bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liraglutide pancreatitis: The ABCD nationwide liraglutide audit
Authors: Ryder REJ , Thong KY , Blann AD , Phillips SM , Barwell ND , Kelly CJG , Semple C , Cull ML , Gupta P Sen ,   for the ABCD nationwide liraglutide audit contributors
Published: September 2013

Introduction: There is concern that glucagon-like peptide-1 (GLP1) receptor agonists may be associated with acute pancreatitis. The data from the ABCD nationwide liraglutide audit (November 2009–June 2013; 6010 patients) provide an opportunity to assess the extent of the problem in routine clinical practice in the UK. Methods: At every patient visit, audit-contributors were invited to submit, via an electronic form, clinical data collected as part of routine clinical practice, including data on possible side effects of treatment. Cases of ‘possible pancreatitis’ were identified and we contacted the centres concerned to obtain full details. Results: To date, the audit has monitored 3720 years of exposure to liraglutide. There were four cases of possible pancreatitis documented from the 6010 patients on liraglutide: three patients had likely causes of pancreatitis identified and one patient had no aetiological cause. This sole case represents an incidence of 0.027/100 patient-years of exposure to liraglutide. Conclusion: In cases of acute pancreatitis of a patient on liraglutide, if another cause can be found (usually gall stones associated with obesity), the drug is not be necessarily culpable. People with Type 2 diabetes are at greater risk of acute pancreatitis (hazard ratio between 1.5 and 2.8). Thus, the possibility of liraglutide-associated pancreatitis in ‘real-world’ clinical practice (0.027/100 patient years) represents a very small risk.
Graphical assessment of consistency in treatment effect among countries in multi-regional clinical trials
Authors: Chen Joshua , Zheng Hao , Quan Hui , Li Gang , Gallo Paul , Ouyang Soo Peter , Binkowitz Bruce , Ting Naitee , Tanaka Yoko , Luo Xiaolong , Ibia Ekopimo ,   for the Society for Clinical Trials (SCT) Multi-regional Clinical Trial (MRCT) Consistency Working Group
Published: September 2013

Background One key objective of a multi-regional clinical trial (MRCT) is to use the trial results to ‘bridge’ from the global level to local region in support of local registrations. However, data from each individual country are typically limited and the large number of countries will increase the chance of false positive findings. Purpose Graphical tools to facilitate identification of potential outlying countries could be useful for country-level assessment. Existing methods such as funnel plot and expected range of treatment effect can substantially increase the false positive rate. The expected range approach can also have a very low power when there are a large number of small countries, which is typical in a MRCT. Methods In this article, we apply normal probability plots, commonly used as a diagnostic tool in linear regression analysis, to assess the differences among countries. Evidence of possible inconsistency, which incorporates both the estimated treatment effect and sample size, is plotted against its expected order statistic. Results A simulation study is conducted to assess the impact of the negative correlation among residuals due to unequal sample sizes among countries and the performance of the proposed methods compared to existing approaches. The proposed methods tend to have a balanced consideration with substantially smaller false positive rate and reasonable probability to identify outlying countries in realistic scenarios. Limitations While much lower than that of commonly used methods, the false positive rates of the proposed methods are not strictly controlled. This may be acceptable for these graphical tools with intention to flag potential outliers for investigation. Conclusions We recommend routine use of normal probability plots in MRCTs as a tool to identify potential outliers. If the normal probability plot is approximately linear but has heavy tails with a few outlying countries, these potential outliers should be examined carefully to understand the possible reasons.
Prophylactic antiepileptic treatment reduces seizure frequency in natalizumab-associated progressive multifocal leukoencephalopathy
Authors: Hoepner Robert , Dahlhaus Stefanie , Kollar Susanne , Zurawski Barbara , Chan Andrew , Kleiter Ingo , Gold Ralf , Hellwig Kerstin 
Published: September 2013

Objective: Little is known about seizures in natalizumab-associated progressive multifocal leukoencephalopathy (NAT-PML). Methods: A review of clinical records of 15 NAT-PML patients with multiple sclerosis (MS) treated at a German university hospital. Results: Some 53% (8/15) of our patients developed seizures with often multiple semiologies (seven grand mal, three simple partial motor and two psychomotor seizures). Series of seizures or status epilepticus occurred in seven of these eight. Seizure onset was on average 61 days after onset of NAT-PML and was associated with immune reconstitution inflammatory syndrome (IRIS) in five of eight patients. After having observed severe seizures during NAT-PML in seven of our first nine patients, we started preventive antiepileptic treatment (PAT) with levetiracetam (1000–1750 mg/day). Patient subgroups analyzed for seizures and PAT did not differ in baseline characteristics. Only one of six patients, who received PAT, had a seizure compared with seven of nine patients without PAT (2-tailed Fisher’s exact test, p = 0.04). Conclusions: Although the small sample size and retrospective nature of the study are limitations, we propose to treat NAT-PML patients with PAT early after diagnosis, as seizures seem to be common and severe in NAT-PML.
IL-21 and CD40L signals from autologous T cells can induce antigen-independent proliferation of CLL cells
Authors: Pascutti Maria Fernanda , Jak Margot , Tromp Jacqueline M. , Derks Ingrid A. M. , Remmerswaal Ester B. M. , Thijssen Rachel , van Attekum Martijn H. A. , van Bochove Gregor G. , Luijks Dieuwertje M. , Pals Steven T. , van Lier René A. W. , Kater Arnon P. , van Oers Marinus H. J. , Eldering Eric 
Published: September 2013

Key Points
Autologous activated T cells can drive antigen-independent proliferation of CLL cells through CD40 and IL-21 signaling. An IL-21 gene induction signature, IL-21 mRNA, and protein can be found in CLL lymph node samples.
The control of hematopoietic stem cell maintenance, self-renewal, and differentiation by Mysm1-mediated epigenetic regulation
Authors: Wang Tao , Nandakumar Vijayalakshmi , Jiang Xiao-Xia , Jones Lindsey , Yang An-Gang , Huang Xue F. , Chen Si-Yi 
Published: September 2013

Key Points
Mysm1 is required to maintain the quiescence and pool size of HSC, and its deletion severely impairs the survival and function of HSC. Mysm1 controls HSC homeostasis by regulating Gfi1 expression via modulating histone modifications and transcriptional factors recruitment.
Treatment factors affecting outcomes in HIV-associated non-Hodgkin lymphomas: a pooled analysis of 1546 patients
Authors: Barta Stefan K. , Xue Xiaonan , Wang Dan , Tamari Roni , Lee Jeannette Y. , Mounier Nicolas , Kaplan Lawrence D. , Ribera Josep-Maria , Spina Michele , Tirelli Umberto , Weiss Rudolf , Galicier Lionel , Boue Francois , Wilson Wyndham H. , Wyen Christoph , Oriol Albert , Navarro José-Tomás , Dunleavy Kieron , Little Richard F. , Ratner Lee , Garcia Olga , Morgades Mireia , Remick Scot C. , Noy Ariela , Sparano Joseph A. 
Published: September 2013

Key Points
Rituximab use is associated with significant improvement in all outcomes for patients with HIV-associated CD20-positive lymphomas. Infusional EPOCH chemotherapy is associated with better overall survival in patients with AIDS-related diffuse large B-cell lymphoma (DLBCL).
Meis1 regulates Foxn4 expression during retinal progenitor cell differentiation
Authors: Islam Mohammed M. , Li Ying , Luo Huijun , Xiang Mengqing , Cai Li 
Published: September 2013

Summary
The transcription factor forkhead box N4 (Foxn4) is a key regulator in a variety of biological processes during development. In particular, Foxn4 plays an essential role in the genesis of horizontal and amacrine neurons from neural progenitors in the vertebrate retina. Although the functions of Foxn4 have been well established, the transcriptional regulation of Foxn4 expression during progenitor cell differentiation remains unclear. Here, we report that an evolutionarily conserved 129 bp noncoding DNA fragment (Foxn4CR4.2 or CR4.2), located ∼26 kb upstream of Foxn4 transcription start site, functions as a cis-element for Foxn4 regulation. CR4.2 directs gene expression in Foxn4-positive cells, primarily in progenitors, differentiating horizontal and amacrine cells. We further determined that the gene regulatory activity of CR4.2 is modulated by Meis1 binding motif, which is bound and activated by Meis1 transcription factor. Deletion of the Meis1 binding motif or knockdown of Meis1 expression abolishes the gene regulatory activity of CR4.2. In addition, knockdown of Meis1 expression diminishes the endogenous Foxn4 expression and affects cell lineage development. Together, we demonstrate that CR4.2 and its interacting Meis1 transcription factor play important roles in regulating Foxn4 expression during early retinogenesis. These findings provide new insights into molecular mechanisms that govern gene regulation in retinal progenitors and specific cell lineage development.
Mutations in the Arabidopsis RPK1 gene uncouple cotyledon anlagen and primordia by modulating epidermal cell shape and polarity
Authors: Luichtl Miriam , Fiesselmann Birgit S. , Matthes Michaela , Yang Xiaomeng , Peis Ottilie , Brunner Andrä , Torres-Ruiz Ramon A. 
Published: September 2013

Summary
Plant seedlings have either one or two cotyledons. The mechanisms that regulate this organ number are poorly understood. Mutations in the RECEPTOR-LIKE PROTEIN KINASE1 (RPK1) gene of the dicot Arabidopsis have only one cotyledon, with low penetrance due to complex genetic redundancy. An analysis of patterning genes required for cotyledon initiation showed that these have normal expression patterns, defining the cotyledon anlagen, in rpk1. This was also true for key genes, which organize the shoot apical meristem (SAM). By contrast, epidermal cell shape and polarity were compromised in rpk1 embryos, as evidenced by disturbed polarity of the auxin efflux carrier PIN1. PIN1 is required for the establishment of auxin maxima, which induce and maintain organ primordia. The effects in rpk1 mutants manifest in a spatially and timely stochastic fashion probably due to redundancy of RPK1-like functions. Consistently, auxin maxima showed a stochastic distribution in rpk1 embryos, being at times entirely absent and at other times supernumerary. This variability may explain how monocotyledonous seedlings and cotyledon shape variants can developmentally arise in Arabidopsis and possibly in other plants.
The sirtuin SIRT6 regulates stress granules formation in C. elegans and in mammals
Authors: Jedrusik-Bode Monika , Studencka Maja , Smolka Christian , Baumann Tobias , Schmidt Henning , Kampf Jan , Paap Franziska , Martin Sophie , Tazi Jamal , Müller Kristian M. , Krüger Marcus , Braun Thomas , Bober Eva 
Published: September 2013

SIRT6 is a NAD+-dependent deacetylase that modulates chromatin structure and safeguards genomic stability. So far, SIRT6 has been assigned to the nucleus and only nuclear targets of SIRT6 are known. Here, we demonstrate that in response to stress, C. elegans SIR-2.4 and its mammalian orthologue SIRT6 localize to cytoplasmic stress granules (SGs), interact with various SGs components and induce their assembly. Loss of SIRT6 or inhibition of its catalytic activity in MEF cells impairs SGs formation and delays disassembly during recovery, while deficiency of SIR-2.4 diminishes maintenance of P granules and decreases survival of C. elegans under stress condition.
Our findings uncover a novel, evolutionary conserved function of SIRT6 in maintenance of SGs in response to stress.
Why translation counts for mitochondria – retrograde signalling links mitochondrial protein synthesis to mitochondrial biogenesis and cell proliferation
Authors: Battersby Brendan J. , Richter Uwe 
Published: September 2013

Summary
Organelle biosynthesis is a key requirement for cell growth and division. The regulation of mitochondrial biosynthesis exhibits additional layers of complexity compared with that of other organelles because they contain their own genome and dedicated ribosomes. Maintaining these components requires gene expression to be coordinated between the nucleo-cytoplasmic compartment and mitochondria in order to monitor organelle homeostasis and to integrate the responses to the physiological and developmental demands of the cell. Surprisingly, the parameters that are used to monitor or count mitochondrial abundance are not known, nor are the signalling pathways. Inhibiting the translation on mito-ribosomes genetically or with antibiotics can impair cell proliferation and has been attributed to defects in aerobic energy metabolism, even though proliferating cells rely primarily on glycolysis to fuel their metabolic demands. However, a recent study indicates that mitochondrial translational stress and the rescue mechanisms that relieve this stress cause the defect in cell proliferation and occur before any impairment of oxidative phosphorylation. Therefore, the process of mitochondrial translation in itself appears to be an important checkpoint for the monitoring of mitochondrial homeostasis and might have a role in establishing mitochondrial abundance within a cell. This hypothesis article will explore the evidence supporting a role for mito-ribosomes and translation in a mitochondria-counting mechanism.
First Metabolic Profile of XLR-11, a Novel Synthetic Cannabinoid, Obtained by Using Human Hepatocytes and High-Resolution Mass Spectrometry
Authors: Wohlfarth Ariane , Pang Shaokun , Zhu Mingshe , Gandhi Adarsh S , Scheidweiler Karl B , Liu Hua-fen , Huestis Marilyn A 
Published: September 2013

BACKGROUNDSince the mid-2000s synthetic cannabinoids have been abused as recreational drugs, prompting scheduling of these substances in many countries. To circumvent legislation, manufacturers constantly market new compounds; [1-(5-fluoropentyl)indol-3-yl]-(2,2,3,3-tetramethylcyclopropyl)methanone (XLR-11), the fluorinated UR-144 analog, is one of the most recent and widely abused drugs, and its use is now linked with acute kidney injury. Our goal was to investigate XLR-11 metabolism for identification of major urinary targets in analytical methods and to clarify the origin of metabolites when one or more parent synthetic cannabinoids can be the source.METHODSWe incubated 10 μmol/L XLR-11 with pooled human hepatocytes and sampled after 1 and 3 h. Samples were analyzed by high-resolution mass spectrometry with a TOF scan followed by information-dependent acquisition triggered product ion scans with dynamic BACKGROUND subtraction and mass defect filters. Scans were thoroughly data mined with different data processing algorithms (Metabolite Pilot 1.5).RESULTSXLR-11 underwent phase I and II metabolism, producing more than 25 metabolites resulting from hydroxylation, carboxylation, hemiketal and hemiacetal formation, internal dehydration, and further glucuronidation of some oxidative metabolites. No sulfate or glutathione conjugation was observed. XLR-11 also was defluorinated, forming UR-144 metabolites. On the basis of mass spectrometry peak areas, we determined that the major metabolites were 2′-carboxy-XLR-11, UR-144 pentanoic acid, 5-hydroxy-UR-144, hydroxy-XLR-11 glucuronides, and 2′-carboxy-UR-144 pentanoic acid. Minor metabolites were combinations of the biotransformations mentioned above, often glucuronidated.CONCLUSIONSThese are the first data defining major urinary targets of XLR-11 metabolism that could document XLR-11 intake in forensic and clinical investigations.
Thyroid dysfunction in thalassaemic patients: ferritin as a prognostic marker and combined iron chelators as an ideal therapy
Authors: Chirico Valeria , Antonio Lacquaniti , Vincenzo Salpietro , Luca Nicoletta , Valeria Ferraù , Basilia Piraino , Luciana Rigoli , Carmelo Salpietro , Teresa Arrigo 
Published: September 2013

ObjectiveEndocrine complications characterised patients with β thalassaemia (βT). In particular, thyroid dysfunction occurs frequently in βT major, but its long-term natural history is poorly understood.DesignA total of 72 βT patients were followed for 8 years. The incidence of thyreopathies, defined as the primary study endpoint, was assessed. The aim of this study was to analyse the prognostic role of ferritin for thyreopathies in patients with major and intermedia βT. The power of different iron chelators to treat iron overload and to prevent or reverse thyreopathies was also assessed.MethodsPatients were treated with chelators with different chelation strategies during the study. Receiver operating characteristics analysis was employed to calculate the area under the curve for serum ferritin to find the best cutoff values capable of identifying thyroid dysfunction in thalassaemic patients. Kaplan–Meier curves were generated to assess incidence of thyreopathy. Adjusted risk estimates for thyreopathy were calculated using univariate followed by multivariate Cox proportional hazard regression analysis.ResultsPatients with thyroid dysfunction were characterised by higher ferritin when compared with patients without thyreopathies (1500 (872–2336) vs 513 (370–698) μg/l;P<0.0001). Patients with ferritin values above 1800 μg/l experienced a significantly faster evolution to endpoint (log-rank (χ2): 7.7;P=0.005). Ferritin predicted high risk of thyroid dysfunction independently of confounding factors (hazard ratio: 1.20;P<0.0001). The intensification of chelation therapy led to an amelioration of thyroid function.ConclusionsFerritin represents a prognostic marker for βT patients and a predictive factor for progression to thyroid dysfunction. Intensive chelation therapy allows the prevention and reversibility of thyroid complications.
Studies on the Enantiomers of RC-33 as Neuroprotective Agents: Isolation, Configurational Assignment, and Preliminary Biological Profile
Authors: Rossi Daniela , Pedrali Alice , Marra Annamaria , Pignataro Luca , Schepmann Dirk , Wünsch Bernhard , Ye Lian , Leuner Kristina , Peviani Marco , Curti Daniela , Azzolina Ornella , Collina Simona 
Published: September 2013

ABSTRACTIn this study we addressed the role of chirality in the biological activity of RC-33, recently studied by us in its racemic form. An asymmetric synthesis procedure was the first experiment, leading to the desired enantioenriched RC-33 but with an enantiomeric excess (ee) not good enough for supporting the in vitro investigation. An enantioselective high‐performance liquid chromatography (HPLC) procedure was then successfully carried out, yielding both RC-33 enantiomers in amounts and optical purity suitable for the pharmacological study. The absolute configuration of pure enantiomers was easily assigned exploiting the asymmetric synthesis previously devised. As emerged in the preliminary in vitro biological investigation, (S)‐ and (R)-RC-33 possess a comparable affinity towards the σ1 receptor and a very a similar behavior in the calcium influx assay, resulting in an equally effective σ1 receptor agonist. Overall, the results obtained so far suggest that the interaction with the biological target is nonstereoselective and leads us to hypothesize that there is a lack of stereoselectivity in the biological activity of RC-33. Chirality 25:814–822, 2013. © 2013 Wiley Periodicals, Inc.
Enantioseparation and Determination of the Chiral Fungicide Furametpyr Enantiomers in Rice, Soil, and Water by High‐Performance Liquid Chromatography
Authors: Dong Fengshou , Chen Xiu , Xu Jun , Liu Xingang , Chen Zenglong , Li Yuanbo , Zhang Hongjun , Zheng Yongquan 
Published: September 2013

ABSTRACTThe chiral fungicide furametpyr is widely used in the rice field to control rice sheath blight; however, furametpyr enantiomers are treated as just one compound in traditional achiral analysis, which gives only partial information. An effective chiral analytical method was developed for the resolution and determination of the fungicide furametpyr enantiomers in rice, soil, and water samples. Furametpyr enantiomers were excellently separated and determined on a Chiralpak AD‐H column with n‐hexane/ethanol (90:10, v/v) as mobile phase at a flow rate of 0.8 mL min‐1 with UV detection at 220 nm. The resolution was up to 8.85. The first eluted enantiomer was (+)‐furametpyr and the second eluted one was (−)‐furametpyr. The effects of mobile‐phase composition and column temperature on the enantioseparation were evaluated. The method was validated for linearity, repeatability, accuracy, limit of detection (LOD), and limit of quantification LOQ. LOD was 2.0 µg kg‐1 in water, 0.02 mg kg‐1 in soil, and 0.07 mg kg‐1 in rice with an LOQ of 6.7 µg kg‐1 in water, 0.07 mg kg‐1 in soil, and 0.23 mg kg‐1 in rice. The average recoveries of the pesticide in all matrices ranged from 73.1 to 101.8% for all fortification levels. The precision values associated with the analytical method, expressed as relative standard deviation (RSD) values, were below 14.0% in all matrices. The methodology was successfully applied for the enantioselective analysis of furametpyr enantiomers in real samples. Chirality 25:904–909, 2013. © 2013 Wiley Periodicals, Inc.
Comparative validity of the chinese versions of the bulimic inventory test edinburgh and eating attitudes test for DSM‐IV eating disorders among high school dance and nondance students in taiwan
Authors: Tseng Mei‐Chih Meg , Fang David , Lee Ming‐Been 
Published: September 2013

ABSTRACTObjectivesTo compare the validity of the Eating Attitudes Test (EAT) and the Bulimic Investigatory Test Edinburgh (BITE) as screening tools for eating disorders (EDs), and to identify a new threshold for each questionnaire to detect ED cases among dance and nondance students.MethodDance students enrolled in high schools with gifted dance programs and nondance students randomly chosen from the same or nearby schools were invited to participate in a 2‐phase ED survey. Participants completed the EAT and BITE questionnaires in the first phase. All participants who screened positive and 10% of the participants who screened negative were interviewed blindly using the Structured Clinical Interview for DSM‐IV‐TR Axis I Disorders Patient Edition.ResultsThe BITE had better accuracy than the EAT in detecting ED in general among both dance and non‐dance students. BITE scores of 19 and 16 were the optimal cutoff values for determining ED among dance and nondance students, respectively. The optimal cutoff value for the EAT to diagnose an ED was 19 for dance students and 12 for nondance students. Both questionnaires showed higher sensitivity and lower specificity in dance students than nondance students at the same cutoff points.DiscussionThe BITE had better diagnostic performance than the EAT in this nonclinical population, although its ability to detect restrictive behaviors is likely as limited as that of the EAT. Plausible explanations for these results and limitations of this study are discussed in the text. © 2013 Wiley Periodicals, Inc. (Int J Eat Disord 2014; 47:105–111)