bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence and clinical features of opioid‐induced constipation in the general population: A French study of 15,000 individuals
Authors: Ducrotté P , Milce J , Soufflet C , Fabry C 
Published: July 2016

BackgroundConstipation is common during opioid therapy and can compromise analgesia.AimThe aim of this article is to determine the prevalence and clinical characteristics of opioid‐induced constipation (OIC) in France.MethodsA questionnaire study was conducted in a representative sample of the French general population. Participants completed a 31‐item questionnaire covering opioid use during the previous six months, and the occurrence of constipation (defined as <3 bowel movements per week, straining during defaecation, or both) during opioid treatment.ResultsData were obtained from 15,213 participants, of whom 4753 (31.2%) reported opioid use. Most analgesics (96.5%) were classified as World Health Organization step II analgesics, and the remainder were step III. The most common indications for opioids were bone or joint pain, and soft tissue pain. Overall, 414/4753 (8.7%) opioid users reported OIC while the prevalence of OIC reached 21% in case of regular or prolonged (>1 month) opioid use. Other characteristics associated with OIC included female gender, age ≥50 years and use of step III opioids. Only 177/414 (42.8%) participants with OIC had used medications (most commonly osmotic laxatives) to treat constipation, and satisfaction with constipation medication was moderate (mean (SD) score 7.2 (1.3) on a scale of 0–10).ConclusionsApproximately one‐third of a representative French population had used opioids within the previous six months, and 9% of users had experienced OIC, which is more frequent in case of regular use. OIC appears to be under‐treated, and participants’ satisfaction with their constipation medications was only moderate, suggesting that significant unmet need remains in OIC management.
Cognitive evolution in natalizumab-treated multiple sclerosis patients
Authors: Jacques Francois H , Harel Brian T , Schembri Adrian J , Paquette Chantal , Bilodeau Brigitte , Kalinowski Pawel , Roy Reshmi 
Published: July 2016

Background Cognitive dysfunction affects up to 65% of multiple sclerosis (MS) patients and progresses over time. Natalizumab has been shown to be superior to placebo in preserving cognition for the first two years of therapy. Objectives The objectives of this study are to understand the impact of natalizumab on cognition beyond two years of therapy and to investigate whether baseline characteristics are predictive of clinical response. Methods This is a single-center, 24-month, observational study. Sixty-three patients treated with natalizumab were assessed prior to monthly infusions using a Cogstate battery and the Symbol Digit Modalities Test (SDMT). Patient demographics were collected at baseline. A linear mixed model was conducted with duration of natalizumab therapy as a between-subjects factor (≤2 or >2 years), assessment as a within-subjects factor, and Multiple Sclerosis Severity Score (MSSS) as a covariate. Results Aside from the MSSS ( p = 0.0074), the two groups were identical. No patient showed evidence of sustained cognitive deterioration over the 24-month period. Baseline parameters including impaired cognition did not influence the trajectory of cognitive change over 24 months. Conclusions Our results suggest that natalizumab preserves cognition following four to seven years of continuous therapy. This occurs irrespective of baseline characteristics, including impaired cognition.
Biochemical and structural analysis of the interaction between β-amyloid and fibrinogen
Authors: Zamolodchikov Daria , Berk-Rauch Hanna E. , Oren Deena A. , Stor Daniel S. , Singh Pradeep K. , Kawasaki Masanori , Aso Kazuyoshi , Strickland Sidney , Ahn Hyung Jin 
Published: July 2016

Abstract
The majority of patients with Alzheimer disease (AD) suffer from impaired cerebral circulation. Accumulating evidence suggests that fibrinogen, the main protein component of blood clots, plays an important role in this circulatory dysfunction in AD. Fibrinogen interacts with β-amyloid (Aβ), forming plasmin-resistant abnormal blood clots, and increased fibrin deposition is found in the brains of AD patients and mouse models. In this study, we investigated the biochemical and structural details of the Aβ-fibrinogen interaction. We identified the central region of Aβ42 as the most critical region for the interaction, which can be inhibited by specific antibodies against the central region of Aβ and by naturally occurring p3 peptides, Aβ17-40 and Aβ17-42. X-ray crystallographic analysis revealed that Aβ42 binding to fragment D of fibrinogen induced a structural change in the C-terminal region of the fibrinogen β-chain (β384-393). Furthermore, we identified an additional Aβ-binding site within the αC region of fibrinogen. Aβ binding to this αC region blocked plasmin-mediated fibrin cleavage at this site, resulting in the generation of increased levels of a plasmin-resistant fibrin degradation fragment. Overall, our study elucidates the Aβ-fibrinogen interaction and clarifies the mechanism by which Aβ-fibrinogen binding delays fibrinolysis by plasmin. These results may facilitate the development of effective therapeutics against the Aβ-fibrinogen interaction to treat cerebrovascular abnormalities in AD.
Accelerated telomere attrition in children and teenagers with α1-antitrypsin deficiency
Authors: Escribano Amparo , Pastor Sara , Reula Ana , Castillo Silvia , Vicente Silvia , Sanz Francisco , Casas Francisco , Torres María , Fernández-Fabrellas Estrella , Codoñer-Franch Pilar , Dasí Francisco 
Published: July 2016

Numerous studies have shown that oxidative stress accelerates telomere shortening in several lung pathologies. Since oxidative stress is involved in the pathophysiology of α1-antitrypsin deficiency (AATD), we hypothesised that telomere shortening would be accelerated in AATD patients. This study aimed to assess telomere length in AATD patients and to study its association with α1-antitrypsin phenotypes.Telomere length, telomerase activity, telomerase reverse transcriptase (hTERT) expression and biomarkers of oxidative stress were measured in 62 children and teenagers (aged 2–18 years) diagnosed with AATD and 18 controls (aged 3–16 years).Our results show that intermediate-risk (MZ; SZ) and high-risk (ZZ) AATD patients have significantly shorter telomeres and increased oxidative stress than controls. Correlation studies indicate that telomere length was related to oxidative stress markers in AATD patients. Multiple hypothesis testing revealed an association between telomere length, telomerase activity,hTERTexpression and AATD phenotypes; high-risk patients showed shorter telomeres, lowerhTERTexpression and decreased telomerase activity than intermediate-risk and low-risk patients.AATD patients show evidence of increased oxidative stress leading to telomere attrition. An association between telomere and α1-antitrypsin phenotypes is observed suggesting that telomere length could be a promising biomarker for AATD disease progression.
An assessment of the diagnostic criteria for sessile serrated adenoma/polyps: SSA/Ps using image processing software analysis for Ki67 immunohistochemistry
Authors: Fujimori Yukari , Fujimori Takahiro , Imura Johji , Sugai Tamotsu , Yao Takashi , Wada Ryo , Ajioka Yoichi , Ohkura Yasuo 
Published: July 2016

Abstract

Background
Serrated polyps belong to a heterogeneous group of lesions that are generally characterized morphologically. This type of lesion is thought to be the precursor of sporadic carcinomas with microsatellite instability, and probably also the precursor for CpG island-methylated microsatellite-stable carcinomas. For practical purposes, according to the 2010 WHO classification, the diagnostic criteria for sessile serrated adenomas/polyps (SSA/Ps) was established by the research project “Potential of Cancerization of Colorectal Serrated Lesions” led by the Japanese Society for Cancer of the Colon and Rectum. The aim of this study was to evaluate the validity of the morphologic characteristics established in Japan by using immunohistochemical staining for Ki-67.

Methods
To calculate the target cells, 2 contiguous crypts which could be detected from the bottom of the crypt to the surface of the colorectal epithelium were selected. To validate the proliferative activity, we evaluated the percentage and the asymmetrical staining pattern of Ki67 positive cells in each individual crypt. To examine the immunoreactivity of Ki67, computer-assisted cytometrical analysis was performed.

Results
SSA/Ps had a higher proliferative activity as compared to hyperplastic polyps (HPs) based on the difference in incidence of Ki67 positive cells, and the former also exhibited a significantly higher asymmetric distribution of these cells as compared to HPs, even in lesions with a diameter <10 mm.

Conclusion
We conclude that assessment of the pathological findings of SSA/Ps, including crypt dilation, irregularly branching crypts, and horizontally arranged basal crypts (inverted T- and/or L-shaped crypts) is appropriate to show a significantly higher proliferative activity as compared to HPs. Further, the use of two-dimensional image analysis software is an objective and reproducible method for this type of histological examination.

Virtual slides
The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6718091416698112
The Glasgow‐Maastricht foot model, evaluation of a 26 segment kinematic model of the foot
Authors: Oosterwaal Michiel , Carbes Sylvain , Telfer Scott , Woodburn James , Tørholm Søren , Al‐Munajjed Amir A. , van Rhijn Lodewijk , Meijer Kenneth 
Published: July 2016

AbstractBackgroundAccurately measuring of intrinsic foot kinematics using skin mounted markers is difficult, limited in part by the physical dimensions of the foot. Existing kinematic foot models solve this problem by combining multiple bones into idealized rigid segments. This study presents a novel foot model that allows the motion of the 26 bones to be individually estimated via a combination of partial joint constraints and coupling the motion of separate joints using kinematic rhythms.MethodsSegmented CT data from one healthy subject was used to create a template Glasgow‐Maastricht foot model (GM‐model). Following this, the template was scaled to produce subject‐specific models for five additional healthy participants using a surface scan of the foot and ankle. Forty‐three skin mounted markers, mainly positioned around the foot and ankle, were used to capture the stance phase of the right foot of the six healthy participants during walking. The GM‐model was then applied to calculate the intrinsic foot kinematics.ResultsDistinct motion patterns where found for all joints. The variability in outcome depended on the location of the joint, with reasonable results for sagittal plane motions and poor results for transverse plane motions.ConclusionsThe results of the GM‐model were comparable with existing literature, including bone pin studies, with respect to the range of motion, motion pattern and timing of the motion in the studied joints. This novel model is the most complete kinematic model to date. Further evaluation of the model is warranted.
Clozapinev. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis
Authors: Siskind Dan , McCartney Lara , Goldschlager Romi , Kisely Steve 
Published: July 2016

BackgroundAlthough clozapine is the ‘gold standard’ for treatment-refractory schizophrenia, meta-analyses of clozapine for this condition are lacking.AimsWe conducted a systematic review and meta-analysis of clozapine treatment for people with treatment-refractory schizophrenia.MethodWe searched the Cochrane Schizophrenia Group's trial register, PubMed and EMBASE and hand-searched key papers for randomised controlled trials of clozapine for treatment-refractory schizophrenia.ResultsTwenty-one papers with 25 comparisons were included. The number needed to treat was 9. Clozapine was superior for positive symptoms in both the short and long term. In the short term only clozapine was superior for total and negative symptoms, with higher response rates. Both funding source and dosage affected results. Higher baseline psychosis scores predicted better outcomes for clozapine in a meta-regression.ConclusionsClozapine is superior for treatment-refractory disorder but if there is no response by 6 months medications with lower adverse reactions should be considered.
Use of lithium and cancer risk in patients with bipolar disorder: population-based cohort study
Authors: Huang Ru-Yu , Hsieh Kun-Pin , Huang Wan-Wen , Yang Yi-Hsin 
Published: July 2016

BackgroundLithium inhibits glycogen synthase kinase-3, which is an enzyme involved in the pathogenesis of cancer.AimsTo investigate the association between lithium and cancer risk in patients with bipolar disorder.MethodA retrospective cohort study was designed using the National Health Insurance Research Database (NHIRD) in Taiwan. Patients using lithium comprised the index drug group and patients using anticonvulsants only comprised the control group. Time-dependent Cox regression was used to evaluate the hazard ratios (HRs) for risk of cancer.ResultsCompared with anticonvulsant-only exposure, lithium exposure was associated with significantly lower cancer risk (HR = 0.735, 95% CI 0.554–0.974). The hazard ratios for the first, second and third tertiles of the cumulative defined daily dose were 0.762 (95% CI 0.516–1.125), 0.919 (95% CI 0.640–1.318) and 0.552 (95% CI 0.367–0.831), respectively.ConclusionsLithium is associated with reduced overall cancer risk in patients with bipolar disorder. A dose–response relationship for cancer risk reduction was observed.
Plasmodium AdoMetDC/ODC bifunctional enzyme is essential for male sexual stage development and mosquito transmission
Authors: Hart Robert J. , Ghaffar Atif , Abdalal Shaymaa , Perrin Benjamin , Aly Ahmed S. I. 
Published: July 2016

ABSTRACT
Polyamines are positively-charged organic molecules that are important for cellular growth and division. Polyamines and their synthesizing enzymes are particularly abundant in rapidly proliferating eukaryotic cells such as parasitic protozoa and cancer cells. Polyamine biosynthesis inhibitors, such as Elfornithine, are now being considered for cancer prevention and have been used effectively against Trypanosoma brucei. Inhibitors of polyamine biosynthesis have caused growth arrest of Plasmodium falciparum blood stages in vitro, but in P. berghei only partial inhibition has been observed. While polyamine biosynthesis enzymes are characterized and conserved in Plasmodium spp., little is known on the biological roles of these enzymes inside malaria parasite hosts. The bifunctional polyamine biosynthesis enzyme S-adenosyl methionine decarboxylase/ornithine decarboxylase (AdoMetDC/ODC) was targeted for deletion in P. yoelii. Deletion of AdoMetDC/ODC significantly reduced blood stage parasitemia but Anopheles transmission was completely blocked. We showed that male gametocytogenesis and male gamete exflagellation were abolished and consequently no ookinetes or oocyst sporozoites could be generated from adometdc/odc(–) parasites. Supplementation of putrescine and spermidine did not rescue the defective phenotypes of male gametocytes and gametes of the knockout parasites. These results highlight the crucial role of polyamine homeostasis in the development and functions of Plasmodium erythrocytic stages in the blood and in the mosquito vector and validate polyamine biosynthesis pathway enzymes as drug targeting candidates for malaria parasite transmission blocking.
Ultra-superovulation for the CRISPR-Cas9-mediated production of gene-knockout, single-amino-acid-substituted, and floxed mice
Authors: Nakagawa Yoshiko , Sakuma Tetsushi , Nishimichi Norihisa , Yokosaki Yasuyuki , Yanaka Noriyuki , Takeo Toru , Nakagata Naomi , Yamamoto Takashi 
Published: July 2016

ABSTRACT
Current advances in producing genetically modified mice using genome-editing technologies have indicated the need for improvement of limiting factors including zygote collection for microinjection and their cryopreservation. Recently, we developed a novel superovulation technique using inhibin antiserum and equine chorionic gonadotropin to promote follicle growth. This method enabled the increased production of fertilized oocytes via in vitro fertilization compared with the conventional superovulation method. Here, we verify that the ultra-superovulation technique can be used for the efficient generation of clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9)-mediated knockout mice by microinjection of plasmid vector or ribonucleoprotein into zygotes. We also investigated whether single-amino-acid-substituted mice and conditional knockout mice could be generated. Founder mice bearing base substitutions were generated more efficiently by co-microinjection of Cas9 protein, a guide RNA and single-stranded oligodeoxynucleotide (ssODN) than by plasmid microinjection with ssODN. The conditional allele was successfully introduced by the one-step insertion of an ssODN designed to carry an exon flanked by two loxP sequences and homology arms using a double-cut CRISPR-Cas9 strategy. Our study presents a useful method for the CRISPR-Cas9-based generation of genetically modified mice from the viewpoints of animal welfare and work efficiency.
The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN
Authors: Guan J. , Tucker E. R. , Wan H. , Chand D. , Danielson L. S. , Ruuth K. , El Wakil A. , Witek B. , Jamin Y. , Umapathy G. , Robinson S. P. , Johnson T. W. , Smeal T. , Martinsson T. , Chesler L. , Palmer R. H. , Hallberg B. 
Published: July 2016

ABSTRACT
The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo. In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse model of high-risk neuroblastoma driven by Th-ALKF1174L/MYCN. Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients.
Small heat shock proteins mediate cell-autonomous and -nonautonomous protection in a Drosophila model for environmental-stress-induced degeneration
Authors: Kawasaki Fumiko , Koonce Noelle L. , Guo Linda , Fatima Shahroz , Qiu Catherine , Moon Mackenzie T. , Zheng Yunzhen , Ordway Richard W. 
Published: July 2016

ABSTRACT
Cell and tissue degeneration, and the development of degenerative diseases, are influenced by genetic and environmental factors that affect protein misfolding and proteotoxicity. To better understand the role of the environment in degeneration, we developed a genetic model for heat shock (HS)-stress-induced degeneration in Drosophila. This model exhibits a unique combination of features that enhance genetic analysis of degeneration and protection mechanisms involving environmental stress. These include cell-type-specific failure of proteostasis and degeneration in response to global stress, cell-nonautonomous interactions within a simple and accessible network of susceptible cell types, and precise temporal control over the induction of degeneration. In wild-type flies, HS stress causes selective loss of the flight ability and degeneration of three susceptible cell types comprising the flight motor: muscle, motor neurons and associated glia. Other motor behaviors persist and, accordingly, the corresponding cell types controlling leg motor function are resistant to degeneration. Flight motor degeneration was preceded by a failure of muscle proteostasis characterized by diffuse ubiquitinated protein aggregates. Moreover, muscle-specific overexpression of a small heat shock protein (HSP), HSP23, promoted proteostasis and protected muscle from HS stress. Notably, neurons and glia were protected as well, indicating that a small HSP can mediate cell-nonautonomous protection. Cell-autonomous protection of muscle was characterized by a distinct distribution of ubiquitinated proteins, including perinuclear localization and clearance of protein aggregates associated with the perinuclear microtubule network. This network was severely disrupted in wild-type preparations prior to degeneration, suggesting that it serves an important role in muscle proteostasis and protection. Finally, studies of resistant leg muscles revealed that they sustain proteostasis and the microtubule cytoskeleton after HS stress. These findings establish a model for genetic analysis of degeneration and protection mechanisms involving contributions of environmental factors, and advance our understanding of the protective functions and therapeutic potential of small HSPs.
THE ADMINISTRATIVE AND LEGAL CHARACTERISTIC OF COMPETENCE OF THE RUSSIAN PRESIDENT, FEDERAL ASSEMBLY OF THE RUSSIAN FEDERATION AND THE GOVERNMENT OF THE RUSSIAN FEDERATION IN THE SPHERE OF MANAGEMENT OF CIVIL AVIATION IN RUSSIA
Authors: Шустова Мария , Shustova Mariya 
Published: July 2016

In the scientific article organizational and legal aspects of realization of competence of the Russian President, Federal Assembly of the Russian Federation and the Government of the Russian Federation in the sphere of management of civil aviation in Russia as most important part of domestic economy are analyzed. The positions of
the leading scientists connected with disclosure of the maintenance of
the basic concepts used in the field are considered. The perspective of
functioning and development of air transport is considered.
Learning to Manage and Managing to Learn: The Effects of Student Leadership Service
Authors: Anderson Michael L. , Lu Fangwen 
Published: July 2016

Employers and colleges value individuals with leadership service, but there is limited evidence on whether leadership service itself creates skills. Identification in this context has proved difficult because settings in which leadership service accrues to individuals for ostensibly random reasons are rare. In this study we estimate the effects of random assignment to classroom leadership positions in a Chinese secondary school. We find that leadership service increases test scores, increases students’ political popularity in the classroom, makes students more likely to take initiative, and shapes students’ beliefs about the determinants of success. The results suggest that leadership service may impact human capital and is not solely a signal of preexisting skills. Data are available at http://dx.doi.org/10.1287/mnsc.2016.2483 . This paper was accepted by John List, behavioral economics.