bluuebunny/crossref_metadata_2025_split huggingface dataset:
Depletion of CD52‐positive cells inhibits the development of central nervous system autoimmune disease, but deletes an immune‐tolerance promoting CD8 T‐cell population. Implications for secondary autoimmunity of alemtuzumab in multiple sclerosis
Authors: von Kutzleben Stephanie , Pryce Gareth , Giovannoni Gavin , Baker David 
Published: December 2016

SummaryThe objective was to determine whether CD52 lymphocyte depletion can act to promote immunological tolerance induction by way of intravenous antigen administration such that it could be used to either improve efficiency of multiple sclerosis (MS) inhibition or inhibit secondary autoimmunities that may occur following alemtuzumab use in MS. Relapsing experimental autoimmune encephalomyelitis was induced in ABH mice and immune cell depletion was therapeutically applied using mouse CD52 or CD4 (in conjunction with CD8 or CD20) depleting monoclonal antibodies. Immunological unresponsiveness was then subsequently induced using intravenous central nervous system antigens and responses were assessed clinically. A dose–response of CD4 monoclonal antibody depletion indicated that the 60–70% functional CD4 T‐cell depletion achieved in perceived failed trials in MS was perhaps too low to even stop disease in animals. However, more marked (~75–90%) physical depletion of CD4 T cells by CD4 and CD52 depleting antibodies inhibited relapsing disease. Surprisingly, in contrast to CD4 depletion, CD52 depletion blocked robust immunological unresponsiveness through a mechanism involving CD8 T cells. Although efficacy was related to the level of CD4 T‐cell depletion, the observations that CD52 depletion of CD19 B cells was less marked in lymphoid organs than in the blood provides a rationale for the rapid B‐cell hyper‐repopulation that occurs following alemtuzumab administration in MS. That B cells repopulate in the relative absence of T‐cell regulatory mechanisms that promote immune tolerance may account for the secondary B‐cell autoimmunities, which occur following alemtuzumab treatment of MS.
Adapalene 0.1%/benzoyl peroxide 2.5% gel reduces the risk of atrophic scar formation in moderate inflammatory acne: a split‐face randomized controlled trial
Authors: Dreno B. , Tan J. , Rivier M. , Martel P. , Bissonnette R. 
Published: December 2016

AbstractBackgroundThe efficacy of current topical acne treatments in mitigating the potential for acne scarring is not known.ObjectiveTo evaluate the effect of adapalene 0.1%/benzoyl peroxide 2.5% (A/BPO) gel compared to vehicle in reducing the risk of acne scarring.MethodsMulticentre, randomized, investigator‐blinded, vehicle‐controlled, split‐face study conducted over 6 months. Subjects were adults with active moderate facial acne vulgaris and at least 10 atrophic acne scars at baseline. Efficacy evaluations included counts of atrophic acne scars and primary acne lesions as well as a Scar Global Assessment (SGA; 5‐point scale).ResultsAfter 6 months treatment, scar counts remained stable with A/BPO while increasing by approximately 25% with vehicle (mean scar count 11.58 vs. 13.55, respectively, at Month 6; P = 0.036). The percentage of subjects with a SGA of ‘almost clear’ (hardly visible scars) increased from 9.7% to 45.2% with A/BPO, whereas it did not change with vehicle (P = 0.0032). Total acne lesion counts decreased by 65% with A/BPO and 36% with vehicle (mean lesion count 8.5 vs. 16.1, respectively, at Month 6; P < 0.001).LimitationsRelatively small study group (31 subjects).ConclusionTopical long‐term treatment with A/BPO is effective in reducing the risk of atrophic scars and improving the global severity of scarring.
Microcomputed Tomography Evaluation of Volumetric Shrinkage of Bulk‐Fill Composites in Class II Cavities
Authors: Algamaiah Hamad , Sampaio Camila S. , Rigo Lindiane C. , Janal Malvin N. , Giannini Marcelo , Bonfante Estevam A. , Coelho Paulo G. , Reis Andre F. , Hirata Ronaldo 
Published: December 2016

ABSTRACTPurposeThis study aimed to quantify polymerization shrinkage of one conventional and three bulk‐fill composites, under bonded and unbonded conditions, in Class II preparations using 3D microcomputed tomography (μCT) and report its location.Materials and MethodsPreparations (2.5 mm occlusal depth × 4 mm wide × 4 mm mesial box and 1 mm beyond the CEJ distal box depth) were made in 48 human extracted molars (n = 6). Four composites were tested, one regular (Vitalescence/VIT) and three bulk‐fill: SureFil SDR Flow (SDR), Tetric EvoCeram Bulk Fill (TET), and Filtek flowable Bulk Fill (FIL). Teeth were divided into four groups according to restorative material used and subdivided into two subgroups, according to the presence of an adhesive system (XP Bond) application (bonded [‐B]) or its absence (unbonded [‐U]). Each tooth was scanned three times: (1) after cavity preparation, (2) before and (3) after composite light‐curing. Acquired μCT images were imported into 2D and 3D software for analysis.ResultsSignificantly different volumetric shrinkage between bonded and unbonded conditions was observed only for TET group (p < 0.05), unbonded presenting significantly higher volumetric shrinkage. Among the bonded groups, TET‐B presented significantly lower shrinkage than both SDR‐B and FIL‐B but not significantly different from VIT‐B. Generally, shrinkage occurred at occlusal and distal surfaces.ConclusionsWhen applied to bonded Class II cavities, TET exhibited significantly lower volumetric shrinkage compared to the other bulk‐fill composites. However, it also exhibited the highest difference of volumetric shrinkage values between unbonded and bonded cavities.Clinical SignificanceVolumetric polymerization shrinkage occurred with all composites tested, regardless of material type (conventional or bulk‐fill) or presence or absence of bonding. However, volumetric shrinkage has been reduced or at least maintained when bulk‐fill composites were used compared to a conventional composite resin, which makes them a potential time saving alternative for clinicians. (J Esthet Restor Dent 29:118–127, 2017)
Arabidopsis SUMO protease ASP1 positively regulates flowering time partially through regulating FLC stability
Authors: Kong Xiangxiong , Luo Xi , Qu Gao‐Ping , Liu Peng , Jin Jing Bo 
Published: December 2016

AbstractThe initiation of flowering is tightly regulated by the endogenous and environment signals, which is crucial for the reproductive success of flowering plants. It is well known that autonomous and vernalization pathways repress transcription of FLOWERING LOCUS C (FLC), a focal floral repressor, but how its protein stability is regulated remains largely unknown. Here, we found that mutations in a novel Arabidopsis SUMO protease 1 (ASP1) resulted in a strong late‐flowering phenotype under long‐days, but to a lesser extent under short‐days. ASP1 localizes in the nucleus and exhibited a SUMO protease activity in vitro and in vivo. The conserved Cys‐577 in ASP1 is critical for its enzymatic activity, as well as its physiological function in the regulation of flowering time. Genetic and gene expression analyses demonstrated that ASP1 promotes transcription of positive regulators of flowering, such as FT, SOC1 and FD, and may function in both CO‐dependent photoperiod pathway and FLC‐dependent pathways. Although the transcription level of FLC was not affected in the loss‐of‐function asp1 mutant, the protein stability of FLC was increased in the asp1 mutant. Taken together, this study identified a novel bona fide SUMO protease, ASP1, which positively regulates transition to flowering at least partly by repressing FLC protein stability.
Geology and tectono‐metamorphic evolution of the Himalayan metamorphic core: insights from the Mugu Karnali transect, Western Nepal (Central Himalaya)
Authors: Iaccarino S. , Montomoli C. , Carosi R. , Massonne H.‐J. , Visonà D. 
Published: December 2016

AbstractNew structural and tectono‐metamorphic data are presented from a geological transect along the Mugu Karnali valley, in Western Nepal (Central Himalaya), where an almost continuous cross‐section from the Lesser Himalaya Sequence to the Everest Series through the medium‐high‐grade Greater Himalayan Sequence (GHS) is exposed. Detailed meso‐ and micro‐structural analyses were carried out along the transect. Pressure (P)–temperature (T) conditions and P–T–deformation paths for samples from different structural units were derived by calculating pseudosections in the MnNKCFMASHT system. Systematic increase of P–T conditions, from ~0.75 GPa to 560 °C up to ≥1.0 GPa–750 °C, has been detected starting from the garnet zone up to the K‐feldspar + aluminosilicate zone. Our investigation reveals how these units are characterized by different P–T evolutions and well‐developed tectonic boundaries. Integrating our meso‐ and micro‐structural data with those of metamorphism and geochronology, a diachronism in deformation and metamorphism can be highlighted along the transect, where different crustal slices were underthrust, metamorphosed and exhumed at different times. The GHS is not a single tectonic unit, but it is composed of (at least) three different crustal slices, in agreement with a model of in‐sequence shearing by accretion of material from the Indian plate, where coeval activity of basal thrusting at the bottom with normal shearing at the top of the GHS is not strictly required for its exhumation.
Involvement of chemokine CXCL11 in the development of morphine tolerance in rats with cancer‐induced bone pain
Authors: Guo Genhua , Peng Yawen , Xiong Bingrui , Liu Daiqiang , Bu Huilian , Tian Xuebi , Yang Hui , Wu Zhen , Cao Fei , Gao Feng 
Published: December 2016

AbstractMorphine is viewed as one of the classical treatments for intractable pain, but its role is limited by side effects, including analgesic tolerance. A few chemokines have been reported to be engaged in the mechanisms of morphine tolerance. However, the exact roles of CXC chemokine 11 (CXCL11) in chronic morphine tolerance remain unknown. In this study, Walker 256 mammary gland carcinoma cells were inoculated into the tibia of rats to provoke cancer‐induced bone pain. Then, morphine was intrathecally administered twice daily for seven consecutive days to induce drug tolerance. We found that the level of CXCL11 in lumbar spinal cord was increased during the development of morphine tolerance in cancer‐induced bone pain rats. Meanwhile, CXCL11 was co‐localized with markers of astrocytes and neurons in the spinal cord. Inhibition of CXCL11 by neutralizing antibodies could remarkably attenuate the degree of morphine tolerance and decrease the activation of astrocytes. Moreover, blocking astrocyte activation by d, l‐Fluorocitric acid could distinctly alleviate morphine tolerance and reduce the expression of CXCL11. Finally, morphine stimulation could induce the release of CXCL11 by cultured astrocytes and neurons in vitro. In summary, our results provide evidence that spinal CXCL11 plays a powerful modulatory role in the development of morphine tolerance through cross‐talking between astrocytes and neurons.Read the Review series “Pain”.
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Impact of Calcified Target Lesions on the Outcome of Percutaneous Coronary Intervention for Acute Coronary Syndrome: Insights From the BASE ACS Trial
Authors: Karjalainen Pasi P. , Nammas Wail , Kervinen Kari , de Belder Adam , Rivero‐Crespo Fernando , Ylitalo Antti , Airaksinen Juhani K. E. 
Published: December 2016

ObjectivesWe performed a post hoc analysis of outcome in patients with, versus those without, calcified target lesions from the BASE ACS trial.BackgroundThe outcome of contemporary stent implantation in patients with calcified lesions presenting with acute coronary syndrome is unknown.MethodsThe BASE ACS trial randomized 827 patients (1:1) presenting with acute coronary syndrome to receive either titanium‐nitride‐oxide‐coated stents or everolimus‐eluting stents. Calcified lesions were defined as moderate or severe calcification in the vessel wall by coronary angiography. The primary endpoint was major adverse cardiac events (MACE): a composite of cardiac death, non‐fatal myocardial infarction or ischemia‐driven target lesion revascularization. Follow‐up was planned at 12 months, and yearly thereafter for up to 7 years.ResultsOf 827 patients enrolled in the trial, 352 (42.6%) had calcified target lesions. Median follow‐up was 5.0 years. The incidence of MACE was higher in patients with, versus those without, calcified target lesions (19.6% vs. 12.2%, respectively, P = 0.004). This was driven by more frequent cardiac death and non‐fatal myocardial infarction events (P < 0.05, both). The rates of ischemia‐driven target lesion revascularization were comparable (P > 0.05). MACE and the other endpoints were comparable between the 2 propensity‐score matched subgroups (P > 0.05 for all). Hypertension and smaller vessel size independently predicted MACE in patients treated for calcified lesions.ConclusionsPatients presenting with acute coronary syndrome who were treated for calcified lesions had worse long‐term clinical outcome, compared with those treated for non‐calcified lesions, mainly due to more frequent safety events. In the propensity score‐matched analysis, the outcome was comparable.
Glycaemic control and excess risk of ischaemic and haemorrhagic stroke in patients with type 1 diabetes: a cohort study of 33 453 patients
Authors: Ståhl C. Hedén , Lind M. , Svensson A.‐M. , Gudbjörnsdottir S. , Mårtensson A. , Rosengren A. 
Published: December 2016

AbstractObjectiveTo estimate the excess risk of stroke in relation to glycaemic control in patients with type 1 diabetes.MethodsIn this prospective, matched cohort study, we identified patients with type 1 diabetes, aged ≥18 years, who were registered in the Swedish National Diabetes Register from 1998–2011 and five control subjects for each case from the general population, matched for age, sex and county of residence. The risks of all strokes, ischaemic stroke and haemorrhagic stroke were estimated using Cox hazard regression.ResultsOf 33 453 type 1 diabetes patients [mean age, 35.5 (SD 14.4) years; mean follow‐up, 7.9 (SD 4.3) years; and mean diabetes duration, 20.2 years (SD 14.6)], 762 (2.3%) were diagnosed with stroke compared with 1122 (0.7%) of 159 924 control subjects [mean follow‐up, 8.2 (SD 4.3) years]. The overall multiple‐adjusted hazard ratios (HRs) for type 1 diabetes patients versus control subjects were 3.29 (95% CI: 2.96–3.66) and 2.49 (95% CI: 1.96–3.16) for ischaemic and haemorrhagic stroke, respectively. The risk of ischaemic and haemorrhagic stroke incrementally increased with increasing HbA1c; the risk of ischaemic stroke was significantly increased with HbA1c within target [≤6.9% (≤52 mmol mol‐1)] [multiple‐adjusted HR 1.89 (95% CI: 1.44–2.47)]. For HbA1c ≥9.7% (≥83 mmol mol‐1), there was a markedly increased risk of both ischaemic and haemorrhagic stroke, with multiple‐adjusted HRs of 7.94 (95% CI: 6.29–10.03) and 8.17 (95% CI 5.00–13.35), respectively.ConclusionsIndividuals with type 1 diabetes have an increased risk of ischaemic and haemorrhagic stroke, increasing markedly with poor glycaemic control.
Interferon‐free therapies for patients with chronic hepatitis C genotype 3 infection: A systematic review
Authors: Gimeno‐Ballester V. , Buti M. , San Miguel R. , Riveiro M. , Esteban R. 
Published: December 2016

SummaryTreatment of hepatitis C virus (HCV) infection with genotype 3 remains a challenge. The HCV elimination rate with direct‐acting antivirals (DAAs) is lower than the values reported for other HCV genotypes. In addition, genotype 3‐infected patients have a higher risk of disease progression and hepatocellular carcinoma. The aim of this study was to review the relevant literature concerning the treatment of HCV genotype 3 patients with interferon‐free regimens. A literature search was conducted in the PubMed/Medline, Embase and Web of Science electronic databases. Trials enrolling patients with chronic hepatitis C infection treated with DAAs with or without ribavirin were included. Two investigators independently evaluated the trials for inclusion criteria, risk of bias and data extraction. The primary outcome was sustained virological response (SVR). In total, 323 references were identified, and 29 met the inclusion criteria: 18 general clinical trials, three general observational studies, three studies in patients with decompensated liver cirrhosis and four studies in HIV–HCV‐coinfected patients. Overall, 4068 genotype 3 patients were included. As compared with sofosbuvir and ribavirin for 24 weeks, sofosbuvir/velpatasvir for 12 weeks or sofosbuvir plus daclatasvir plus ribavirin for 12 weeks provided higher SVR rates, particularly in patients with cirrhosis. Treatment of patients with decompensated cirrhosis remains a great challenge. Sofosbuvir/ledipasvir+ribavirin for 12 weeks were associated with an SVR of 85% in these patients. In summary, treatment of HCV genotype 3 patients is improving rapidly, and this population may no longer be considered a difficult‐to‐treat subgroup in the near future.
Pharmacokinetic/pharmacodynamic evaluation of grapiprant in a carrageenan‐induced inflammatory pain model in the rabbit
Authors: De Vito V. , Salvadori M. , Poapolathep A. , Owen H. , Rychshanova R. , Giorgi M. 
Published: December 2016

Grapiprant is the novel selective EP4 receptor inhibitor recently issued on the veterinary market for dogs affected by osteoarthritis. The aim of this study was twofold: to evaluate the pharmacokinetics and the pharmacodynamics of grapiprant in the induced inflammatory pain model in the rabbit after a single IV injection of 2 mg/kg; to compare the thermal antinociception effect after 2 mg/kg IV grapiprant, with that generated by 0.5 mg/kg meloxicam SC injected. Rabbits (n = 12) were randomly assigned to two crossover studies (single‐dose, two‐period crossover). The first study group A (n = 3) received a single IV dose of grapiprant at 2 mg/kg dissolved in ethanol. Group B (n = 3) received a single IV injection of ethanol (equivalent volume to grapiprant volume) at the same site. The second study group C (n = 3) received a single SC dose of meloxicam at 0.5 mg/kg. Group D (n = 3) received a single SC injection of 15% ethanol (equivalent volume to grapiprant volume) at the same site. After a 2‐week washout period, the groups were rotated and the experiments repeated. Blood samples (0.7 mL) were collected from the right ear artery at assigned times and grapiprant plasma concentrations determined by a validated HPLC‐FL method. Three hours prior to administration of the drugs, inflammation was induced by SC injection of lambda carrageenan (200 μL, 3% in physiological saline) under the plantar surface of the right hind paw. At a similar time to the blood collection, an infrared thermal stimuli (40 °C) was applied to the plantar surface of the rabbits’ hindlimbs to evaluate the thermal withdrawal latency (TWL). The thermal antinociceptive effect was expressed as maximum possible response (% MPR). Grapiprant plasma concentrations were detectable up to the 10‐h time point (concentration range 17–7495 ng/mL). The grapiprant‐treated group showed a significant increase in TWL from 1 h and up to 10 h after drug administration compared to the control. In contrast, the meloxicam group showed a significant increase in TWL from 4 up to 10 h after drug administration, compared to control. The maximal MPR% was not statistically different between the grapiprant and meloxicam group from 4 to 8 h, while significant differences were shown at 1, 1.5, 2, 10 and 24 h. Given these findings, grapiprant appears to be an attractive option for antinociception in rabbits, due to its rapid onset and extended duration of effect.
Sulfadimethoxine in giant freshwater prawns (Macrobrachium rosenbergii): an attempt to estimate the withdrawal time by a population pharmacokinetic approach
Authors: Poapolathep A. , Giorgi M. , Toutain P. L. , Poapolathep S. , Imsilp K. , Sakulthaew C. , Wannapat N. , Klangkaew N. 
Published: December 2016

The fates of sulfadimethoxine (SDM) for different routes of administration were investigated in muscle tissue of giant freshwater prawns, Macrobrachium rosenbergii, following either intramuscular (i.m.) or gavage administration at a dosage of 50 mg/kg body weight (b.w.). The depletion patterns of SDM were also examined after medicated feed treatment at the feeding concentration of 10 g/kg of feed twice a day at a rate of 1% of total b.w. for five consecutive days. The concentration of SDM in prawn muscle tissue was measured using a high‐performance liquid chromatography (HPLC) equipped with ultraviolet detector. Noncompartmental analyses were used to estimate basic pharmacokinetic parameters for the i.m. and gavage data, while a population model was developed to analyze the entire data set including the feed group. Using the Monte Carlo simulations, the withdrawal times (WT) for the orally administered SDM in feed supplement were determined. Maximum concentration of SDM was significantly higher in the i.m. than in the gavage group, and the area under the curve (AUC) value for relative bioavailability following gavage administration was 25.6%. Using Monte Carlo simulation, for a maximum residue limit (MRL) of 0.1 μg/g, the WT for muscle after oral administration of SDM in feed was estimated to be 67 h, while for a MRL of 0.2 μg/g, the WT was estimated to be of 54 h.
Reproductive behaviour, testis size and faecal androgen metabolite concentrations in the African lesser bushbaby
Authors: Scheun J. , Bennett N. C. , Nowack J. , Ganswindt A. 
Published: December 2016

AbstractPeriods of reproduction are linked to changes in male behaviour, physiology and physical parameters. Although high androgen concentrations hold numerous advantages, especially during reproductive periods, chronically elevated androgen concentrations over long periods may be costly and thus need to be regulated. As such seasonal breeders will display temporary elevated androgen concentrations, increased testis levels and mating behaviour only during important reproductive periods. We studied a captive as well as a free‐ranging population of the polygamous strepsirrhine primate, the African lesser bushbaby Galago moholi, to clarify the link between androgen concentration, reproductive behaviour and testis size and the importance of the two mating periods observed in the species. To monitor androgen patterns, we used faecal sampling and quantification of faecal androgen metabolites (fAM). We additionally collected testicular measurements and behavioural data. G. moholi displayed a strong degree of reproductive seasonality, with maximum fAM concentration, testicular volume (TV) and behavioural activity focused on the mating periods. In contrast to other studies, TV increased prior to fAM, with reproductive activity being initiated only when fAM concentrations reached high levels. Changes in TV and fAM concentrations were not significantly different between both mating periods. Based on the absence of a significant difference between mating seasons, it is likely that male G. moholi attempt to maximize their reproductive success by utilizing both mating periods equally. This study is the first to describe the reproductive endocrine pattern linked to physical changes and mating behaviour in any galago species, increasing our understanding of the reproductive biology of nocturnal, polygamous primates.