bluuebunny/crossref_metadata_2025_split huggingface dataset:
Application of CYP3A4in vitrodata to predict clinical drug–drug interactions; predictions of compounds as objects of interaction
Authors: Youdim Kuresh A. , Zayed Aref , Dickins Maurice , Phipps Alex , Griffiths Michelle , Darekar Amanda , Hyland Ruth , Fahmi Odette , Hurst Susan , Plowchalk David R. , Cook Jack , Guo Feng , Obach R. Scott 
Published: February 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Numerous retrospective analyses have shown the utility ofin vitrosystems for predicting potential drug–drug interactions (DDIs).• Prediction of DDIs fromin vitrodata is commonly obtained using estimates of enzymeKi, inhibitor and substrate concentrations and absorption rate for substrate and inhibitor.WHAT THIS STUDY ADDS• Using a generic approach for all test compounds, the findings from the current study showed the use of recombinant P450s provide a more robustin vitromeasure of P450 contribution (fraction metabolized,fm) than that achieved when using chemical inhibitors in combination with human liver microsomes, for the prediction of potential CYP3A4 drug–drug interactions prior to clinical investigation.• The current study supported the use of SIMCYP®, a modelling and simulation software in utilizing thein vitromeasures in the prediction of potential drug–drug interactions.AIMSThe aim of this study was to explore and optimize thein vitroandin silicoapproaches used for predicting clinical DDIs. A data set containing clinical information on the interaction of 20 Pfizer compounds with ketoconazole was used to assess the success of the techniques.METHODSThe study calculated the fraction and the rate of metabolism of 20 Pfizer compounds via each cytochrome P450. Two approaches were used to determine fraction metabolized (fm); 1) by measuring substrate loss in human liver microsomes (HLM) in the presence and absence of specific chemical inhibitors and 2) by measuring substrate loss in individual cDNA expressed P450s (also referred to as recombinant P450s (rhCYP)) The fractions metabolized via each CYP were used to predict the drug–drug interaction due to CYP3A4 inhibition by ketoconazole using the modelling and simulation software SIMCYP®.RESULTSWhenin vitrodata were generated using Gentest supersomes, 85% of predictions were within two‐fold of the observed clinical interaction. Using PanVera baculosomes, 70% of predictions were predicted within two‐fold. In contrast using chemical inhibitors the accuracy was lower, predicting only 37% of compounds within two‐fold of the clinical value. Poorly predicted compounds were found to either be metabolically stable and/or have high microsomal protein binding. The use of equilibrium dialysis to generate accurate protein binding measurements was especially important for highly bound drugs.CONCLUSIONSThe current study demonstrated that the use of rhCYPs with SIMCYP®provides a robustin vitrosystem for predicting the likelihood and magnitude of changes in clinical exposure of compounds as a consequence of CYP3A4 inhibition by a concomitantly administered drug.
Prevalence and treatment of isolated and concurrent hypertension and hypercholesterolaemia in the United Kingdom
Authors: MacDonald Thomas M. , Morant Steven V. 
Published: February 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The 1998 and 2003 Health Survey for England revealed a high prevalence of hypertension and hypercholesterolaemia in the population of England.• Major changes in the reimbursement of primary care for the management of both hypertension and hypercholesterolaemia have occurred in the UK. WHAT THIS STUDY ADDS • Using a GP database we have examined the proportion of subjects diagnosed and treated for hypertension and hypercholesterolaemia over time. To examine the true population rates and primary care data we compared the results of the Health survey for England in both 1998 and 2003 with the recorded data on GP computers.• Despite current guidelines, many patients with hypertension and/or hypercholesterolaemia are under‐treated and, even amongst those who are treated, many do not achieve their blood pressure and/or lipid targets.• Although treatment rates in the UK have improved recently, particularly for lipid‐lowering therapies, they remain suboptimal.AIMSTo determine the prevalence and treatment of hypertension, dyslipidaemia and both together in the UK between 1998 and 2006.METHODSWe used The Health Improvement Network (THIN) a general practice‐based database from 1998 to 2006 and we compared the 1998 and 2003 data to that taken from the Health Survey for England (HSE) in 1998 and 2003.RESULTSThe prevalence (treatment) of hypertension was 25.3% (11.4%) in 1998, 27.8% (15.1%) in 2003 and 26.9% (16.2%) in 2006 in THIN. In HSE it was 37.3% (9.6%) in 1998 and 32.9% (13.8%) in 2003. For dyslipidaemia the figures were 8.6% (1.9%), 18.5% (6.5%) and 24.4% (9.8%) for THIN and 67.8% (2.3%) and 74.9% (7.0%) for HSE. Concurrent hypertension and dyslipidaemia in THIN increased from 5.5% (1.1%) in 1998 to 13.5% (4.5%) in 2003 and 17.4% (7.1%) in 2006. The prevalence of both conditions was 30.6% (0.7%) in HSE in 1998 and 28.7% (3.1%) in 2003.CONCLUSIONSThere has been a progressive improvement in the detection and treatment of hypertension, dyslipidaemia and both conditions together between 1998 and 2006. However, much still needs to be done to improve the diagnosis and treatment of hypertension, hypercholesterolaemia and concurrent hypertension and hypercholesterolaemia in the United Kingdom.
Physiological response of the copepod Pseudocalanus sp. in the Baltic Sea at different thermal scenarios
Authors: ISLA JOSÉ ALEJANDRO , LENGFELLNER KATHRIN , SOMMER ULRICH 
Published: February 2008

AbstractWe studied the physiological response of Pseudocalanus sp. under four different temperature elevation regimes: +0, +2, +4 and +6 °C above the decadal average temperature in the Western Baltic Sea. We measured fecal pellet (FP) production rates, which was taken as a proxy of ingestion, egg production (EPR) and respiration rates. Experiments lasted from mid‐February to end April, corresponding most of the observations to the postspring bloom phase. We combined small scale incubations with the use of big (ca. 1400 L) mesocosms, which have previously been shown to be appropriate when studying phyto‐ and zooplankton succession, and the water used for the incubations was taken from the mesocosm tanks. Given that the phytoplankton succession varied between the four thermal scenarios, we evaluated (excepting in the case of the respiration rates, where incubations were carried out using 0.2 μm filtered water) both the temperature and the associated food concentration effects. Respiration and ingestion rates were found to increase with temperature. As for EPR, they also increased with temperature during the bloom, but remained at low and constant values during the postbloom in all the four treatments due to the food limitation. Linked to the temperature rise, we also detected an increase in instantaneous mortality rates and a reduction in the net growth efficiency. Finally, we discuss the potential implications of our findings for the spring phyto‐ and zooplankton succession under the forecasted climate warming, as well as for the fisheries in the Baltic Sea, where Pseudocalanus sp. is a key species.
Scaling‐up knowledge of growing‐season net ecosystem exchange for long‐term assessment of North Dakota grasslands under the Conservation Reserve Program
Authors: PHILLIPS REBECCA L. , BEERI OFER 
Published: February 2008

AbstractScaling‐up knowledge of land‐atmosphere net ecosystem exchange (NEE) from a single experimental site to numerous perennial grass fields in the Northern Great Plains (NGP) requires appropriate scaling protocols. We addressed this problem using synoptic data available from the Landsat sensor for 10 growing seasons (April 15 to September 30) over a North Dakota field‐site, where we continuously measured CO2 exchange using a Bowen Ratio Energy Balance (BREB) system. NEE observed during the growing season at our field‐site from 1997 to 2006 vacillated with drought and deluge, with net carbon (C) losses to the atmosphere in 2006. We used stepwise linear regression with 10 years of Landsat and NEE data to construct and validate a model for estimating grassland growing‐season NEE from field to landscape scales. Eighty‐nine percent of the variability in NEE was explained by year, live biomass, carbon : nitrogen ratio, day of image acquisition, and annual precipitation. We then applied this model on 20 620 ha of North Dakota perennial grass fields enrolled in the Conservation Reserve Program (CRP), including 1272 fields east of the Missouri River and 165 fields west‐river. Growing‐season NEE for individual CRP fields was highly variable from 1997 to 2006, ranging from −366 to 692 g C m−2 growing season−1. Mean annual growing‐season fluxes over 10 years for CRP fields located east‐river and west‐river were 317 g C m−2 growing season−1 and 239 g C m−2 growing season−1, respectively. Average cumulative growing‐season NEE modeled for fields east‐ and west‐river diverged from one another in 2002–2006, when west‐river fields received < 70% of the long‐term annual average precipitation during these years. Results indicate assessment of conservation practices on grassland CO2 exchange during the growing season can be remotely estimated at field and landscape scales under variable environmental conditions and should be followed up with similar, spatially explicit investigations of NEE during the dormant season.
Where did the northern peatland species survive the dry glacials: cloudberry (Rubus chamaemorus) as an example
Authors: Ehrich Dorothee , Alsos Inger Greve , Brochmann Christian 
Published: February 2008

AbstractAim  During the last ice age large parts of the north boreal and subarctic zones were covered by ice, while the climate in ice‐free regions of northern Asia was extremely cold and dry. The extensive peatlands of these zones with their characteristic vegetation developed at the beginning of the Holocene. We combine a phylogeographical approach with maps of pollen records to identify regions where Rubus chamaemorus, a plant of moist, peaty soils, was likely to grow during this period.Location  Circumarctic/circumboreal.Methods  Samples were collected from 45 locations throughout much of the range of R. chamaemorus and 398 plants were analysed with amplified fragment length polymorphism (AFLP). Estimates of diversity and differentiation, principal coordinates analysis and Bayesian clustering methods were used for the analysis of genetic data. Dated pollen records were retrieved from the European and the Global Pollen Databases.Results  The plants from Sakhalin are highly divergent from the rest of the material and represent the previously described var. pseudochamaemorus. The main genetic division in R. chamaemorus sensu stricto is found in the Taymyr region in central Eurasia. Genetic diversity and the relative number of rare markers are highest in central Siberia and eastern Asia and decrease towards Europe and to a lesser extent eastwards through North America. Pollen dating back to the last ice age is found in central and eastern Siberia and Alaska. The maximum observed clone size is about 250 m, and more than one clone is found in nearly every local population.Main conclusions  The genetic data are consistent with the pollen records and indicate that R. chamaemorus was growing in several areas of northern central Siberia and Beringia during the last glaciation. This finding suggests that sufficient humidity for this and other species of peaty soils was present locally in different parts of the generally dry ice‐free areas of northern Asia, as had been previously documented for Beringia. The AFLP data show that var. pseudochamaemorus, which is also morphologically quite divergent, clearly represents a distinct genetic entity.
Reconstructing the biogeographical history of two plant genera with different dispersion capabilities
Authors: Katinas Liliana , Crisci Jorge V. 
Published: February 2008

AbstractAim  The pappus is one of the most distinctive features of the genera belonging to the sunflower family, and is an efficient mechanism for dispersion by wind. The pappose Holocheilus (seven species) and the non‐pappose Panphalea (nine species) are two genera of the monophyletic subtribe Nassauviinae (Asteraceae, Mutisieae), which overlap in their areas of distribution. This paper aims to reconstruct the biogeographical histories that shaped the distribution of these two genera, which are phylogenetically and geographically related, but differ in their means of dispersion. Our initial expectation was that the dispersion capability of the pappus should be reflected in more dispersal events in Holocheilus than in Panphalea.Location  South‐eastern Brazil, Paraguay, Uruguay and Argentina.Methods  Morphological data were acquired from the literature and by analysis of specimens. Two cladistic analyses, one for Holocheilus and one for Panphalea, were based on morphological characters, and data matrices were analysed with the Fitch parsimony algorithm of paup. The ancestral distributions were reconstructed using diva ver. 1.1 according to the dispersal–vicariance optimization method.Results  The Paranense‐fields were identified as the most likely ancestral area of Holocheilus and Panphalea. Biogeographical reconstruction of Holocheilus shows several dispersal events from the Paranense‐fields: two ancestral dispersal events to the Yungas, followed by vicariance events (Paranense‐fields/Yungas) and numerous terminal dispersals to the surrounding areas such as Chacoan, Pampean and Espinal. diva reconstruction of Panphalea distribution also shows frequent terminal dispersals, with no vicariant events, from the Paranense‐fields to the other areas: (1) to Espinal, Pampean‐Uruguayan, Pampean‐oriental; (2) to Paranense‐hills; (3) to Pampean‐Uruguayan; and (4) to Paranense‐pine lands.Main conclusions  In the past, both genera probably originated in the Paranense‐fields area, which was subject to the dry and humid cycles of the Quaternary glaciations. Dispersal was the process that predominantly shaped the distribution of Panphalea and Holocheilus, with approximately the same number of dispersal events in both genera, despite differing ranges of dispersion. The main barriers to dispersal were the dry Cerrado and Chaco, the latter promoting vicariance in Holocheilus. The lack of a pappus in Panphalea was a limitation for its dispersion compared with Holocheilus.
Biogenesis of Fe/S proteins and pathogenicity: IscR plays a key role in allowing Erwinia chrysanthemi to adapt to hostile conditions
Authors: Rincon‐Enriquez Gabriel , Crété Patrice , Barras Frédéric , Py Béatrice 
Published: February 2008

SummaryThe Erwinia chrysanthemi genome is predicted to encode three systems, Nif, Isc and Suf, known to assist Fe/S cluster biogenesis and the CsdAE cysteine desulphurase. Single iscU, hscA and fdx mutants were found sensitive to paraquat and exhibited reduced virulence on both chicory leaves and Arabidopsis thaliana. Depletion of the whole Isc system led to a pleiotropic phenotype, including sensitivity to both paraquat and 2,2′‐dipyridyl, auxotrophies for branched‐chain amino acids, thiamine, nicotinic acid, and drastic alteration in virulence. IscR was able to suppress all of the phenotypes listed above in a sufC‐dependent manner while depletion of the Isc system led to IscR‐dependent activation of the suf operon. No virulence defects were found associated with csdA or nifS mutations. Surprisingly, we found that the sufC mutant was virulent against A. thaliana, whereas its virulence had been found altered in Saintpaulia. Collectively, these results lead us to propose that E. chrysanthemi possess the Fe/S biogenesis strategy suited to the physico‐chemical conditions encountered in its host upon infection. In this view, the IscR regulator, which controls both Isc and Suf, is predicted to play a major role in the ability of E. chrysanthemi to colonize a wide array of different plants.
Overexpression of membrane‐associated acyl‐CoA‐binding protein ACBP1 enhances lead tolerance in Arabidopsis
Authors: Xiao Shi , Gao Wei , Chen Qin‐Fang , Ramalingam Sathishkumar , Chye Mee‐Len 
Published: February 2008

SummaryIn Arabidopsis thaliana, a family of six genes encodes acyl‐CoA‐binding proteins (ACBPs) that show conservation at the acyl‐CoA‐binding domain. They are the membrane‐associated ACBP1 and ACBP2, extracellularly targeted ACBP3, kelch‐motif‐containing ACBP4 and ACBP5, and 10‐kDa ACBP6. The acyl‐CoA domain in each of ACBP1 to ACBP6 binds long‐chain acyl‐CoA esters in vitro, suggestive of possible roles in plant lipid metabolism. We addressed here the use of Arabidopsis ACBPs in conferring lead [Pb(II)] tolerance in transgenic plants because the 10‐kDa human ACBP has been identified as a molecular target for Pb(II) in vivo. We investigated the effect of Pb(II) stress on the expression of genes encoding Arabidopsis ACBP1, ACBP2 and ACBP6. We showed that the expression of ACBP1 and ACBP2, but not ACBP6, in root is induced by Pb(II) nitrate treatment. In vitro Pb(II)‐binding assays indicated that ACBP1 binds Pb(II) comparatively better, and ACBP1 was therefore selected for further investigations. When grown on Pb(II)‐containing medium, transgenic Arabidopsis lines overexpressing ACBP1 were more tolerant to Pb(II)‐induced stress than the wild type. Accumulation of Pb(II) in shoots of the ACBP1‐overepxressing plants was significantly higher than wild type. The acbp1 mutant showed enhanced sensitivity to Pb(II) when germinated and grown in the presence of Pb(II) nitrate and tolerance was restored upon complementation using an ACBP1 cDNA. Our results suggest that ACBP1 is involved in mediating Pb(II) tolerance in Arabidopsis with accumulation of Pb(II) in shoots. Such observations of Pb(II) accumulation, rather than Pb(II) extrusion, in the ACBP1‐overexpressing plants implicate possible use of ACBP1 in Pb(II) phytoremediation.
Rice SVP‐group MADS‐box proteins, OsMADS22 and OsMADS55, are negative regulators of brassinosteroid responses
Authors: Lee Shinyoung , Choi Sang Chul , An Gynheung 
Published: February 2008

SummaryMost short vegetative phase (SVP)‐group MADS‐box genes control meristem identity and flowering time. Among the three SVP‐group genes in rice, OsMADS47 has been reported as a negative regulator of brassinosteroid (BR) responses. Here, we investigated the functional roles of two close homologs, OsMADS22 and OsMADS55, by generating single, double and triple RNAi lines and overexpression lines. Analyses of the plants showed that their roles in regulating meristem identity are well conserved; however, the involvement of these genes in determining flowering time has diversified. Most importantly, OsMADS55 works as a major negative regulator of BR responses, and OsMADS22 functions to support OsMADS55. Whereas single OsMADS55 RNAi plants display weak BR responses in the lamina joint (LJ), OsMADS22‐OsMADS55 double and OsMADS22‐OsMADS47‐OsMADS55 triple RNAi plants manifest dramatic BR responses with regard to LJ inclination, coleoptile elongation and senescence. Stem elongation is also notably reduced in the double and triple RNAi plants, probably because of BR oversensitivity. Expression analyses indicate the diversified roles in age‐dependent BR responses. Altogether, our study demonstrates that all three rice SVP‐group genes work as negative regulators of BR responses, but that their spatial and temporal roles are diversified.
Intertriginous plasmacytosis with plasmoacanthoma: report of a typical case and review of the literature
Authors: Senol Mustafa , Ozcan Atilla , Aydin N. Engin , Hazneci Ersoy , Turan Nergiz 
Published: February 2008

AbstractClinical manifestations of benign (reactive) plasma cell proliferations of the skin and mucosa consist of a relatively rare and distinct group in dermatologic disorders. They have generally been named according to their localization. We report a typical case of mucocutaneous plasmacytosis located on intertriginous areas of the skin as well as mucosa with a perianal tumoral mass diagnosed as plasmoacanthoma. To our knowledge, this is the first detailed case report, at least in English literature.
Two courses of rituximab (anti‐CD20 monoclonal antibody) for recalcitrant pemphigus vulgaris
Authors: Faurschou Annesofie , Gniadecki Robert 
Published: February 2008

AbstractBackground  Pemphigus vulgaris (PV) is a severe autoimmune blistering disease involving the skin and mucous membranes. The response to therapy varies greatly amongst patients and treatment may be challenging. Rituximab is a chimeric monoclonal antibody that selectively targets cell surface antigen CD20, thus depleting mature B cells in vivo.Methods  We report the results of rituximab treatment in two patients with severe PV. In both patients, high‐dose oral prednisolone and adjuvant therapy with intravenous immunoglobulins and mycophenolate mofetil failed to control disease activity. Consequently, the patients were treated with two courses of four weekly intravenous infusions of rituximab (375 mg/m2) with a 6‐month interval.Results  Clinical improvement was already noticeable 3–6 weeks after the first infusion. After the second course, complete remission was achieved. Oral prednisolone was reduced and treatment with mycophenolate mofetil was continued. The patients remained in full remission 6 months after the last rituximab infusion.Conclusion  These cases suggest that two courses rather than a single course of rituximab may be a preferable mode of treatment. Rituximab should be considered as a promising treatment option for recalcitrant PV.
Extramedullary granulocytic sarcoma of the skin, mediastinum, and pericardium
Authors: Diab Mohammad , Coloe Jacquelyn , Bechtel Mark 
Published: February 2008

A 27‐year‐old man, with a past history of developmental delay, presented on 18 November 2005 for the evaluation of an acute onset of multiple red–violaceous nodules on the head, neck, and trunk of 5 days’ duration. The patient had no associated fever, chills, weight loss, night sweats, chest pain, dyspnea, lymphadenopathy, or organomegaly. He had no previous history of malignancies. A biopsy indicated a diagnosis of leukemia cutis (Fig. 1). His initial complete blood count (CBC) was within normal limits. The 2‐week follow‐up revealed enlargement of the previous lesions and the development of new lesions (Fig. 2). By the third week, the patient had developed dyspnea, but with normal breath sounds and oxygen saturation. Chest computed tomography demonstrated a mediastinal mass measuring 16 × 5.2 cm and pericardial thickening (Fig. 3). The diagnosis of granulocytic sarcoma of the skin lesion and mediastinal mass was established on the basis of immunohistochemical stains, with positivity to CD43 and Leder's preparation and negativity to CD3, CD4, CD5, CD8, CD10, CD20, CD23, CD30, CD34, CD56, bcl‐1, terminal deoxynucleotidyl transferase (TdT), and granzyme. The bone marrow was negative for malignant cells. CBC and chemistry panel were all normal. Nevertheless, the patient experienced increased dyspnea and developed a pericardial effusion which required a pericardial window. Cytology of the pericardial fluid was consistent with granulocytic sarcoma. Once the diagnosis of granulocytic sarcoma was established, the patient started a regimen of cytarabine, daunorubicin, and etoposide. Despite this, the skin lesions and mediastinal mass showed minimal response. Repeat computed tomography showed a mediastinal mass measuring 14.5 × 4.4 cm. The patient's respiratory status required intubation and, 2 weeks later, his family requested that he be withdrawn from life support.Immature myelocytic infiltrate in the dermis (hematoxylin and eosin, ×4)imageClinical image of granulocytic sarcomaimageComputed tomography of the chest illustrating mediastinal pericardial involvementimage