% of those with TMR <1/mm2 developed a recurrence compared to 16% of those with TMR ≥1/mm2 (P < 0.0001).

Conclusions

Although TMR ≥1/mm2 is not associated with risk of SLN involvement in T2 melanoma, it is a significant risk factor for recurrence when SLN negative. As such, TMR could be used to stratify follow‐up regimens in SLN negative T2 patients. J. Surg. Oncol. 2015 111:711–715. © 2015 Wiley Periodicals, Inc.
Radical cystectomy in patients over 80 years old in Quebec: A population‐based study of outcomes
Authors: Zakaria Ahmed S. , Santos Fabiano , Tanguay Simon , Kassouf Wassim , Aprikian Armen G.
Published: February 2015

Objectives

To document radical cystectomy (RC) outcomes in patients over 80 years old across Quebec during the years 2000–2009 and to examine potentially related factors.

Methods

Within Quebec health insurance medical services database, we identified patients over 80 years who underwent RC. The outcomes analyzed were post‐operative complications, mortality rates at 30, 60 and 90 days and overall survival.

Results

A total of 275 patients over 80 years old had RC performed in 38 hospitals across Quebec. Among them, 33% had major post‐operative complications with 16% having more than one complication. Mortality rates at 30, 60 and 90 days were 5.8%, 9.8% and 13% respectively. 44.3% of RCs were performed in seven academic hospitals with mortality rates of 2.5%, 6.5% and 9% respectively. Community hospitals had mortality of 8.5%, 12.4% and 16.3% respectively (P < 0.001). The cohort 5‐year overall survival rate was 27%. The presence of post‐operative complications and the number of complications negatively affected overall survival (P < 0.001)

Conclusion

Patients over 80 years of age have high post‐RC mortality rates, especially at 90 days. In addition, it appears that they have lower post‐operative mortality if their RCs were performed in academic centers. Mortality rates and complications can be used when obtaining informed consent. J. Surg. Oncol. 2015 111:917–922. © 2014 Wiley Periodicals, Inc.
Survivors of standard risk acute lymphoblastic leukemia do not have increased risk for overweight and obesity compared to non‐cancer peers: A report from the Children's Oncology Group
Authors: Lindemulder Susan J. , Stork Linda C. , Bostrom Bruce , Lu Xiaomin , Devidas Meenakshi , Hunger Stephen , Neglia Joseph P. , Kadan‐Lottick Nina S.
Published: February 2015

Background

We sought to determine whether survivors of standard risk ALL (SR‐ALL) treated without cranial radiation have increased risk for obesity by assessing changes in body mass index (BMI) during and after treatment; identifying contributing patient and treatment factors; comparing rates of overweight/obese to national health data.

Procedure

Eligibility for this retrospective cohort study included: (i) previous enrollment on legacy therapy trials CCG1922 or CCG1952; (ii) continuous first remission; and (iii) age at follow‐up evaluation of 6–16.99 years. Height and weight from diagnosis, consolidation, start of maintenance, last cycle of maintenance, and off‐therapy were analyzed.

Results

The 269 subjects were a median age of 3.5 years at diagnosis and 13.3 years at follow‐up. BMI% significantly increased from induction to consolidation (+17.6 ± 1.6%), start of maintenance to end‐of‐treatment (+3.3 ± 1.6%) and decreased from end‐of‐treatment to follow‐up (−3.5 ± 1.6%,). Higher BMI% at follow‐up was associated with higher BMI% at diagnosis (P < 0.0001), but not age at diagnosis, gender, or race. Patients previously randomized to dexamethasone had a stronger association between BMI% at diagnosis and BMI% at follow‐up than those who received prednisone (P = 0.0005). At follow‐up, 39% of survivors were overweight or obese; the relative risk of overweight/obese was 1.028 (P = 0.738) compared to the general population.

Conclusions

Our study of patients with SR‐ALL found a significant increase in BMI% largely during the first month of therapy that is greater with dexamethasone than prednisone. However, after therapy, there was no increased risk of overweight/obese BMI compared to non‐cancer peers. Pediatr Blood Cancer 2015;62:1035–1041. © 2015 Wiley Periodicals, Inc.
Information needs in parents of long‐term childhood cancer survivors
Authors: Vetsch Janine , Rueegg Corina S. , Gianinazzi Micòl E. , Bergsträsser Eva , von der Weid Nicolas X. , Michel Gisela ,   for the Swiss Paediatric Oncology Group (SPOG)
Published: February 2015

Background

Parents’ knowledge about cancer, treatment, potential late effects and necessary follow‐up is important to reassure themselves and motivate their child to participate in regular follow‐up. We aimed to describe (i) parents’ perception of information received during and after treatment; (ii) parents’ current needs for information today, and to investigate; and (iii) associations between information needs and socio‐demographic and clinical characteristics.

Methods

As part of the Swiss Childhood Cancer Survivor Study, a follow‐up questionnaire was sent to parents of survivors, diagnosed < 16 years and after 1990, and aged 11–17 years at study. We assessed parents’ perception of information received and information needs, concerns about consequences of the cancer and socio‐demographic information. Information on clinical data was available from the Swiss Childhood Cancer Registry.

Results

Of 309 eligible parents, 189 responded (67%; mean time since diagnosis: 11.3 years, SD = 2.5). Parents perceived to have received verbal information (on illness: verbal 91%, written 40%; treatment: verbal 88%, written 46%; follow‐up: verbal 85% written 27%; late effects: verbal 75%, written 19%). Many parents reported current information needs, especially on late effects (71%). The preferred source was written general (28%) or verbal information (25%), less favored was online information (12%). Information needs were associated with migration background (P = 0.039), greater concerns about consequences of cancer (P = 0.024) and no information received (P = 0.035).

Conclusion

Parents reported that they received mainly verbal information. However, they still needed further information especially about possible late effects. Individual long‐term follow‐up plans, including a treatment summary, should be provided to each survivor, preferably in written format. Pediatr Blood Cancer 2015;62:859–866. © 2015 Wiley Periodicals, Inc.
A unique description of stage IV extranodal marginal zone lymphoma (EMZL) in an adolescent associated with gamma heavy chain disease
Authors: Mittal Nupur , Zhu Bing , Gaitonde Sujata , Lu Yang , Schmidt Mary Lou
Published: February 2015

Extranodal Marginal zone lymphoma (EMZL) is a rare, usually localized disease in children. Advanced stage EMZL in adults is considered incurable, with prolonged remissions after chemotherapy. Gamma heavy chain disease (γHCD) is a rare disease of adults associated with lympho‐proliferative processes with no comparable reports in children. A case of stage‐IV EMZL with γHCD in an adolescent is discussed including treatment with Bendamustine plus Rituximab. The patient remains disease free 18 months from diagnosis. This case highlights necessity for careful diagnostic work‐up to identify indolent lymphomas in children which may respond to less toxic chemotherapy than used for common pediatric lymphomas. Pediatr Blood Cancer 2015;62:905–908. © 2015 Wiley Periodicals, Inc.
Pediatric patients who receive antibiotics for fever and neutropenia in less than 60 min have decreased intensive care needs
Authors: Salstrom Jennifer L. , Coughlin Rebecca L. , Pool Kathleen , Bojan Melissa , Mediavilla Camille , Schwent William , Rannie Michael , Law Dawn , Finnerty Michelle , Hilden Joanne
Published: February 2015

Background

Antibiotic delivery to patients with fever and neutropenia (F&N) in <60 min is an increasingly important quality measure for oncology centers, but several published reports indicate that a time to antibiotic delivery (TTA) of <60 min is quite difficult to achieve. Here we report a quality improvement (QI) effort that sought to decrease TTA and assess associated clinical outcomes in pediatric patients with cancer and F&N.

Procedure

We used Lean‐Methodology and a Plan‐Do‐Study‐Act approach to direct QI efforts and prospectively tracked TTA measures and associated clinical outcomes (length of stay, duration of fever, use of imaging studies to search for occult infection, bacteremia, intensive care unit (ICU) consultation or admission, and mortality). We then performed statistical analysis to determine the impact of our QI interventions on total TTA, sub‐process times, and clinical outcomes.

Results

Our QI interventions significantly improved TTA such that we are now able to deliver antibiotics in <60 min nearly 100% of the time. All TTA sub‐process times also improved. Moreover, achieving TTA <60 min significantly reduced the need for ICU consultation or admission (P = 0.003) in this population.

Conclusion

Here we describe our QI effort along with a detailed assessment of several associated clinical outcomes. These data indicate that decreasing TTA to <60 min is achievable and associated with improved outcomes in pediatric patients with cancer and F&N. Pediatr Blood Cancer 2015;62:807–815. © 2015 The Authors. Pediatric Blood & Cancer, published by Wiley Periodicals, Inc.