bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of human cytochrome P450 mediated bioactivation of amodiaquine and its major metabolite N‐desethylamodiaquine
Authors: Zhang Yongjie , Vermeulen Nico P. E. , Commandeur Jan N. M. 
Published: October 2016

AimsOxidative bioactivation of amodiaquine (AQ) by cytochrome P450s to a reactive quinoneimine is considered as an important mechanism underlying its idiosyncratic hepatotoxicity. However, because internal exposure to its major metabolite N‐desethylamodiaquine (DEAQ) is up to 240‐fold higher than AQ, bioactivation of DEAQ might significantly contribute to covalent binding. The aim of the present study was to compare the kinetics of bioactivation of AQ and DEAQ by human liver microsomes (HLM) and to characterize the CYPs involved in bioactivation of AQ and DEAQ.MethodsGlutathione was used to trap reactive metabolites formed in incubations of AQ and DEAQ with HLM and recombinant human cytochrome P450s (hCYPs). Kinetics of bioactivation of AQ and DEAQ in HLM and involvement of hCYPs were characterized by measuring corresponding glutathione conjugates (AQ‐SG and DEAQ‐SG) using a high‐performance liquid chromatography method.ResultsBioactivation of AQ and DEAQ in HLM both exhibited Michaelis–Menten kinetics. For AQ bioactivation, enzyme kinetical parameters were Km, 11.5 ± 2.0 μmol l–1, Vmax, 59.2 ± 3.2 pmol min−1 mg−1 and CLint, 5.15 μl min−1 mg−1. For DEAQ, parameters for bioactivation were Km, 6.1 ± 1.3 μmol l–1, Vmax, 5.5 ± 0.4 pmol min−1 mg−1 and CLint 0.90 μl min−1 mg−1. Recombinant hCYPs and inhibition studies with HLM showed involvement of CYP3A4, CYP2C8, CYP2C9 and CYP2D6 in bioactivation.ConclusionsThe major metabolite DEAQ is likely to be quantitatively more important than AQ with respect to hepatic exposure to reactive metabolites in vivo. High expression of CYP3A4, CYP2C8, CYP2C9, and CYP2D6 may be risk factors for hepatotoxicity caused by AQ‐therapy.
Effects of policy interventions on the introduction of novel oral anticoagulants in Stockholm: an interrupted time series analysis
Authors: Komen Joris , Forslund Tomas , Hjemdahl Paul , Andersen Morten , Wettermark Björn 
Published: October 2016

AimsThe aim of the present study was to assess the effect of policy interventions – i.e. reimbursement decisions, guidelines and regional recommendations – on the prescribing of oral anticoagulant treatment in patients with atrial fibrillation (AF).MethodsInterrupted time series analyses were carried out using monthly data on all patients with a recorded diagnosis of AF newly initiated (switchers and anticoagulant‐naïve patients alike) on warfarin, dabigatran, rivaroxaban or apixaban in the Stockholm region from April 2011 until February 2016.ResultsA total of 34 165 initiations in 27 942 patients were included. The publication of the European Guidelines was associated with an increase in novel oral anticoagulant (NOAC) initiations of 12.5% [95% confidence interval (CI) 7.3, 17.7] after 5 months. The choice between the different NOACs was mainly associated with changes in the regional recommendations, with apixaban initiations increasing by 19.5% (95% CI 16.3, 22.7) 5 months after the drug was recommended as a first‐line alternative to warfarin. Dabigatran received a second‐line recommendation but initiations decreased by −9.5% (95% CI −12.6, –6.4), and initiations of rivaroxaban, which had no specific recommendation, decreased by −9.2% (95% CI −12.7, –5.7). A steady decrease in warfarin and increase in NOAC initiations was seen throughout the study period and from November 2015, AF patients were more likely to receive apixaban than any other anticoagulant, while less than 20% of the initiations were with warfarin.ConclusionsAfter reimbursement and inclusion in the European guidelines, the NOACs started gaining in popularity, while changes in regional recommendations were associated with the biggest change in prescribers’ choice between the different NOACs.
Long‐term Use of Z‐Hypnotics and Co‐medication with Benzodiazepines and Opioids
Authors: Sakshaug Solveig , Handal Marte , Hjellvik Vidar , Berg Christian , Ripel Åse , Gustavsen Ingebjørg , Mørland Jørg , Skurtveit Svetlana 
Published: October 2016

AbstractBenzodiazepine‐like drugs (z‐hypnotics) are the most commonly used drugs for treatment of insomnia in Norway. Z‐hypnotics are recommended for short‐term treatment not exceeding 4 weeks. We aimed to study the use of z‐hypnotics in the adult population in Norway with focus on recurrent use in new users, treatment intensity and co‐medication with benzodiazepines and opioids in long‐term users. Data were obtained from the Norwegian Prescription Database. New users in 2009 were followed through 2013. Recurrent z‐hypnotic use was defined as new fillings at least once in each of the four 365‐day follow‐up periods. Age groups of 18–39, 40–64 and 65+ years were analysed separately for men and women. In 2013, 354,571 (8.9%) of the population filled at least one prescription of z‐hypnotics and the prevalence was relatively stable over time. Among the 92,911 new users of z‐hypnotics in 2009, 13,996 (16.8%) received z‐hypnotics all four 365‐day periods of follow‐up. In these long‐term recurrent users, the treatment intensity was high already the second year, with mean annual amounts of 199 and 169 DDDs per patient in men and women, respectively. The interquartile differences were greatest in the youngest age group. 27.9% of the long‐term recurrent users of z‐hypnotics used benzodiazepines the fourth year and 33.9% used opioids. The proportions with co‐medication increased with level of z‐hypnotic treatment intensity. Overall, many z‐hypnotic users had medicines dispensed for longer periods than recommended, and co‐medications with drugs that may reinforce the central depressing and intoxicating effects were common.
Predictors of anticoagulation quality in 15 834 patients performing patient self‐management of oral anticoagulation with vitamin K antagonists in real‐life practice: a survey of the International Self‐Monitoring Association of Orally Anticoagulated Patients
Authors: Schaefer Christian , Wuillemin Walter A. , Kessels Alfons , Jacobson Alan , Nagler Michael 
Published: October 2016

SummaryAlthough patient self‐management (PSM) of oral anticoagulation with vitamin K antagonists is recommended for patients requiring long‐term anticoagulation, important aspects are still unclear. Using data from a large international survey (n = 15 834; median age 72 years; 30·1% female), we studied predictors of poor anticoagulation control (percentage of International Normalized Ratio values within therapeutic range below 75%) and developed a simple prediction model. The following variables were identified as risk factors for poor anticoagulation control and included in the final model: higher intensity of therapeutic range (odds ratio [OR] on every level 1·9; 95% confidence interval [CI] 1·8–2·0), long intervals between measurements (>14 d; 1·5; 95% CI 1·3–1·7), female sex (OR 1·3; 95% CI 1·2–1·4), and management other than PSM (OR 1·4; 95% CI 1·2–1·6). At a threshold of 0·2 (at least one variable present), the model predicted poor anticoagulation control with a sensitivity of 85·3% (95% CI: 84·0, 86·4) and a specificity of 28·5% (27·6, 29·5). The area under the receiver operated characteristic curve was 0·65. Using the proposed prediction model, physicians will be able to identify patients with a low chance of performing well, considering additional training, regular follow‐up, or adjustment of therapeutic ranges.
Similar incidence of severe acute GVHD and less severe chronic GVHD in PBSCT from unmanipulated, haploidentical donors compared with that from matched sibling donors for patients with haematological malignancies
Authors: Li Hong‐Hua , Li Fei , Gao Chun‐Ji , Huang Wen‐Rong , Bo Jian , Dou Li‐Ping , Wang Li‐Li , Jing Yu , Wang Lu , Li Wen‐Jun , Yu Li , Liu Dai‐Hong 
Published: October 2016

SummaryThe features of graft‐versus‐host disease (GVHD) were compared between patients who underwent myeloablative conditioning and received a peripheral blood stem cell transplant (PBSCT) from either a haploidentical donor (HID) or a matched sibling donor (MSD) during the same period of time. The HID group included more patients with advanced disease. Both groups received the same GVHD prophylaxis with the addition of antithymoglobulin (ATG) in HID group. Higher cumulative incidences (CI) of acute GVHD grade 2–4 (35·1% vs. 13·9%, P = 0·003), similar CI of grade 3–4 (14·5% vs. 9·8%, P = 0·595), less 3‐year CI of extensive chronic GVHD (17·1% vs. 41·5%, P = 0·017) and less severe chronic GVHD (5·8% vs. 21·2%, P = 0·049) occurred in the HID group compared with the MSD group. There was no difference in the sites of the involved organs between these two groups. Higher 3‐year CI of non‐relapse mortality (24·0% vs. 10·2%, P = 0·014), relapse (39·0% vs. 22·6%, P = 0·032) and inferior disease‐free survival (45·7% vs. 78·9%, P = 0·000) were recorded in the HID cohort compared with the MSD group. More HID patients had Karnofsky scores above 90 than those in MSD group (P = 0·016). In conclusion, ATG plays a key role in the unmanipulated HID PBSCT protocol, producing better quality of life in survivors.
Histamine H4 receptor agonist‐induced relief from painful peripheral neuropathy is mediated by inhibition of spinal neuroinflammation and oxidative stress
Authors: Sanna Maria Domenica , Lucarini Laura , Durante Mariaconcetta , Ghelardini Carla , Masini Emanuela , Galeotti Nicoletta 
Published: October 2016

Background and PurposeNeuropathic pain is under‐treated, with a detrimental effect on quality of life, partly because of low treatment efficacy, but also because pathophysiological mechanisms are not fully elucidated. To clarify the pathobiology of neuropathic pain, we studied the contribution of neuroinflammation and oxidative stress in a model of peripheral neuropathy. We also assessed an innovative treatment for neuropathic pain by investigating the effects of histamine H4 receptor ligands in this model.Experimental ApproachA peripheral mononeuropathy was induced in mice, by spared nerve injury (SNI). Neuroinflammation and oxidative stress parameters were evaluated by spectrophotometry. The mechanical (von Frey test) and thermal (plantar test) nociceptive thresholds were evaluated.Key ResultsSNI mice showed increased expression of the pro‐inflammatory cytokines IL‐1ß and TNF‐α, decreased antioxidant enzyme Mn‐containing SOD (MnSOD), increased levels of 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG), an indicator of oxidative DNA damage, and of PARP, nuclear enzyme activated upon DNA damage. Intrathecal administration of VUF 8430 (H4 receptor agonist) reversed the mechanical and thermal allodynia and was associated with decreased expression of IL‐1ß, TNF‐α, 8‐OHdG and PARP and with restoration of MnSOD activity in the spinal cord and sciatic nerve. These effects were prevented by JNJ 10191584 (H4 receptor antagonist).Conclusion and ImplicationsIn the SNI mouse model of neuropathic pain, neuronal H4 receptor stimulation counteracts hyperalgesia and reduces neuroinflammation and oxidative stress in the spinal cord and sciatic nerve. Targeting both oxidative stress and pro‐neuroinflammatory pathways through H4 receptor‐mediated mechanisms could have promising therapeutic potential for neuropathic pain management.
Role of oxidative stress in oxaliplatin‐induced enteric neuropathy and colonic dysmotility in mice
Authors: McQuade Rachel M , Carbone Simona E , Stojanovska Vanesa , Rahman Ahmed , Gwynne Rachel M , Robinson Ainsley M , Goodman Craig A , Bornstein Joel C , Nurgali Kulmira 
Published: October 2016

Background and PurposeOxaliplatin is a platinum‐based chemotherapeutic drug used as a first‐line therapy for colorectal cancer. However, its use is associated with severe gastrointestinal side‐effects resulting in dose limitations and/or cessation of treatment. In this study, we tested whether oxidative stress, caused by chronic oxaliplatin treatment, induces enteric neuronal damage and colonic dysmotility.Experimental ApproachOxaliplatin (3 mg·kg−1 per day) was administered in vivo to Balb/c mice intraperitoneally three times a week. The distal colon was collected at day 14 of treatment. Immunohistochemistry was performed in wholemount preparations of submucosal and myenteric ganglia. Neuromuscular transmission was studied by intracellular electrophysiology. Circular muscle tone was studied by force transducers. Colon propulsive activity studied in organ bath experiments and faeces were collected to measure water content.Key ResultsChronic in vivo oxaliplatin treatment resulted in increased formation of reactive oxygen species (O2ˉ), nitration of proteins, mitochondrial membrane depolarisation resulting in the release of cytochrome c, loss of neurons, increased inducible NOS expression and apoptosis in both the submucosal and myenteric plexuses of the colon. Oxaliplatin treatment enhanced NO‐mediated inhibitory junction potentials and altered the response of circular muscles to the NO donor, sodium nitroprusside. It also reduced the frequency of colonic migrating motor complexes and decreased circular muscle tone, effects reversed by the NO synthase inhibitor, Nω‐Nitro‐L‐arginine.Conclusion and ImplicationsOur study is the first to provide evidence that oxidative stress is a key player in enteric neuropathy and colonic dysmotility leading to symptoms of chronic constipation observed in oxaliplatin‐treated mice.
Why did heterospory evolve?
Authors: Petersen Kurt B. , Burd Martin 
Published: October 2016

ABSTRACTThe primitive land plant life cycle featured the production of spores of unimodal size, a condition called homospory. The evolution of bimodal size distributions with small male spores and large female spores, known as heterospory, was an innovation that occurred repeatedly in the history of land plants. The importance of desiccation‐resistant spores for colonization of the land is well known, but the adaptive value of heterospory has never been well established. It was an addition to a sexual life cycle that already involved male and female gametes. Its role as a precursor to the evolution of seeds has received much attention, but this is an evolutionary consequence of heterospory that cannot explain the transition from homospory to heterospory (and the lack of evolutionary reversal from heterospory to homospory). Enforced outcrossing of gametophytes has often been mentioned in connection to heterospory, but we review the shortcomings of this argument as an explanation of the selective advantage of heterospory. Few alternative arguments concerning the selective forces favouring heterospory have been proposed, a paucity of attention that is surprising given the importance of this innovation in land plant evolution. In this review we highlight two ideas that may lead us to a better understanding of why heterospory evolved. First, models of optimal resource allocation – an approach that has been used for decades in evolutionary ecology to help understand parental investment and other life‐history patterns – suggest that an evolutionary increase in spore size could reach a threshold at which small spores yielding small, sperm‐producing gametophytes would return greater fitness per unit of resource investment than would large spores and bisexual gametophytes. With the advent of such microspores, megaspores would evolve under frequency‐dependent selection. This argument can account for the appearance of heterospory in the Devonian, when increasingly tall and complex vegetative communities presented competitive conditions that made large spore size advantageous. Second, heterospory is analogous in many ways to anisogamy. Indeed, heterospory is a kind of re‐invention of anisogamy within the context of a sporophyte‐dominant land plant life cycle. The evolution of anisogamy has been the subject of important theoretical and empirical investigation. Recent work in this area suggests that mate‐encounter dynamics set up selective forces that can drive the evolution of anisogamy. We suggest that similar dispersal and mating dynamics could have underlain spore size differentiation. The two approaches offer predictions that are consistent with currently available data but could be tested far more thoroughly. We hope to re‐establish attention on this neglected aspect of plant evolutionary biology and suggest some paths for empirical investigation.
How lichens impact on terrestrial community and ecosystem properties
Authors: Asplund Johan , Wardle David A. 
Published: October 2016

ABSTRACTLichens occur in most terrestrial ecosystems; they are often present as minor contributors, but in some forests, drylands and tundras they can make up most of the ground layer biomass. As such, lichens dominate approximately 8% of theEarth's land surface. Despite their potential importance in driving ecosystem biogeochemistry, the influence of lichens on community processes and ecosystem functioning have attracted relatively little attention. Here, we review the role of lichens in terrestrial ecosystems and draw attention to the important, but often overlooked role of lichens as determinants of ecological processes. We start by assessing characteristics that vary among lichens and that may be important in determining their ecological role; these include their growth form, the types of photobionts that they contain, their key functional traits, their water‐holding capacity, their colour, and the levels of secondary compounds in their thalli. We then assess how these differences among lichens influence their impacts on ecosystem and community processes. As such, we consider the consequences of these differences for determining the impacts of lichens on ecosystem nutrient inputs and fluxes, on the loss of mass and nutrients during lichen thallus decomposition, and on the role of lichenivorous invertebrates in moderating decomposition. We then consider how differences among lichens impact on their interactions with consumer organisms that utilize lichen thalli, and that range in size from microfauna (for which the primary role of lichens is habitat provision) to large mammals (for which lichens are primarily a food source). We then address how differences among lichens impact on plants, through for example increasing nutrient inputs and availability during primary succession, and serving as a filter for plant seedling establishment. Finally we identify areas in need of further work for better understanding the role of lichens in terrestrial ecosystems. These include understanding how the high intraspecific trait variation that characterizes many lichens impacts on community assembly processes and ecosystem functioning, how multiple species mixtures of lichens affect the key community‐ and ecosystem‐level processes that they drive, the extent to which lichens in early succession influence vascular plant succession and ecosystem development in the longer term, and how global change drivers may impact on ecosystem functioning through altering the functional composition of lichen communities.
A Lattice Model of the Development of Reading Comprehension
Authors: Connor Carol McDonald 
Published: October 2016

AbstractIn this article, I present a developmental model of how children learn to comprehend what they read, which builds on current models of reading comprehension and integrates findings from instructional research and evidence‐based models of development in early and middle childhood. The lattice model holds that children's developing reading comprehension is a function of the interacting, reciprocal, and bootstrapping effects of developing text‐specific, linguistic, and social‐cognitive processes, which interact with instruction as Child Characteristic × Instruction (C × I) interaction effects. The processes develop over time and in the context of classroom, home, peer, community, and other influences to affect children's development of proficient reading comprehension. First, I describe models of reading comprehension; then, I review the basic processes in the model, the role of instruction, and C × I interactions in the context of the lattice model. Finally, I discuss implications for instruction and research.
Innate immune responses in the ageing lung
Authors: Boe D M , Boule L A , Kovacs E J 
Published: October 2016

SummaryThe world is undergoing an unprecedented shift in demographics, with the number of individuals over the age of 60 years projected to reach 2 billion or more by 2050, representing 22% of the global population. Elderly people are at a higher risk for chronic disease and more susceptible to infection, due in part to age-related dysfunction of the immune system resulting from low-grade chronic inflammation known as ‘inflamm-ageing’. The innate immune system of older individuals exhibits a diminished ability to respond to microbial threats and clear infections, resulting in a greater occurrence of many infectious diseases in elderly people. In particular, the incidence of and mortality from lung infections increase sharply with age, with such infections often leading to worse outcomes, prolonged hospital stays and life-threatening complications, such as sepsis or acute respiratory distress syndrome. In this review, we highlight research on bacterial pneumonias and pulmonary viral infections and discuss age-related changes in innate immunity that contribute to the higher rate of these infections in older populations. By understanding more clearly the innate immune defects in elderly individuals, we can design age-specific therapies to address lung infections in such a vulnerable population.
History of Guillain–Barré syndrome
Authors: Kusunoki Susumu 
Published: October 2016

AbstractGuillain–Barré syndrome (GBS) is an acute self‐limited polyneuropathy. The original paper was reported by Guillain, Barré and Strohl in 1916. GBS was considered to be a demyelinating disease of the peripheral nervous system, called acute inflammatory demyelinating polyneuropathy. In the 1980s, the acute axonal type of GBS was first reported. This subtype was later called acute motor axonal neuropathy. In addition to acute inflammatory demyelinating polyneuropathy and acute motor axonal neuropathy, several subtypes including Miller Fisher syndrome were reported. GBS was shown to be an immune‐mediated disease. The frequent presence of antibodies against various glycolipids have been reported in the acute‐phase sera from GBS patients since the end of the 1980s, including anti‐GM1 antibody in acute motor axonal neuropathy and anti‐GQ1b antibody in Miller Fisher syndrome. The efficacy of plasmapheresis and intravenous immunoglobulin therapy has been established since the mid 1980s. However, despite those therapies, there are still severe or refractory cases. Further investigation is necessary for the development of novel therapeutic strategies.
Parental reaction towards radicalization in young people
Authors: Sikkens Elga , Sieckelinck Stijn , van San Marion , de Winter Micha 
Published: October 2016

AbstractThis paper focuses on radicalization from a parenting perspective; we propose an approach that sees radicalization as a possibility in adolescent development, and as part of the interaction with the adolescent's social environment and socialization. The aim of the study is to discover how parents react when their adolescent develops extreme ideals. Using 55 in‐depth interviews with young people who have extreme ideals and their parents, the parental reactions towards these ideals are explored. Subsequently, the reactions are categorized according to two dimensions (control and support). This study shows how parents struggle when confronted with radicalization and shift to less demanding responses due to powerlessness, dissociation and parental uncertainty.