bluuebunny/crossref_metadata_2025_split huggingface dataset:
The orphan receptor NOR1 participates in isoprenaline‐induced cardiac hypertrophy by regulating PARP‐1
Authors: Feng Xiao‐Jun , Gao Hui , Gao Si , Li Zhuoming , Li Hong , Lu Jing , Wang Jiao‐Jiao , Huang Xiao‐Yang , Liu Min , Zou Jian , Ye Jian‐Tao , Liu Pei‐Qing 
Published: January 2015

Background and PurposeThe orphan nuclear receptor NOR1 belongs to the NR4A subfamily of the nuclear hormone receptor superfamily, and is involved in glucose and fat metabolism. However, its potential contribution to cardiovascular diseases remains to be assessed. Here, the roles of NOR1 in cardiac hypertrophy induced by isoprenaline and the underlying molecular mechanisms were investigated.Experimental ApproachNOR1 was expressed in cardiomyocytes treated with isoprenaline. After NOR1 overexpression or knockdown in neonatal rat cardiomyocytes, cellular hypertrophy was monitored by measuring cell surface area and the mRNA of hypertrophic biomarkers. Interactions between NOR1 and PARP‐1 were investigated by co‐immunoprecipitation. NOR1 expression and PARP‐1 activity were measured in rats with cardiac hypertrophy induced by isoprenaline.Key ResultsTreatment with isoprenaline significantly up‐regulated NOR1 expression and PARP‐1 activity both in vivo and in vitro. Specific gene silencing of NOR1 attenuated isoprenaline‐induced cardiomyocyte hypertrophy, whereas NOR1 overexpression exacerbated cardiac hypertrophy. We identified a physical interaction between NOR1 and PARP‐1, which was enhanced by NOR1 transfection and thereby led to PARP‐1 activation. Overexpression of NOR1, but not C293Y, a NOR1 mutant lacking the PARP‐1 binding activity, increased cellular surface area and the mRNA levels of atrial natriuretic factor and brain natriuretic polypeptide, effects blocked by the PARP‐1 inhibitor 3‐aminobenzamide or siRNA for PARP‐1.Conclusions and ImplicationsThis is the first evidence that NOR1 was involved in isoprenaline‐induced cardiac hypertrophy. The pro‐hypertrophic effect of NOR1 can be partly attributed to its regulation of PARP‐1 enzymic activity.
A novel selective and orally bioavailable Nav1.8 channel blocker, PF‐01247324, attenuates nociception and sensory neuron excitability
Authors: Payne Claire Elizabeth , Brown Adam R , Theile Jonathon W , Loucif Alexandre J C , Alexandrou Aristos J , Fuller Mathew D , Mahoney John H , Antonio Brett M , Gerlach Aaron C , Printzenhoff David M , Prime Rebecca L , Stockbridge Gillian , Kirkup Anthony J , Bannon Anthony W , England Steve , Chapman Mark L , Bagal Sharan , Roeloffs Rosemarie , Anand Uma , Anand Praveen , Bungay Peter J , Kemp Mark , Butt Richard P , Stevens Edward B 
Published: January 2015

Background and PurposeNaV1.8 ion channels have been highlighted as important molecular targets for the design of low MW blockers for the treatment of chronic pain. Here, we describe the effects of PF‐01247324, a new generation, selective, orally bioavailable Nav1.8 channel blocker of novel chemotype.Experimental ApproachThe inhibition of Nav1.8 channels by PF‐01247324 was studied using in vitro patch‐clamp electrophysiology and the oral bioavailability and antinociceptive effects demonstrated using in vivo rodent models of inflammatory and neuropathic pain.Key ResultsPF‐01247324 inhibited native tetrodotoxin‐resistant (TTX‐R) currents in human dorsal root ganglion (DRG) neurons (IC50: 331 nM) and in recombinantly expressed h Nav1.8 channels (IC50: 196 nM), with 50‐fold selectivity over recombinantly expressed TTX‐R hNav1.5 channels (IC50: ∼10 μM) and 65–100‐fold selectivity over TTX‐sensitive (TTX‐S) channels (IC50: ∼10–18 μM). Native TTX‐R currents in small‐diameter rodent DRG neurons were inhibited with an IC50 448 nM, and the block of both human recombinant Nav1.8 channels and TTX‐R from rat DRG neurons was both frequency and state dependent. In vitro current clamp showed that PF‐01247324 reduced excitability in both rat and human DRG neurons and also altered the waveform of the action potential. In vivo experiments n rodents demonstrated efficacy in both inflammatory and neuropathic pain models.Conclusions and ImplicationsUsing PF‐01247324, we have confirmed a role for Nav1.8 channels in both inflammatory and neuropathic pain. We have also demonstrated a key role for Nav1.8 channels in action potential upstroke and repetitive firing of rat and human DRG neurons.
Glucocorticoid receptor function in health and disease
Authors: Caratti Giorgio , Matthews Laura , Poolman Toryn , Kershaw Stephen , Baxter Matthew , Ray David 
Published: January 2015

SummaryGlucocorticoid hormones are essential for life in vertebrates. They act through the glucocorticoid receptor (GR), which is expressed in virtually all cells of the human body. Yet the actions of glucocorticoids (GCs) are specific to particular cell types. Broadly GCs regulate carbohydrate metabolism, inflammation, stress and cell fate. Synthetic GCs are widely used in medicine and are by far the most frequent cause of Cushing's syndrome in routine practice. The advent of novel drugs targeting the GR offers new opportunities to treat patients with immune, or malignant disease, and may also offer new opportunities to manage patients with adrenal insufficiency also. This review covers the latest understanding of how GCs work, how their actions are affected by disease, and where the new drugs may take us.
Trial and error: attending to language barriers in child welfare service provision from the perspective of frontline workers
Authors: Maiter Sarah , Alaggia Ramona , Chan Adrienne S. , Leslie Bruce 
Published: January 2015

AbstractThis paper reports on a qualitative study that used focus groups to gather data from the perspective of child protection workers on their experiences in providing services to clients with limited English proficiency (LEP). The goals of the study were to understand processes of relationship building and service provision that could contribute to improved practice. Focus groups are ideal in obtaining data on how a group deals with particular situations and for understanding their decision‐making processes. Measures to ensure rigour and trustworthiness were taken throughout the study. Findings provide rich and multilayered insights into the complexity of providing services for families with LEP showing that agencies use bilingual workers as well as interpreters for services. Participants noted, however, that services continued to be inconsistent with unclear guidelines and training about how and when to access interpreters. Lack of training for bilingual workers was also identified. Confidentiality issues, barriers to engaging with clients, problems with the quality of interpretation and role confusion together with benefits including interpreters being cultural and language ‘conduits’ and links to culturally specific services; enhanced communication decreasing the possibility of inaccurate assessments and lessening power differentials; and help with workload were noted.
Guidelines for diagnosis, prevention and treatment of hand eczema
Authors: Diepgen Thomas L , Andersen Klaus E , Chosidow Oliver , Coenraads Peter Jan , Elsner Peter , English John , Fartasch Manigé , Gimenez‐Arnau Ana , Nixon Rosemary , Sasseville Denis , Agner Tove 
Published: January 2015

SummaryThe guidelines aim to provide advice on the management of hand eczema (HE), using an evidence‐ and consensus‐based approach. The guidelines consider a systematic Cochrane review on interventions for HE, which is based on a systematic search of the published literature (including hand‐searching). In addition to the evidence‐ and consensus‐based recommendation on the treatment of HE, the guidelines cover mainly consensus‐based diagnostic aspects and preventive measures (primary and secondary prevention). Treatment recommendations include non‐pharmacological interventions, topical, physical and systemic treatments. Topical corticosteroids are recommended as first line treatment in the management of HE, however continuous long‐term treatment beyond six weeks only when necessary and under careful medical supervision. Alitretinoin is recommended as a second line treatment (relative to topical corticosteroids) for patients with severe chronic HE. Randomized control trials (RCT) are missing for other used systemic treatments and comparison of systemic drugs in “head‐to‐head” RCTs are needed.The guidelines development group is a working group of the European Society of Contact Dermatitis (ESCD) and has carefully tried to reconcile opposite views, define current optimal practice and provide specific recommendations, and meetings have been chaired by a professional moderator of the AWMF (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften; Association of the Scientific Medical Societies in Germany).No financial support was given by any medical company. The guidelines are expected to be valid until December 2017 at the latest.
Elevation of plasma 1‐deoxy‐sphingolipids in type 2 diabetes mellitus: a susceptibility to neuropathy?
Authors: Dohrn M. F. , Othman A. , Hirshman S. K. , Bode H. , Alecu I. , Fähndrich E. , Karges W. , Weis J. , Schulz J. B. , Hornemann T. , Claeys K. G. 
Published: January 2015

Background and purposeDiabetic distal sensorimotor polyneuropathy (DSPN) is a frequent, disabling complication of diabetes mellitus. There is increasing evidence that sphingolipids play a role in insulin resistance and type 2 diabetes (T2DM). Whether neurotoxic 1‐deoxy‐sphingolipids are elevated in DSPN patients' plasma and whether levels correlate to the DSPN stage were examined.MethodsThe plasma profile of 12 sphingoid bases in patients with DSPN and T2DM(n = 39) were cross‐sectionally compared to other nerve disorders including chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 13), transthyretin‐related familial amyloid polyneuropathy (FAP) (n = 10), amyotrophic lateral sclerosis (ALS) (n = 13) and small fibre neuropathy (n = 12) by liquid chromatography mass spectrometry. Correlations to the DSPN stage were additionally performed. Furthermore, the sphingoid base distribution in sural nerve specimens was measured in patients with DSPN (n = 6) compared to CIDP (n = 3).ResultsA significantly increased amount of 1‐deoxy‐sphingolipids [1‐deoxy‐sphinganine (0.11 ± 0.06 μmol/l), 1‐deoxy‐sphingosine (0.24 ± 0.16 μmol/l)] in patients with DSPN was observed compared to age‐matched healthy controls (0.06 ± 0.03 μmol/l; 0.12 ± 0.05 μmol/l) and to the other groups. (Para)clinical parameters including sensory loss, neuropathic pain, weakness, vibration perception, nerve conduction velocity, sensory nerve action potentials (sural nerve) and duration of T2DM did not correlate with plasma 1‐deoxy‐sphingolipid levels, neither did the clinical stage according to the Dyck classification for DSPN. Sphingolipid levels in sural nerve biopsies showed no differences between DSPN and CIDP. Contrarily, patients with a small fibre neuropathy had decreased C20‐sphingosine plasma levels.Conclusion1‐deoxy‐sphingolipid plasma levels are significantly elevated in DSPN. They are already detectable in early disease stages but do not correlate with the clinical course. Further knowledge on 1‐deoxy‐sphingolipids might lead to a better pathophysiological understanding and future treatment options in DSPN.
The challenge of managing the Columbia River Basin for energy and fish
Authors: Leonard N. J. , Fritsch M. A. , Ruff J. D. , Fazio J. F. , Harrison J. , Grover T. 
Published: January 2015

AbstractThe Columbia River Basin (Basin) is located in the Pacific Northwest, United States. The 370 hydroelectric dams in the Basin provide the Pacific Northwest with many services including hydropower generation, flood control, agricultural irrigation and navigation. The basin also provides habitat for a variety of anadromous and resident fishes and wildlife species. Balancing the energy demands with the needs of fish and wildlife is a daunting task. Through the implementation of the Pacific Northwest Electric Power Planning and Conservation Act (Power Act), the Council, in collaboration with state, federal, tribal and non‐governmental partners, attempts to address the needs of fish and wildlife with that of hydropower generation. The implementation has become increasingly challenging as the Basin's ecosystem continues to be impacted by societal demands and the resulting environmental impacts. The focus of this paper is the ongoing challenge of meeting the demands on hydropower generation and of the basin's fish species.
Large amounts of labile organic carbon in permafrost soils of northern Alaska
Authors: Mueller Carsten W. , Rethemeyer Janet , Kao‐Kniffin Jenny , Löppmann Sebastian , Hinkel Kenneth M. , G. Bockheim James 
Published: January 2015

AbstractPermafrost‐affected soils of the northern circumpolar region represent 50% of the terrestrial soil organic carbon (SOC) reservoir and are most strongly affected by climatic change. There is growing concern that this vast SOC pool could transition from a net C sink to a source. But so far little is known on how the organic matter (OM) in permafrost soils will respond in a warming future, which is governed by OM composition and possible stabilization mechanisms. To investigate if and how SOC in the active layer and adjacent permafrost is protected against degradation, we employed density fractionation to separate differently stabilized SOM fractions. We studied the quantity and quality of OM in different compartments using elemental analysis, 13C solid‐phase nuclear magnetic resonance (13C‐NMR) spectroscopy, and 14C analyses. The soil samples were derived from 16 cores from drained thaw lake basins, ranging from 0 to 5500 years of age, representing a unique series of developing Arctic soils over time. The normalized SOC stocks ranged between 35.5 and 86.2 kg SOC m−3, with the major amount of SOC located in the active layers. The SOC stock is dominated by large amounts of particulate organic matter (POM), whereas mineral‐associated OM especially in older soils is of minor importance on a mass basis. We show that tremendous amounts of over 25 kg OC per square meter are stored as presumably easily degradable OM rich in carbohydrates. Only about 10 kg OC per square meter is present as presumably more stable, mineral‐associated OC. Significant amounts of the easily degradable, carbohydrate‐rich OM are preserved in the yet permanently frozen soil below the permafrost table. Forced by global warming, this vast labile OM pool could soon become available for microbial degradation due to the continuous deepening of the annually thawing active layer.
PHT3D‐UZF: A Reactive Transport Model for Variably‐Saturated Porous Media
Authors: Wu Ming Zhi , Post Vincent E.A. , Salmon S. Ursula , Morway Eric D. , Prommer Henning 
Published: January 2015

AbstractA modified version of the MODFLOW/MT3DMS‐based reactive transport model PHT3D was developed to extend current reactive transport capabilities to the variably‐saturated component of the subsurface system and incorporate diffusive reactive transport of gaseous species. Referred to as PHT3D‐UZF, this code incorporates flux terms calculated by MODFLOW's unsaturated‐zone flow (UZF1) package. A volume‐averaged approach similar to the method used in UZF‐MT3DMS was adopted. The PHREEQC‐based computation of chemical processes within PHT3D‐UZF in combination with the analytical solution method of UZF1 allows for comprehensive reactive transport investigations (i.e., biogeochemical transformations) that jointly involve saturated and unsaturated zone processes. Intended for regional‐scale applications, UZF1 simulates downward‐only flux within the unsaturated zone. The model was tested by comparing simulation results with those of existing numerical models. The comparison was performed for several benchmark problems that cover a range of important hydrological and reactive transport processes. A 2D simulation scenario was defined to illustrate the geochemical evolution following dewatering in a sandy acid sulfate soil environment. Other potential applications include the simulation of biogeochemical processes in variably‐saturated systems that track the transport and fate of agricultural pollutants, nutrients, natural and xenobiotic organic compounds and micropollutants such as pharmaceuticals, as well as the evolution of isotope patterns.
Novel characterization of a breakpoint in F8: an individualized approach to gene analysis when PCR and MLPA results contradict
Authors: Pezeshkpoor B. , Theophilus B. D. M. , Guilliatt A. M. , Oldenburg J. , Williams M. D. , El‐Maarri O. 
Published: January 2015

SummaryHaemophilia A is an X‐linked bleeding disorder caused by heterogeneous mutations in the F8 gene. Two inversion hotspots in intron 22 and intron 1, as well as point mutations, small insertions and deletions in the F8 gene account for causal mutations leading to severe haemophilia A. Rarely, novel molecular mechanisms lead to a haemophilia A phenotype which cannot be completely characterized by routine molecular diagnostic methods. Here, we characterized the molecular abnormality in a boy with a severe haemophilia A phenotype. On investigation by PCR and DNA sequencing, exon 18 of F8 repeatedly failed to amplify. However, analysis by multiplex ligation‐dependent probe amplification demonstrated the presence of exon 18 sequence, suggesting a more complex rearrangement than a single exon deletion. The analysis of exon 18 and its flanking regions by inverse PCR revealed a complex mutation comprising insertions of extragenic sequences from Xq28 along with a partial duplication of exon 18. Based on the successful analysis and characterization of the familial breakpoint, we developed a PCR‐based diagnostic approach to detect this defect in family members in whom no diagnostic test could be offered until this time.
Efficacy and safety of OBI‐1, an antihaemophilic factor VIII (recombinant), porcine sequence, in subjects with acquired haemophilia A
Authors: Kruse‐Jarres R. , St‐Louis J. , Greist A. , Shapiro A. , Smith H. , Chowdary P. , Drebes A. , Gomperts E. , Bourgeois C. , Mo M. , Novack A. , Farin H. , Ewenstein B. 
Published: January 2015

SummaryAcquired haemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against human factor VIII (hFVIII). OBI‐1 is an investigational, B‐domain deleted, recombinant FVIII, porcine sequence, with low cross‐reactivity to anti‐hFVIII antibodies. Efficacy can be monitored with FVIII activity levels in addition to clinical assessments. This prospective, open label, phase 2/3 study was designed to evaluate the efficacy of OBI‐1 treatment for bleeding episodes in subjects with AHA. After an initial dose of 200 U kg−1, OBI‐1 was titrated to maintain target FVIII activity levels, in correlation with clinical assessments, throughout the treatment phase. All 28 subjects with AHA had a positive response to OBI‐1 treatment 24 h after initiation despite inhibition of FVIII activity levels immediately after infusion in 10 subjects with baseline anti‐porcine FVIII inhibitors. Control of the qualifying bleed was ultimately achieved in 24 of 28 subjects. No related serious adverse events, thrombotic events, allergic reactions or thrombocytopaenia occurred. The results of this study indicate that OBI‐1 is safe and effective in treating bleeding episodes in subjects with AHA. The ability to safely and effectively titrate dosing based on FVIII activity levels in this study demonstrates that OBI‐1 fulfils the unmet medical need to monitor the key coagulation parameter in AHA patients.
Bleeding phenotype and correlation with factor XI (FXI) activity in congenital FXI deficiency: results of a retrospective study from a single centre
Authors: Santoro C. , Di Mauro R. , Baldacci E. , De Angelis F. , Abbruzzese R. , Barone F. , Bochicchio R. A. , Ferrara G. , Guarini A. , Foà R. , Mazzucconi M. G. 
Published: January 2015

SummaryBleeding phenotype in factor XI (FXI)‐deficient patients is variable, and not related to baseline FXI:Act. Aims of our study were to describe the characteristics and the management of surgery and deliveries in FXI‐deficient patients, and to investigate the relationship between the haemorrhagic phenotype and the baseline FXI:Act. Ninety‐five patients were diagnosed and followed in our centre for a median follow‐up of 0.9 years (0.1–36.2); median FXI:Act of all patients: 38% (0.5–69%). Fifty‐six patients (59%) experienced bleeding episodes not surgery‐related. Prior to diagnosis, 64 patients underwent 132 surgeries, and after diagnosis, 23 patients underwent 36 surgeries. Globally 26 of 168 surgeries were prophylactically treated, whereas 142 of 168 were not. As regard as surgeries performed without prophylaxis, 30 bleeding events (21%) occurred in 21 patients. At diagnosis, the median FXI:Act of bleeding and non‐bleeding patients was 28% and 37%, respectively, without statistically significant difference between the two groups (P = 0.26). As regard as surgeries performed under prophylactic treatment just 1 bleeding event occurred. Prior to diagnosis, 31 spontaneous deliveries (SD) and eight caesarian sections (CS) were performed without prophylaxis: 4 postpartum haemorrhages (10.5%) occurred (patients FXI:Act: 2%, 6%, 27%, 52.3% respectively). After diagnosis, four SD and five CS were performed with prophylaxis: no postpartum haemorrhages occurred. We confirm the wide bleeding phenotype variability in FXI‐deficient patients, not related to the baseline FXI:Act levels. We highlight the importance of performing a correct diagnosis and follow‐up, because a good management of prophylactic treatment, dramatically reduces the bleeding rate in case of surgery or deliveries.
Potency determination of factor VIII and factor IX for new product labelling and postinfusion testing: challenges for caregivers and regulators
Authors: Dodt J. , Hubbard A. R. , Wicks S. J. , Gray E. , Neugebauer B. , Charton E. , Silvester G. 
Published: January 2015

SummaryA workshop organized by the European Medicines Agency and the European Directorate for the Quality of Medicines and HealthCare was held in London, UK on November 28–29, 2013, to provide an overview of the current knowledge of the characterization of new factor VIII (FVIII) and factor IX (FIX) concentrates with respect to potency assays and testing of postinfusion material. The objective was to set the basis for regulatory authorities' discussion on the most appropriate potency assay for the individual products, and European Pharmacopoeia (Ph. Eur.) discussion on whether to propose revision of the Ph. Eur. monographs with respect to potency assays in the light of information on new FVIII and FIX concentrates. The workshop showed that for all products valid assays vs. the international concentrate standards were obtained and potency could be expressed in International Units. The Ph. Eur. chromogenic potency assay gave valid assay results which correlate with in vivo functionality of rFVIII products. For some modified rFVIII products and all modified rFIX products, one‐stage clotting assay methods result in different potencies depending on the activated partial thromboplastin time reagent. As a consequence, monitoring of patients' postinfusion levels is challenging but it was pointed out that manufacturers are responsible for providing the users with appropriate information for use and laboratory testing of their product. Strategies to avoid misleading determination of patents' plasma levels, e.g. information on suitable assays, laboratory standards or correction factors were discussed.