bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of cellular and viral factors related to anti‐hepatitis C virus activity of cyclophilin inhibitor
Authors: Goto Kaku , Watashi Koichi , Inoue Daisuke , Hijikata Makoto , Shimotohno Kunitada 
Published: June 2009

We have so far reported that an immunosuppressant cyclosporin A (CsA), a well‐known cyclophilin (CyP) inhibitor (CPI), strongly suppressed hepatitis C virus (HCV) replication in cell culture, and that CyPB was a cellular cofactor for viral replication. To further investigate antiviral mechanisms of CPI, we here developed cells carrying CsA‐resistant HCV replicons, by culturing the HCV subgenomic replicon cells for 4 weeks in the presence of CsA with G418. Transfection of total RNA from the isolated CsA‐resistant cells to naïve Huh7 cells conferred CsA resistance, suggesting that the replicon RNA itself was responsible for the resistant phenotype. Of the identified amino acid mutations, D320E in NS5A conferred the CsA resistance. The replicon carrying the D320E mutation was sensitive to interferon‐α, but was resistant to CsA and other CPIs including NIM811 and sanglifehrin A. Knockdown of individual CyP subtypes revealed CyP40, in addition to CyPA and CyPB, contributed to viral replication, and CsA‐resistant replicons acquired independence from CyPA for efficient replication. These data provide important evidence on the mechanisms underlying the regulation of HCV replication by CyP and for designing novel and specific anti‐HCV strategies with CPIs. (Cancer Sci 2009; 100: 1943–1950)
Tumor histology in lymph vessels and lymph nodes for the accurate prediction of outcome among breast cancer patients treated with neoadjuvant chemotherapy
Authors: Tamura Nobuko , Hasebe Takahiro , Okada Nao , Houjoh Takashi , Akashi‐Tanaka Sadako , Shimizu Chikako , Shibata Tatsuhiro , Sasajima Yuko , Iwasaki Motoki , Kinoshita Takayuki 
Published: June 2009

The present study investigated fibrotic foci (FFs), the grading system for lymph vessel tumor emboli (LVTEs), and the histological characteristics of nodal metastatic tumors that were significantly associated with the outcomes of 115 patients with invasive ductal carcinoma (IDC) who had received neoadjuvant chemotherapy. We compared the outcome predictive power of FFs, the grading system for LVTEs, and the histological characteristics of metastatic tumors in lymph nodes with the well‐known clinicopathological characteristics of tumor recurrence and tumor‐related death in multivariate analyses. The presence of FFs, as assessed by a biopsy performed before neoadjuvant chemotherapy, significantly increased the hazard rates (HRs) for tumor‐related death in all the cases and in cases with nodal metastasis. The grading system for LVTEs, which was assessed using surgical specimens obtained after neoadjuvant chemotherapy, was significantly associated with increasing hazard rates (HRs) for tumor recurrence and tumor‐related death in all the cases and in cases with nodal metastasis. Moderate to severe stroma in nodal metastatic tumors and five or more mitotic figures in nodal metastatic tumors were significantly associated with elevated HRs for tumor recurrence and tumor‐related death among all the cases. These results indicated that FFs, the grading system for LVTEs, and the histological characteristics of tumor cells in lymph nodes play important roles in predicting the tumor progression of IDCs of the breast in patients treated with neoadjuvant chemotherapy. (Cancer Sci 2009; 100: 1823–1833)
Nicotiana plumbaginifolia plants silenced for the ATP‐binding cassette transporter gene NpPDR1 show increased susceptibility to a group of fungal and oomycete pathogens
Authors: BULTREYS ALAIN , TROMBIK TOMASZ , DROZAK ANNA , BOUTRY MARC 
Published: June 2009

SUMMARYThe behaviour of Nicotiana plumbaginifolia plants silenced for the ATP‐binding cassette transporter gene NpPDR1 was investigated in response to fungal and oomycete infections. The importance of NpPDR1 in plant defence was demonstrated for two organs in which NpPDR1 is constitutively expressed: the roots and the petal epidermis. The roots of the plantlets of two lines silenced for NpPDR1 expression were clearly more sensitive than those of controls to the fungal pathogens Botrytis cinerea, Fusarium oxysporum sp., F. oxysporum f. sp. nicotianae, F. oxysporum f. sp. melonis and Rhizoctonia solani, as well as to the oomycete pathogen Phytophthora nicotianae race 0. The Ph gene‐linked resistance of N. plumbaginifolia to P. nicotianae race 0 was totally ineffective in NpPDR1‐silenced lines. In addition, the petals of the NpPDR1‐silenced lines were spotted 15%–20% more rapidly by B. cinerea than were the controls. The rapid induction (after 2–4 days) of NpPDR1 expression in N. plumbaginifolia and N. tabacum mature leaves in response to pathogen presence was demonstrated for the first time with fungi and one oomycete: R. solani, F. oxysporum and P. nicotianae. With B. cinerea, such rapid expression was not observed in healthy mature leaves. NpPDR1 expression was not observed during latent infections of B. cinerea in N. plumbaginifolia and N. tabacum, but was induced when conditions facilitated B. cinerea development in leaves, such as leaf ageing or an initial root infection. This work demonstrates the increased sensitivity of NpPDR1‐silenced N. plumbaginifolia plants to all of the fungal and oomycete pathogens investigated.
Health care seeking for abdominal bloating and visible distention
Authors: JIANG X. , LOCKE G. R. , ZINSMEISTER A. R. , SCHLECK C. D. , TALLEY N. J. 
Published: June 2009

SummaryBackground  While knowledge has accumulated regarding health care seeking in several functional gastrointestinal disorders (FGIDs), little is known about health care seeking in those with bloating and distention.Aim  To identify predictors of health care seeking for bloating and distention.Methods  The validated Talley Bowel Disease Questionnaire was mailed to a cohort selected at random from the population of Olmsted County, Minnesota; 2259 subjects (53% females; mean age 62 years) answered questions about bloating and distention. The complete medical record of each respondent was reviewed. Logistic regression was used to compare consulting for bloating and distention with consulting for other GI symptoms, and nonconsulters.Results  A total of 131 (6%) subjects in the community consulted a physician for bloating or distention. Older age [odds ratio (OR), 1.8; 95% confidence interval (CI): 1.5, 2.1], higher somatic symptom scores (OR, 2.0; CI: 1.4, 2.8), lower education level (OR, 2.7; CI: 1.2, 5.6), early satiety (OR, 2.0; CI: 1.1, 3.8) and abdominal pain (OR, 2.4; CI: 1.6, 3.7) were associated with people seeking health care for bloating or distention vs. non‐consulters. Similarly, older age (OR, 1.4; CI: 1.2, 1.7), chronic constipation (OR, 2.0; CI: 1.2, 3.2) and visible distention (OR, 3.0; CI: 1.8, 4.9) had greater odds of presenting for bloating or distention compared with presenting for other GI symptoms; somatic symptoms were not a predictor (OR, 1.1; CI: 0.8, 1.5).Conclusions  Factors that lead people to present for bloating and distention are similar to those for other GI symptoms visits; however, specific biological rather than somatic features may predict visits for bloating and distention.
Population pharmacokinetics and optimal design of paediatric studies for famciclovir
Authors: Ogungbenro Kayode , Matthews Ivan , Looby Michael , Kaiser Guenther , Graham Gordon , Aarons Leon 
Published: June 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Famciclovir is licensed in adults for the treatment of herpes zoster and herpes simplex viral infections.• The pharmacokinetics of famciclovir has been extensively studied in adults, but no population pharmacokinetic model has been published to date.• There is limited information about the pharmacokinetics of famciclovir in children.WHAT THIS STUDY ADDS• A population pharmacokinetic model of penciclovir (famciclovir is a prodrug of penciclovir) was developed in adults and children.• New paediatric pharmacokinetic studies have been designed using a 10 mg kg−1dose in children that gives similar exposure to 500 mg in adults.• A sampling windows design for sparse sampling based on an adequate number of subjects in three paediatric age groups has also been developed.AIMSTo develop a population pharmacokinetic model for penciclovir (famciclovir is a prodrug of penciclovir) in adults and children and suggest an appropriate dose for children. Furthermore, to develop a limited sampling design based on sampling windows for three different paediatric age groups (1–2, 2–5 and 5–12 years) using an adequate number of subjects for future pharmacokinetic studies.METHODSPenciclovir plasma data from six different adult and paediatric studies were supplied by Novartis. Population pharmacokinetic modelling was undertaken in NONMEM version VI. Simulations in MATLAB were used to select an oral paediatric dose that gives similar exposure to 500 mg in adults. Optimal sampling times and sampling windows were obtained in MATLAB and simulations in NONMEM were used to select adequate sample sizes for three paediatric age groups.RESULTSA two‐compartment, first‐order absorption model with an absorption lag time, allometric weight models onV1,V2andQ, and an allometric weight model, age and creatinine clearance as covariates on CL adequately describe the pharmacokinetics of penciclovir in adults and children. Estimated CL (l h−1 70 kg−1) andVss(l.70 kg−1) were 31.2 and 83.1, respectively. An oral dose of 10 mg kg−1body weight in children was predicted to give similar exposure as 500 mg in adults. A single sampling windows design (0.25–0.4, 0.5–1, 1.25–1.75, 2.75–3.5 and 7.25–8 h) for five samples per subject and 10 subjects in each of the paediatric age groups is recommended for future studies.CONCLUSIONSA population pharmacokinetic model of penciclovir in adults and children has been developed. A prospective study design, including dose adjustment, cohort size and blood sampling design has been recommended.
Proposals for model‐based paediatric medicinal development within the current European Union regulatory framework
Authors: Manolis Efthymios , Pons Gérard 
Published: June 2009

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT • The use of modelling and simulation (M&S) in paediatric drug development has been the subject of numerous scientific publications in the last decade.• Many scientific teams have elaborated on the methodology and provided successful examples of the added value of M&S in this area.• Furthermore, regulatory bodies and the US Food and Drug Administration in particular have provided guidance on good modelling and simulation practice and on the role of M&S in drug development. WHAT THIS STUDY ADDS • This paper attempts to position M&S in the European regulatory environment based on European Medicines Agency (EMEA) guidelines.• It presents the personal views of the authors on the issues discussed in the EMEA workshop on modelling in paediatric medicines (14–15 April 2008) [1].• It proposes an algorithm for the practical implementation of M&S in paediatric drug development and a forum for further discussions.The new paediatric European Union (EU) regulation and the consequent demand for paediatric studies on one hand and the ethical need for minimizing the burden of studies in children on the other hand necessitate optimal techniques in the assessment of safety/efficacy and use of drugs in children. Modelling and simulation (M&S) is one way to circumvent some difficulties in developing medicinal products in children. M&S allows the quantitative use of sparse sampling, characterization and prediction of pharmacokinetics/ pharmacodynamics (PK/PD), extrapolation from adults to children, interpolation between paediatric age subsets, optimal use of scientific literature and in vitro/preclinical data. Together, industry, academia and regulators recognize the usefulness of modelling and simulation in this setting. However, even if M&S is an emerging science, its integration in the EU regulatory decision making is for the time being deficient and M&S expertise is concentrated in big pharmaceutical companies and academic institutions. The European Medicines Agency, acknowledging all the above conditions, organized and hosted a Workshop on Modelling in Paediatric Medicines. The article presents the personal views of the authors on the issues presented and discussed in the workshop. We attempt to identify the regulatory framework for the use of M&S in paediatric medicinal development and to make proposals for model‐based paediatric medicinal development. The objective is to open the discussion between industry, academia, paediatricians and regulators on the optimal use of M&S in paediatric medicinal development.
Abnormal centrosome‐centriole cycle in chronic myeloid leukaemia?
Authors: Patel Hetal , Gordon Myrtle Y. 
Published: June 2009

SummaryAbnormal numbers, structures and functions of centrosomes in chronic myeloid leukaemia (CML) may influence cell proliferation and genomic instability, which are features of the disease. Centrosomes are regulators of mitotic spindle orientation and can act as scaffolds for centrosome‐associated regulators of the cell cycle. This study showed, for the first time, that p210BCR‐ABL1 and p145ABL1 are both centrosome‐associated proteins, as demonstrated by co‐immunoprecipitation with the pericentriolar protein, pericentrin. Furthermore, when CML cells were treated with imatinib there was a 55% and 20% reduction of p210BCR‐ABL1 and p145ABL1 binding to pericentrin, respectively. Cell lines expressing p210BCR‐ABL1 and primary CD34+ cells from CML patients exhibited more numerical and structural centrosomal abnormalities than p210BCR‐ABL1 negative cells. Primary cells from CML blast crisis (BC) patients exhibited a distinctive amorphous staining pattern of pericentrin compared to normal and CML chronic phase (CP) patients, suggesting a possible defect in pericentrin localisation at the centrosomes. Proteins, such as aurora kinases, pericentrin, survivin and separase, regulate centrosome structure and function, cell cycle and mitotic spindle formation. Levels of the protease, separase are abnormally high in CML CP and BC cells in comparison to normal CD34+ cells. The data imply that expression of p210BCR‐ABL1 is associated with abnormalities in the centrosome‐centriole cycle and increased separase expression.
Doppler‐defined pulmonary hypertension and the risk of death in children with sickle cell disease followed for a mean of three years
Authors: Lee Margaret T. , Small Tania , Khan Muhammad A. , Rosenzweig Erika B. , Barst Robyn J. , Brittenham Gary M. 
Published: June 2009

SummaryPulmonary hypertension (PH) is associated with increased mortality in adults with sickle cell disease (SCD), but its prognostic significance in children is unknown. Eighty‐eight children with SCD were followed after echocardiographic screening for PH. After a mean follow‐up of 3 years, all 18 subjects with PH were alive. In our children, as in adults with SCD, PH was associated with increased haemolysis. In contrast, our subjects with PH did not have overt systemic disease observed in adults. PH may be a manifestation of progressive organ damage from chronic haemolysis and systemic vasculopathy that ultimately leads to early death in adulthood.
Methods to assess impaired post‐prandial metabolism and the impact for early detection of cardiovascular disease risk
Authors: Su J. W. , Nzekwu M.‐M. U. , Cabezas M. C. , Redgrave T. , Proctor S. D. 
Published: June 2009

AbstractPost‐prandial lipaemia has emerged as a key contributor to cardiovascular disease (CVD) risk and progression. Specifically, delayed clearance of chylomicrons (CM) and their remnants increase the delivery of triglyceride and cholesteryl ester to the vessel wall and can accelerate the progression of atherosclerosis, which may be particularly pertinent to individuals with insulin resistance and/or obesity. As the number of studies linking post‐prandial metabolism and chronic disease increases, interest has grown in the use of parameters reflecting CM metabolism as a possible indicator of early CVD risk. This, in turn has raised the question of what method might be most appropriate to detect CM and their remnants in plasma accurately. However, the handful of techniques able to measure CM metabolism (triglyceride‐rich lipoprotein fractions; remnant‐lipoprotein cholesterol; retinyl esters, CM‐like emulsion; sodium dodecyl sulphate–polyacrylamide gel electrophoresis; immunoblotting, enzyme‐linked immunoabsorbent assays; C13 breath test; capillary finger prick) differ in their specificity, cost and applicability in research and in the clinical setting. In this review, we explore the scientific and clinical implications of CM methodology to better understand early risk assessment of CVD. We raise ongoing issues of the need to appreciate differential separation of very low‐density lipoprotein and CM fractions, as well as to identify the technical basis for imprecision between assays for apolipoprotein B48. We also highlight emerging issues with respect to the practicality of measuring post‐prandial metabolism in large clinical studies and offer opinions on the appropriateness of existing techniques in this field.
Serum hepcidin concentration in chronic haemodialysis patients: associations and effects of dialysis, iron and erythropoietin therapy
Authors: Weiss G. , Theurl I. , Eder S. , Koppelstaetter C. , Kurz K. , Sonnweber T. , Kobold U. , Mayer G. 
Published: June 2009

AbstractBackground  Hepcidin, a liver‐derived peptide induced by iron overload and inflammation, is a major regulator of iron homeostasis. As hepcidin decreases gastrointestinal iron absorption and recirculation from monocytes, over‐expression is associated with the development of anaemia.Methods  We studied the associations between circulating hepcidin levels and various laboratory parameters related to anaemia and/or inflammation in 20 patients on chronic haemodialysis. Furthermore, we determined the impact of dialysis and iron and/or erythropoietin (rhEpo) supplementation therapy on hepcidin serum concentrations. The patients were withheld from iron and rhEpo for 2 weeks before study entry. Hepcidin was measured by liquid chromatography‐mass spectrometry (LC‐MS/MS); serum iron and haematological parameters, cytokines and pro‐hepcidin by commercially available enzyme‐linked immunosorbent assays (ELISA) or standard automated methods.Results  While hepcidin levels at baseline were not correlated to pro‐hepcidin, interleukin‐6 or transforming growth factor‐beta concentrations, we found significant associations with reticulocyte count (r = −0·55; P = 0·015), serum iron (r = 0·7; P = 0·004) and ferritin levels (r = 0·63; P = 0·004) and transferrin saturation (r = 0·69, P = 0·001). Dialysis using either a high or a low flux biocompatible dialyser resulted in a significant decrease of hepcidin concentrations, which returned to pre‐dialysis values before the next dialysis session. When studying the effects of anaemia treatment, we observed a significant reduction of hepcidin levels following administration of rhEpo but not iron.Conclusions  Hepcidin levels in stable haemodialysis patients appear to reflect systemic iron load, but not inflammation. Due to the negative association between reticulocyte counts and hepcidin, the reduction of circulating hepcidin concentrations by dialysis and/or rhEpo treatment may positively affect erythropoiesis.
Choline supplementation reduces oxidative stress in mouse model of allergic airway disease
Authors: Mehta A. K. , Arora N. , Gaur S. N. , Singh B. P. 
Published: June 2009

AbstractBackground  Asthma is a multi‐factorial inflammatory disease associated with increased oxidative stress and altered antioxidant defences. We have evaluated the effect of choline on oxidative stress in a mouse model of airway disease.Materials and methods  Balb/c mice were sensitised with 100 μg of ovalbumin on days 0 and 14, and challenged with aerosolized ovalbumin on days 25–27. Mice were administered 1 mg kg–1 of choline via oral gavage or intranasal route on days 14–27. Mice were also administered 100 mg kg–1 of α‐lipoic acid as standard antioxidant. Total cell counts, eosinophils and eosinophil peroxidase (EPO) activity were determined in bronchoalveolar lavage (BAL) fluid. Reactive oxygen species (ROS), lipid peroxidation and isoprostanes levels were measured in BAL fluid. IL‐13 and tumour necrosis factor‐alpha (TNF‐α) levels were also measured in BAL fluid and spleen cell culture supernatant. Nuclear factor κB (NFκB) p65 protein expression was measured after last ovalbumin challenge in nuclear and cytosolic extracts of lungs.Results  Compared with ovalbumin‐challenged mice, choline and α‐lipoic acid treated mice had significantly reduced eosinophilic infiltration and EPO activity in BAL fluid. Choline and α‐lipoic acid treatment reduced ROS production and isoprostanes level significantly in BAL fluid and thus suppressed oxidative stress. Choline and α‐lipoic acid administration by either route decreased lipid peroxidation levels and down regulated NFκB activity. Further, choline and/or α‐lipoic acid treatment suppressed TNF‐α level significantly as compared with that of ovalbumin‐challenged mice.Conclusions  Choline administration reduces oxidative stress possibly by modulating the redox status of the cell and inhibits inflammatory response in a mouse model.