bluuebunny/crossref_metadata_2025_split huggingface dataset:
99Tc‐methylene diphosphonate improves rheumatoid arthritis disease activity by increasing the frequency of peripheral γδ T cells and CD4+CD25+Foxp3+Tregs
Authors: Su Dinglei , Shen Minning , Gu Bingjie , Wang Xiaoqin , Wang Dandan , Li Xia , Sun Lingyun 
Published: January 2014

AbstractAimγδ T cells exhibit important functions in the pathogenesis of rheumatoid arthritis (RA). In recent years, numerous studies harnessed the γδ T cell‐activating capacity of aminobiphosphonates for the treatment of malignant tumors. As 99Tc‐methylene diphosphonate (99Tc‐MDP) has long been widely used for the treatment of RA in China with good efficacy, we are interested in whether this drug exerts its therapeutic effect on RA by modulating peripheral γδ T cells of RA patients.ObjectivesTo investigate the effect of 99Tc‐MDP on the frequency of γδ T cells and CD4+CD25+Foxp3+Tregs in the peripheral blood of patients with active RA.MethodsNineteen patients with active RA were treated with 99Tc‐MDP intravenously at a dose of 20 μg/day consecutively for 10–14 days. Before and after treatment, the main clinical and laboratory parameters for each patient were evaluated. The frequency of CD3+γδ+T cells and CD4+CD25+Foxp3+Tregs was detected by flow cytometry. Serum levels of interferon (IFN)‐γ, tumor necrosis factor (TNF)‐α, interleukin (IL)‐6, IL‐10 and transforming growth factor (TGF)‐β were measured with enzyme‐linked immunosorbent assay.ResultsAfter intravenous 99Tc‐MDP therapy, the frequency of peripheral CD3+γδ+T cells and CD4+CD25+Foxp3+Tregs were significantly elevated, paralleled with decreased serum levels of TNF‐α and IL‐6 and increased level of serum TGF‐β. The elevation of peripheral CD3+γδ+T cells was positively correlated with increased serum TGF‐β and decreased disease activity.Conclusion99Tc‐MDP may improve the activity of RA through upregulating the frequency of peripheral γδ T cells and CD4+CD25+Foxp3+Tregs as well as affecting the serum cytokine environment by increasing TGF‐β and decreasing TNF‐α and IL‐6.
Anxiety and depression in adult patients with familial Mediterranean fever: a study comparing patients living in Germany and Turkey
Authors: Giese Arnd , Örnek Ahmet , Kilic Levent , Kurucay Mustafa , Şendur Süleyman N. , Lainka Elke , Henning Bernhard F. 
Published: January 2014

AbstractAimTo determine the prevalence of anxiety and depression among patients with familial Mediterranean fever (FMF) living in Germany or Turkey a prospective study was conducted.MethodsForty FMF patients living in Turkey (T), 40 FMF patients living in Germany (G) and 40 healthy controls living in Germany (C) were included. Patients and controls were of Turkish ancestry. G were compared to T and C. The Hospital Anxiety and Depression Scale (HADS) was used with a cut‐off of ≥ 8 for each subdomain score (HADS‐A, HADS‐D).ResultsBaseline characteristics of G were comparable to T and C except for age (T: 30.5 years, G: 35.2 years, C: 34.6 years; T vs. G P = 0.045), duration of disease (T: 14.4 years, G: 24; P < 0.001), C‐reactive protein (T: 0.78 mg/dL, G: 0.78 mg/dL, C: 0.35 mg/dL; G vs. C P = 0.03). Prevalence of anxiety was higher in G compared to C (T: 65%, G: 52.5%, C: 22.5%: G vs. C P < 0.05). No difference was found for the prevalence of depression (T: 30%, G: 35%, C: 20%). The association between FMF and anxiety in subjects living in Germany persisted after adjusting for age and gender in a regression analysis and was robust to an adjustment for coexisting depression. Anxiety and depression did not correlate with FMF disease severity assessed with the Pras score.ConclusionAnxiety, but not depression is more common among FMF patients living in Germany compared to healthy controls. No significant difference could be found between FMF patients living in Germany or Turkey concerning the prevalence of anxiety or depression.
Comparison of methods for stable isotope ratio (δ13C, δ15N, δ2H, δ18O) measurements of feathers
Authors: Bontempo Luana , Ceppa Florencia , Ziller Luca , Pedrini Paolo , Hobson Keith A. , Wassenaar Leonard I. , Camin Federica 
Published: January 2014

Summary

Natural variations in the stable isotope ratios of bioelements in bird feathers are being increasingly used by animal ecologists to investigate different aspects of bird life. However, to ensure reliability of the data, a critical and very delicate aspect is the preparatory phase (cleaning, drying and subsampling) and the proper analysis, mainly in relation to δ2H and δ18O, respectively, for the presence of exchangeable Hs and of nitrogen and sulphur in keratin.

With respect to determination of the isotope ratios of C, N, O and H, in this work, we compare the cleaning mixture most commonly used in the literature (chloroform : methanol 2 : 1) with diethylether : methanol 2 : 1, which avoids the use of the carcinogenic solvent chloroform. We also compared oven‐drying with air‐drying of samples, as well as subsampling of feathers by cutting with surgical scissors or cryogenic pulverization. Finally, we investigated whether stable isotope ratios varied along the vane and between the rachis and vane.

The different methods compared in the three preparatory stages showed no differences performance‐wise and can therefore be used interchangeably. Variability in stable isotope ratios can be considerable, both along the vane and between rachis and vane, which is because their compositions register changes in diet, area and climate. However, in this specific study, when the parts of the feather closest to the calamus were removed, the delta values were clearly more homogeneous. Finally, we demonstrate that a casein with a known δ2H value, although probably differing from keratin in the number of exchangeable Hs, can be used to normalize the δ2H values of feathers, although only in the range of values close to that of the reference material. In determining δ18O, the use of a longer gas chromatography‐GC column, its frequent change and the use of a linear equation built with matrix match equivalent reference materials seems to reduce the drift of GC column performance due to the presence of nitrogen and the accumulation of sulphur.
Using commonality analysis in multiple regressions: a tool to decompose regression effects in the face of multicollinearity
Authors: Ray‐Mukherjee Jayanti , Nimon Kim , Mukherjee Shomen , Morris Douglas W. , Slotow Rob , Hamer Michelle 
Published: January 2014

Summary1. In the face of natural complexities and multicollinearity, model selection and predictions using multiple regression may be ambiguous and risky. Confounding effects of predictors often cloud researchers’ assessment and interpretation of the single best ‘magic model’. The shortcomings of stepwise regression have been extensively described in statistical literature, yet it is still widely used in ecological literature. Similarly, hierarchical regression which is thought to be an improvement of the stepwise procedure, fails to address multicollinearity.2. We propose that regression commonality analysis (CA), a technique more commonly used in psychology and education research will be helpful in interpreting the typical multiple regression analyses conducted on ecological data.3. CA decomposes the variance of R2 into unique and common (or shared) variance (or effects) of predictors, and hence, it can significantly improve exploratory capabilities in studies where multiple regressions are widely used, particularly when predictors are correlated. CA can explicitly identify the magnitude and location of multicollinearity and suppression in a regression model.In this paper, using a simulated (from a correlation matrix) and an empirical dataset (human habitat selection, migration of Canadians across cities), we demonstrate how CA can be used with correlated predictors in multiple regression to improve our understanding and interpretation of data. We strongly encourage the use of CA in ecological research as a follow‐on analysis from multiple regressions.
Genetic risk factors for insidious equine recurrent uveitis inAppaloosa horses
Authors: Fritz K. L. , Kaese H. J. , Valberg S. J. , Hendrickson J. A. , Rendahl A. K. , Bellone R. R. , Dynes K. M. , Wagner M. L. , Lucio M. A. , Cuomo F. M. , Brinkmeyer‐Langford C. L. , Skow L. C. , Mickelson J. R. , Rutherford M. S. , McCue M. E. 
Published: January 2014

SummaryAppaloosa horses are predisposed to equine recurrent uveitis (ERU), an immune‐mediated disease characterized by recurring inflammation of the uveal tract in the eye, which is the leading cause of blindness in horses. Nine genetic markers from theECA1 region responsible for the spotted coat color of Appaloosa horses, and 13 microsatellites spanning the equine major histocompatibility complex (ELA) onECA20, were evaluated for association withERUin a group of 53 AppaloosaERUcases and 43 healthy Appaloosa controls. Three markers were significantly associated (correctedP‐value <0.05): aSNPwithin intron 11 of theTRPM1gene onECA1, anELAclass I microsatellite located near the boundary of theELAclassIIIand classIIregions and anELAclassIImicrosatellite located in intron 1 of theDRAgene. Association between these three genetic markers and theERUphenotype was confirmed in a second population of 24 insidiousERUAppaloosa cases and 16 Appaloosa controls. The relative odds of being anERUcase for each allele of these three markers were estimated by fitting a logistic mixed model with each of the associated markers independently and with all three markers simultaneously. The risk model using these markers classified ~80% ofERUcases and 75% of controls in the second population as moderate or high risk, and low risk respectively. Future studies to refine the associations atECA1 andELAloci and identify functional variants could uncover alleles conferring susceptibility toERUin Appaloosa horses.
Comprehensive screening for a complete set of Japanese‐population‐specific filaggrin gene mutations
Authors: Kono M. , Nomura T. , Ohguchi Y. , Mizuno O. , Suzuki S. , Tsujiuchi H. , Hamajima N. , McLean W. H. I. , Shimizu H. , Akiyama M. 
Published: January 2014

AbstractMutations in FLG coding profilaggrin cause ichthyosis vulgaris and are an important predisposing factor for atopic dermatitis. Until now, most case–control studies and population‐based screenings have been performed only for prevalent mutations. In this study, we established a high‐throughput FLG mutation detection system by real‐time PCR with a set of two double‐dye probes and conducted comprehensive screening for almost all of the Japanese‐population‐specific FLG mutations (ten FLG mutations). The present comprehensive screening for all ten FLG mutations provided a more precise prevalence rate for FLG mutations (11.1%, n = 820), which seemed high compared with data of previous reports based on screening for limited numbers of FLG mutations. Our comprehensive screening suggested that population‐specific FLG mutations may be a significant predisposing factor for hay fever (odds ratio = 2.01 [95% CI: 1.027–3.936, P < 0.05]), although the sample sizes of this study were too small for reliable subphenotype analysis on the association between FLG mutations and hay fever in the eczema patients and the noneczema individuals, and it is not clear whether the association between FLG mutations and hay fever is due to the close association between FLG mutations and hay fever patients with eczema.
Rituximab, alkylating agents or combination therapy for gastric mucosa‐associated lymphoid tissue lymphoma: a monocentric non‐randomised observational study
Authors: Amiot A. , Lévy M. , Copie‐Bergman C. , Dupuis J. , Szablewski V. , Le Baleur Y. , Baia M. , Belhadj K. , Sobhani I. , Leroy K. , Haioun C. , Delchier J‐C. 
Published: January 2014

SummaryBackgroundThere is no consensus on the standard treatment of gastric mucosa‐associated lymphoid tissue (MALT) lymphoma for Helicobacter pylori‐negative patients and for patients with persistent disease despite H. pylori eradication.AimTo evaluate the comparative efficacy and safety of alkylating agents and rituximab alone or in combination.MethodsIn this monocentric retrospective study, which included 106 patients who had not been previously treated with anti‐cancer agents, we evaluated the efficacy and safety of oral alkylating agents monotherapy (n = 48), rituximab monotherapy (n = 28) and the therapy combining both drugs (n = 30). Evaluations were performed at weeks 6 (W6), 25 (W25), and 52 (W52) and after 2 years (W104).ResultsAfter a median follow‐up period of 4.9 years (range 0.4–17.2 years), complete remission and overall response were significantly higher in patients in the combination therapy group at W104 (92% and 100% respectively) compared with patients treated with alkylating agents alone (66% and 68%) and rituximab alone (64% and 73%). The 5‐year progression‐free survival probabilities were 68%, 70% and 89% in patients treated with alkylating agents alone, rituximab alone and combination therapy respectively. Haematological adverse events were reported in 32 (30%) patients (mostly grade 1) and were more frequent in the two groups receiving alkylating agents (P = 0.05 and P < 0.001). No toxicity‐related death was reported.ConclusionsThe use of anti‐cancer systemic therapy is safe and efficient in gastric MALT lymphoma. In this retrospective study, the combination of rituximab plus chlorambucil seems more efficient than rituximab or alkylating agents alone. Rituximab has a better safety profile than regimens containing alkylating agents.
In Vitro Approaches for Detection of Chemical Sensitization
Authors: Roggen Erwin L. 
Published: January 2014

AbstractConcerns, legislation and research needs have precipitated developments such as the mode of action concept, the Tox21 strategy, the concept of pathways of toxicity and the adverse outcome pathway framework. New technologies and paradigms are currently transforming these concepts into applicable animal‐free toxicity testing systems. The adverse outcome pathway framework provides a structure for collecting, organizing and evaluating the available data that describe the compound and the events resulting in an adverse outcome at a biological level of organization. The current chapter intends to provide a non‐exhaustive review of (i) our current understanding of the molecular mechanisms driven the key events of the mode of action for sensitization induction by chemicals, (ii) the tools that were developed on the basis of the available knowledge and (iii) the major gaps that need to be filled.
Chronic myelomonocytic leukaemia: a concise clinical and pathophysiological review
Authors: Patnaik Mrinal M. , Parikh Sameer A. , Hanson Curtis A. , Tefferi Ayalew 
Published: January 2014

SummaryChronic myelomonocytic leukaemia (CMML) is a clonal haematopoietic stem cell disorder with myelodysplastic and myeloproliferative overlap features, and an inherent tendency to transform to acute myeloid leukaemia. Approximately 30% of patients present with clonal cytogenetic abnormalities, while almost 90% have molecular aberrations involving epigenetic regulation, the spliceosome component machinery, tumour suppressor genes and transcription factors/regulators. Numerous prognostic models exist for CMML, with more recent models incorporating prognostic mutations, such as those involving ASXL1. Other variables that seem to consistently affect outcomes include the degree of leucocytosis/monocytosis, anaemia and thrombocytopenia. Allogeneic stem cell transplant remains the only curative option for CMML, while hypomethylating agents can be used for transplant‐ineligible patients or those without suitable stem cell sources. Targeting biological pathways activated in CMML offers potential hope for more effective and less toxic therapies.
The role of apoptosis in megakaryocytes and platelets
Authors: Kile Benjamin T. 
Published: January 2014

SummaryThe role of apoptotic pathways in the development and function of the megakaryocyte lineage has generated renewed interest in recent years. This has been driven by the advent of BH3 mimetic drugs that target BCL2 family proteins to induce apoptosis in tumour cells: agents such as ABT‐263 (navitoclax, which targets BCL2, BCL‐XL [BCL2L1] and BCL2L2) and ABT‐199 (a BCL2‐specific agent) are showing great promise in early stage clinical trials. However, the major dose‐limiting toxicity of navitoclax has proven to be thrombocytopenia, an on‐target effect of inhibiting BCL‐XL. It transpires that the anucleate platelet contains a classical intrinsic apoptosis pathway, which at steady state regulates its life span in the circulation. BCL‐XL is the critical pro‐survival protein that restrains apoptosis and maintains platelet viability. These findings have paved the way to a deeper understanding of apoptotic pathways and processes in platelets, and their precursor cell, the megakaryocyte.
Epac and the high affinity rolipram binding conformer of PDE4 modulate neurite outgrowth and myelination using an in vitro spinal cord injury model
Authors: Boomkamp S D , McGrath M A , Houslay M D , Barnett S C 
Published: January 2014

Background and PurposecAMP and pharmacological inhibition of PDE4, which degrades it, are promising therapeutic targets for the treatment of spinal cord injury (SCI). Using our previously described in vitro SCI model, we studied the mechanisms by which cAMP modulators promote neurite outgrowth and myelination using enantiomers of the PDE4‐specific inhibitor rolipram and other modulators of downstream signalling effectors.Experimental ApproachRat mixed neural cell myelinating cultures were cut with a scalpel and treated with enantiomers of the PDE4‐specific inhibitor rolipram, Epac agonists and PKA antagonists. Neurite outgrowth, density and myelination were assessed by immunocytochemistry and cytokine levels analysed by qPCR.Key ResultsInhibition of the high‐affinity rolipram‐binding state (HARBS), rather than the low‐affinity rolipram binding state (LARBS) PDE4 conformer promoted neurite outgrowth and myelination. These effects were mediated through the activation of Epac and not through PKA. Expression of the chemokine CXCL10, known to inhibit myelination, was markedly elevated in astrocytes after Rho inhibition and this was blocked by inhibition of Rho kinase or PDE4.Conclusions and ImplicationsPDE4 inhibitors targeted at the HARBS conformer or Epac agonists may provide promising novel targets for the treatment of SCI. Our study demonstrates the differential mechanisms of action of these compounds, as well as the benefit of a combined pharmacological approach and highlighting potential promising targets for the treatment of SCI. These findings need to be confirmed in vivo.
δ‐Opioid receptor agonists inhibit migraine‐related hyperalgesia, aversive state and cortical spreading depression in mice
Authors: Pradhan Amynah A , Smith Monique L , Zyuzin Jekaterina , Charles Andrew 
Published: January 2014

Background and PurposeMigraine is an extraordinarily common brain disorder for which treatment options continue to be limited. Agonists that activate the δ‐opioid receptor may be promising for the treatment of migraine as they are highly effective for the treatment of chronic rather than acute pain, do not induce hyperalgesia, have low abuse potential and have anxiolytic and antidepressant properties. The aim of this study was to investigate the therapeutic potential of δ‐opioid receptor agonists for migraine by characterizing their effects in mouse migraine models.Experimental ApproachMechanical hypersensitivity was assessed in mice treated with acute and chronic doses of nitroglycerin (NTG), a known human migraine trigger. Conditioned place aversion to NTG was also measured as a model of migraine‐associated negative affect. In addition, we assessed evoked cortical spreading depression (CSD), an established model of migraine aura, in a thinned skull preparation.Key ResultsNTG evoked acute and chronic mechanical and thermal hyperalgesia in mice, as well as conditioned place aversion. Three different δ‐opioid receptor agonists, SNC80, ARM390 and JNJ20788560, significantly reduced NTG‐evoked hyperalgesia. SNC80 also abolished NTG‐induced conditioned place aversion, suggesting that δ‐opioid receptor activation may also alleviate the negative emotional state associated with migraine. We also found that SNC80 significantly attenuated CSD, a model that is considered predictive of migraine preventive therapies.Conclusions and ImplicationsThese data show that δ‐opioid receptor agonists modulate multiple basic mechanisms associated with migraine, indicating that δ‐opioid receptors are a promising therapeutic target for this disorder.
Elucidation of the molecular mechanism and the efficacy in vivo of a novel 1,4‐benzoquinone that inhibits 5‐lipoxygenase
Authors: Schaible A M , Filosa R , Temml V , Krauth V , Matteis M , Peduto A , Bruno F , Luderer S , Roviezzo F , Di Mola A , de Rosa M , D'Agostino B , Weinigel C , Barz D , Koeberle A , Pergola C , Schuster D , Werz O 
Published: January 2014

Background and Purpose1,4‐Benzoquinones are well‐known inhibitors of 5‐lipoxygenase (5‐LOX, the key enzyme in leukotriene biosynthesis), but the molecular mechanisms of 5‐LOX inhibition are not completely understood. Here we investigated the molecular mode of action and the pharmacological profile of the novel 1,4‐benzoquinone derivative 3‐((decahydronaphthalen‐6‐yl)methyl)‐2,5‐dihydroxycyclohexa‐2,5‐diene‐1,4‐dione (RF‐Id) in vitro and its effectiveness in vivo.Experimental ApproachMechanistic investigations in cell‐free assays using 5‐LOX and other enzymes associated with eicosanoid biosynthesis were conducted, along with cell‐based studies in human leukocytes and whole blood. Molecular docking of RF‐Id into the 5‐LOX structure was performed to illustrate molecular interference with 5‐LOX. The effectiveness of RF‐Id in vivo was also evaluated in two murine models of inflammation.Key ResultsRF‐Id consistently suppressed 5‐LOX product synthesis in human leukocytes and human whole blood. RF‐Id also blocked COX‐2 activity but did not significantly inhibit COX‐1, microsomal PGE2 synthase‐1, cytosolic PLA2 or 12‐ and 15‐LOX. Although RF‐Id lacked radical scavenging activity, reducing conditions facilitated its inhibitory effect on 5‐LOX whereas cell stress impaired its efficacy. The reduced hydroquinone form of RF‐Id (RED‐RF‐Id) was a more potent inhibitor of 5‐LOX as it had more bidirectional hydrogen bonds within the 5‐LOX substrate binding site. Finally, RF‐Id had marked anti‐inflammatory effects in mice in vivo.Conclusions and ImplicationsRF‐Id represents a novel anti‐inflammatory 1,4‐benzoquinone that potently suppresses LT biosynthesis by direct inhibition of 5‐LOX with effectiveness in vivo. Mechanistically, RF‐Id inhibits 5‐LOX in a non‐redox manner by forming discrete molecular interactions within the active site of 5‐LOX.