bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linkage Analysis of Discrete Traits
Authors: Borecki Ingrid B. , Rice John P. 
Published: February 2010

INTRODUCTIONLinkage analysis is an important tool for the investigation of the genetic basis of disease traits and has led to the discovery of the single genes underlying such diseases as cystic fibrosis, Duchenne muscular dystrophy, Huntington’s disease, and a wide variety of metabolic disorders. For certain kinds of traits, linkage analysis allows the localization of trait loci on a known genetic map, which can be followed up with fine mapping based on linkage disequilibrium (LD) and ultimate identification of the gene. Successes using this approach have been largely confined to Mendelian monogenic disorders or oligogenic disorders (e.g., breast cancer, Alzheimer’s disease). Complex diseases (e.g., asthma, schizophrenia) involving several to many loci, as well as environmental factors, may require additional strategies to locate risk loci.
Adipocytokines as new promising markers of colorectal tumors: Adiponectin for colorectal adenoma, and resistin and visfatin for colorectal cancer
Authors: Nakajima Takako Eguchi , Yamada Yasuhide , Hamano Tetsutaro , Furuta Koh , Matsuda Takahisa , Fujita Shin , Kato Ken , Hamaguchi Tetsuya , Shimada Yasuhiro 
Published: February 2010

Adipocytokines are adipocyte‐secreted hormones associated with some malignancies such as colorectal, breast, and prostate cancer. We hypothesized that changes in the levels of adipocytokines may indicate the carcinogenesis and progression of colorectal cancer and adenoma, and investigated the association of the blood levels of several adipocytokines through a case‐control study. Blood levels of adiponectin, leptin, resistin, visfatin, and C‐peptide at diagnosis were measured in 115 colorectal cancer patients and 115 age‐, sex‐, and body mass index‐matched controls. The same analysis was performed in 72 colorectal adenoma patients and 72 controls. Logistic regression models were used for estimating odds ratios and 95% confidence intervals, and one‐way anova was performed to determine the prevalence of each variable between two or more groups. Resistin and visfatin levels in cancer patients were significantly higher than those of controls on multivariate analysis (P = 0.03 and P < 0.01, respectively). Stage progression significantly correlated with resistin and visfatin levels (P < 0.01 for both). The adiponectin level in adenoma patients was significantly lower than that of controls on multivariate analysis (P = 0.04). Its level was inversely correlated with the number of adenoma (P = 0.02), but not correlated with the size of adenoma. Resistin and visfatin may be good biomarkers of colorectal malignant potential and stage progression. Adiponectin level may be a good biomarker of colorectal adenoma.(Cancer Sci 2010; 101: 1286–1291)
Secular trends in breast cancer mortality in five East Asian populations: Hong Kong, Japan, Korea, Singapore and Taiwan
Authors: Shin Hai‐Rim , Boniol Mathieu , Joubert Clementine , Hery Clarisse , Haukka Jari , Autier Philippe , Nishino Yoshikazu , Sobue Tomotaka , Chen Chien‐Jen , You San‐Lin , Ahn Sei Hyun , Jung Kyu Won , Law Stephen Chun‐Key , Mang Oscar , Chia Kee‐Seng 
Published: February 2010

Breast cancer risk is increasing in most Asian female populations, but little is known about the long‐term mortality trend of the disease among these populations. We extracted data for Hong Kong (1979–2005), Japan (1963–2006), Korea (1985–2006), and Singapore (1963–2006) from the World Health Organization (WHO) mortality database and for Taiwan (1964–2007) from the Taiwan cancer registry. The annual age‐standardized, truncated (to ≥20 years) breast cancer death rates for 11 age groups were estimated and joinpoint regression was applied to detect significant changes in breast cancer mortality. We also compared age‐specific mortality rates for three calendar periods (1975–1984, 1985–1994, and 1995–2006). After 1990, breast cancer mortality tended to decrease slightly in Hong Kong and Singapore except for women aged 70+. In Taiwan and Japan, in contrast, breast cancer death rates increased throughout the entire study period. Before the 1990s, breast cancer death rates were almost the same in Taiwan and Japan; thereafter, up to 1996, they rose more steeply in Taiwan and then they began rising more rapidly in Japan than in Taiwan after 1996. The most rapid increases in breast cancer mortality, and for all age groups, were in Korea. Breast cancer mortality trends are expected to maintain the secular trend for the next decade mainly as the prevalence of risk factors changes and population ages in Japan, Korea, and Taiwan. Early detection and treatment improvement will continue to reduce the mortality rates in Hong Kong and Singapore as observed in Western countries.(Cancer Sci2010; 101: 1141–1246)
Molecular characterization of swine leucocyte antigen class II genes in outbred pig populations
Authors: Ho C.‐S. , Lunney J. K. , Lee J.‐H. , Franzo‐Romain M. H. , Martens G. W. , Rowland R. R. R. , Smith D. M. 
Published: February 2010

SummaryThe highly polymorphic swine leucocyte antigen (SLA) genes are among the most important determinants of swine immune responses to disease and vaccines. Accurate and effective SLA genotyping methods are required to understand how SLA gene polymorphisms affect immunity, especially in outbred pigs with diverse genetic backgrounds. In this study, we present a simple and rapid molecular‐based typing system for characterizing SLA class II alleles of the DRB1, DQB1 and DQA loci. This system utilizes a set of 47 sequence‐specific PCR primers developed to differentiate alleles by groups that share similar sequence motifs. We applied this typing method to investigate the SLA class II diversity in four populations of outbred pigs (n = 206) and characterized a total of 19 SLA class II haplotypes, six of which were shared by at least three of the sampled pig populations. We found that Lr‐0.1 (DRB1*01XX–DQB1*01XX–DQA*01XX) was the most prevalent haplotype with a combined frequency of 16.0%, followed by Lr‐0.2 (DRB1*02XX–DQB1*02XX–DQA*02XX) with 14.6% and Lr‐0.15b (DRB1*04XX–DQB1*0202–DQA*02XX) with 14.1%. Over 70% of the pigs (n = 147) had at least one copy of one of these three haplotypes. The PCR‐based typing system described in this study demonstrates a reliable and unambiguous detection method for SLA class II alleles. It will be a valuable tool for studying the influence of SLA diversity on various immunological, pathological and physiological traits in outbred pigs.
Intracellular and plasma steady‐state pharmacokinetics of raltegravir, darunavir, etravirine and ritonavir in heavily pre‐treated HIV‐infected patients
Authors: Ter Heine Rob , Mulder Jan Willem , Van Gorp Eric C. M. , Wagenaar Jiri F. P. , Beijnen Jos H. , Huitema Alwin D. R. 
Published: February 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The combination of raltegravir, etravirine and ritonavir boosted darunavir is a potent antiretroviral regimen for patients who have been heavily pre‐treated for HIV‐infection. All these agents have to exert their action intracellularly. However, only little is known about the cellular pharmacology of these agents. WHAT THIS STUDY ADDS • We investigated the steady‐state plasma and cellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir and the observed distinct intracellular accumulation ratios indicated that these antiretroviral drugs have different affinity for the cellular compartment.AIM To study the steady‐state plasma and intracellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir in heavily pre‐treated patients.METHODS Patients on a salvage regimen containing raltegravir, etravirine, darunavir and ritonavir were eligible for inclusion. During a 12 h dosing interval plasma and peripheral blood mononuclear cells were collected. Drug concentrations were measured using a validated LC‐MS/MS assay and pharmacokinetic analysis was performed using non‐linear mixed effect modelling.RESULTS Irregular absorption was observed with raltegravir and darunavir, which may be caused by enterohepatic cycling. Relative bioavailability of ritonavir was low, when compared with other ritonavir regimens. Raltegravir plasma pharmacokinetics showed wide interpatient variability, while intracellular raltegravir concentrations could not be detected (<0.001 mg l−1 in cell lysate). The intracellular to plasma ratios for etravirine, darunavir and ritonavir were 12.9, 1.32 and 7.72, respectively, and the relative standard error of these estimates were 16.3%, 12.3% and 13.0%.CONCLUSIONS The observed distinct intracellular accumulation indicated that these drugs have different affinity for the cellular compartment. The relatively high intracellular accumulation of etravirine may explain its efficacy and its previously described absence of PK–PD relationships in the therapeutic concentration range, when compared with other non‐nucleoside reverse transcriptase inhibitors. Lastly, the intracellular concentrations of ritonavir seem sufficient for inhibition of viral replication in the cellular compartment in PI‐naive patients, but not in patients with HIV harbouring PI resistance.
Pharmacokinetics, immunogenicity and bioactivity of the therapeutic antibody catumaxomab intraperitoneally administered to cancer patients
Authors: Ruf Peter , Kluge Michael , Jäger Michael , Burges Alexander , Volovat Constantin , Heiss Markus Maria , Hess Jürgen , Wimberger Pauline , Brandt Birgit , Lindhofer Horst 
Published: February 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The trifunctional antibody catumaxomab is a highly effective anti‐cancer therapeutic that is administered to patients suffering from malignant ascites intraperitoneally (i.p.) in microgram (µg) doses. So far, no clinical pharmacokinetic data are available. WHAT THIS STUDY ADDS • Catumaxomab attains effective local concentrations in the ascites fluid and shows low systemic exposure with an acceptable safety profile confirming the appropriateness of the i.p. application scheme.AIMS Catumaxomab is the first EMEA approved trifunctional anti‐EpCAM×anti‐CD3 antibody for the treatment of cancer patients with malignant ascites. A phase II pharmacokinetic study was conducted to determine local and systemic antibody concentrations and anti‐drug antibody (ADA) development.METHODS Thirteen cancer patients with symptomatic malignant ascites were treated with four ascending doses of 10, 20, 50, and 150 µg catumaxomab intraperitoneally (i.p.) infused on days 0, 3, 6 or 7 and 10. The pharmacokinetics of catumaxomab were studied by implementation of supportive data from a non clinical mouse tumour model. Additionally, ADA development was monitored.RESULTS Ten out of 13 patients were evaluable for pharmacokinetic analysis. Catumaxomab became increasingly concentrated in ascites during the course of treatment, attaining effective concentrations in the ng ml−1 range. Catumaxomab remained immunologically active even after several days in the circulation. The observed systemic catumaxomab exposure was low (<1%), with a maximal median plasma concentration (Cmax) of 403 pg ml−1. The mean elimination half‐life in the plasma was 2.13 days. All patients developed ADA, but not before the last infusion. High observed inter‐individual variability and low systemic exposure may be explained by the inverse correlation between tumour burden, effector cell numbers and systemic antibody bioavailability as demonstrated in a defined mouse tumour model.CONCLUSIONS Based on the high and effective local concentrations, low systemic exposure and acceptable safety profile, we confirmed that the i.p. application scheme of catumaxomab for the treatment of malignant ascites is appropriate.
Detection of exhaled hydrogen sulphide gas in healthy human volunteers during intravenous administration of sodium sulphide
Authors: Toombs Christopher F. , Insko Michael A. , Wintner Edward A. , Deckwerth Thomas L. , Usansky Helen , Jamil Khurram , Goldstein Brahm , Cooreman Michael , Szabo Csaba 
Published: February 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Hydrogen sulphide (H2S) is a biological mediator and a potential therapeutic agent. In animal studies, the metabolism and pharmacokinetics of H2S have been characterized. WHAT THIS STUDY ADDS • This study is first to demonstrate the pharmacokinetics of an intravenously administered H2S formulation in humans, and to characterize the exhaled H2S response in humans.INTRODUCTION Hydrogen sulphide (H2S) is an endogenous gaseous signaling molecule and potential therapeutic agent. Emerging studies indicate its therapeutic potential in a variety of cardiovascular diseases and in critical illness. Augmentation of endogenous sulphide concentrations by intravenous administration of sodium sulphide can be used for the delivery of H2S to the tissues. In the current study, we have measured H2S concentrations in the exhaled breath of healthy human volunteers subjected to increasing doses sodium sulphide in a human phase I safety and tolerability study.METHODS We have measured reactive sulphide in the blood via ex vivo derivatization of sulphide with monobromobimane to form sulphide‐dibimane and blood concentrations of thiosulfate (major oxidative metabolite of sulphide) via ion chromatography. We have measured exhaled H2S concentrations using a custom‐made device based on a sulphide gas detector (Interscan).RESULTS Administration of IK‐1001, a parenteral formulation of Na2S (0.005–0.20 mg kg−1, i.v., infused over 1 min) induced an elevation of blood sulphide and thiosulfate concentrations over baseline, which was observed within the first 1–5 min following administration of IK‐1001 at 0.10 mg kg−1 dose and higher. In all subjects, basal exhaled H2S was observed to be higher than the ambient concentration of H2S gas in room air, indicative of on‐going endogenous H2S production in human subjects. Upon intravenous administration of Na2S, a rapid elevation of exhaled H2S concentrations was observed. The amount of exhaled H2S rapidly decreased after discontinuation of the infusion of Na2S.CONCLUSION Exhaled H2S represents a detectable route of elimination after parenteral administration of Na2S.
Correlates of spontaneous reporting of adverse drug reactions within primary care: the paradox of low prescribers who are high reporters
Authors: Cox Anthony R. , Anton Christopher , McDowell Sarah E. , Marriott John F. , Ferner Robin E. 
Published: February 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Under‐reporting of adverse drug reactions to regulatory authorities is common, and there is concern about falling numbers of general practitioner reports.• Although previous work has suggested high prescribers are less interested in pharmacovigilance, a recent examination of reporting to the Yellow Card scheme has suggested ADR reporting is correlated with high prescribing rates.• This study aimed to examine influences on the reporting of ADRs to the Yellow Card scheme in primary care. WHAT THIS STUDY ADDS • High prescribing rates within primary care are correlated with low ADR reporting rates.• Several Primary Care Trust characteristics related to general practitioners, such as increased proportions of single‐handed general practitioners and larger list sizes, are associated with low ADR reporting rates.AIM(S) To examine Primary Care Trust (PCT) demographics influencing general practitioner (GP) involvement in pharmacovigilance.METHODS PCT adverse drug reaction (ADR) reports to the Yellow Card scheme between April 2004 and March 2006 were obtained for the UK West Midlands region. Reports were analysed by all drugs, and most commonly reported drugs (‘top drugs’). PCT data, adjusted for population size, were aggregated. Prescribing statistics and other characteristics were obtained for each PCT, and associations between these characteristics and ADR reporting rates were examined.RESULTS During 2004–06, 1175 reports were received from PCTs. Two hundred and eighty (24%) of these reports were for 14 ‘top drugs’. The mean rate of reporting for PCTs was 213 reports per million population. A total of 153 million items were prescribed during 2004–06, of which 33% were ‘top drugs’. Reports for all drugs and ‘top drugs’ were inversely correlated with the number of prescriptions issued per thousand population (rs=−0.413, 95% CI −0.673, −0.062, P < 0.05, and r=−0.420, 95% CI −0.678, −0.071, P < 0.05, respectively). Reporting was significantly negatively correlated with the percentages of male GPs within a PCT, GPs over 55 years of age, single‐handed GPs within a PCT, the average list size of a GP within a PCT, the overall deprivation scores and average QOF total points. ADR reports did not correlate significantly with the proportion of the population over 65 years old.CONCLUSIONS Some PCT characteristics appear to be associated with low levels of ADR reporting. The association of low prescribing areas with high ADR reporting rates replicates previous findings.
Add‐on montelukast to inhaled corticosteroids protects against excessive airway narrowing
Authors: Ulrik C. S. , Diamant Z. 
Published: February 2010

SummaryRationale
Excessive airway narrowing in response to broncho‐active stimuli is a predictor for severe exacerbations in asthma. Leukotriene receptor antagonists (LTRAs) have complementary properties to inhaled corticosteroids (ICS) on asthma control.Objectives
The LTRA montelukast may provide an additional protection against excessive airway narrowing. We tested the add‐on effects of montelukast on the maximal response plateau and PD20 to inhaled methacholine in asthmatics on a stable dose of ICS.Methods
Thirty‐one patients with allergic asthma [14M/17F, 19–50 years, forced expiratory volume in 1 s (FEV1) >70% pred., PD20 <3.9 μmol methacholine], with a twice documented response plateau to methacholine, were randomized in a double‐blind (montelukast 10 mg or matching placebo once daily), 12‐week parallel study. Bronchoprovocation tests with methacholine (0.03–256 μmol or 40% decline in FEV1) were repeated every 4 weeks and after wash‐out. The main study objectives were changes from baseline in maximal FEV1 decline at the response plateau (i.e. >2 post‐dose FEV1 values within 5%) and PD20 to methacholine after 12 weeks' treatment.Results
Neither treatment affected baseline FEV1 (P=0.62). Compared with placebo, montelukast significantly decreased the maximal response plateau to methacholine (mean difference 9.4%; 95% confidence interval 3.9–15.7; P<0.005), improved the FEV1 decline (mean change in FEV1 decline was 2.1% [montelukast] and −0.8% [placebo], respectively, P<0.05), and increased PD20 methacholine (mean change in PD20 of 5.3 [montelukast] and 1.4 [placebo] doubling doses, respectively, P<0.001).Conclusion
Add‐on montelukast to ICS has disease‐modifying effects in adults with persistent asthma, and hence reduces the risk of excessive airway narrowing (NCT 00913328). Cite this as: C. S. Ulrik and Z. Diamant, Clinical & Experimental Allergy, 2010 (40) 576–581.
Fine needle aspiration cytology and flow cytometry immunophenotyping of non‐Hodgkin lymphoma: can we do better?
Authors: Zeppa P. , Vigliar E. , Cozzolino I. , Troncone G. , Picardi M. , De Renzo A. , Grimaldi F. , Pane F. , Vetrani A. , Palombini Lucio 
Published: February 2010

P. Zeppa, E. Vigliar, I. Cozzolino, G. Troncone, M. Picardi, A. De Renzo, F. Grimaldi, F. Pane, A. Vetrani and L. Palombini Fine needle aspiration cytology and flow cytometry immunophenotyping of non‐Hodgkin lymphoma: can we do better?Objective:  To evaluate the diagnostic efficiency of fine needle aspiration cytology/flow cytometry (FNAC/FC) in the diagnosis and classification of non‐Hodgkin lymphoma (NHL) in a series of 446 cases and to compare the results with those of previous experiences to evaluate whether there had been an improvement in FNAC/FC diagnostic accuracy.Methods:  FNAC/FC was used to analyse 446 cases of benign reactive hyperplasia (BRH), NHL and NHL relapse (rNHL) in 362 lymph nodes and 84 extranodal lesions. When a diagnosis of NHL was reached, a classification was attempted combining FC data and cytological features. Sensitivity, specificity and positive and negative predictive values (PPV and NPV) of FNAC/FC in the diagnosis and classification of NHL were calculated and compared with those available in the literature.Results:  FNAC/FC provided a diagnosis of NHL and rNHL in 245 cases and of BRH in 188 cases. In nine cases, the diagnosis was ‘suggestive of NHL’ (sNHL) and in four cases was inadequate. Histology and clinical follow‐up confirmed 102 cases of NHL and detected one false positive. In 18 cases of BRH diagnosed by FNAC/FC, histological examination revealed 14 BRH and four NHL (false negatives). All nine cases diagnosed as sNHL were confirmed by histology. Including sNHL cases as false negatives, statistical analysis showed 94.9% sensitivity, 99.4% specificity, 99.6% PPV and 93.4% NPV in the diagnosis of NHL. A specific subtype was diagnosed in 125 cases and confirmed in 67 of 70 cases that had histological biopsies. Statistical analysis did not demonstrate significant improvements between the present series and previous studies either in diagnosis or in classification of NHL.Conclusions:  FNAC/FC is a fundamental tool in the diagnosis and classification of NHL but the exiguity of diagnostic material and other technical and clinical limitations will probably continue to limit further improvement of the technique.
The concerted action of bZip and cMyb transcription factors FlbB and FlbD induces brlA expression and asexual development in Aspergillus nidulans
Authors: Garzia Aitor , Etxebeste Oier , Herrero‐García Erika , Ugalde Unai , Espeso Eduardo A. 
Published: February 2010

SummaryFungi are capable of generating diverse cell types through developmental processes that stem from hyphae, acting as pluripotent cells. The formation of mitospores on emergence of hyphae to the air involves the participation of transcription factors, which co‐ordinate the genesis of new cell types, eventually leading to spore formation.In this investigation, we show that bZip transcription factor FlbB, which has been attributed to participate in transducing the aerial stimulus signal, activates the expression of c‐Myb transcription factor FlbD. Both factors then jointly activate brlA, a C2H2 zinc finger transcription factor, which plays a central role in spore formation. This sequence of regulatory events resembles developmental control mechanisms involving c‐Myb and bZip counterparts in metazoans and plants.
A bacterial elongation factor G homologue exclusively functions in ribosome recycling in the spirochaete Borrelia burgdorferi
Authors: Suematsu Takuma , Yokobori Shin‐ichi , Morita Hiroyuki , Yoshinari Shigeo , Ueda Takuya , Kita Kiyoshi , Takeuchi Nono , Watanabe Yoh‐ichi 
Published: February 2010

SummaryTranslation elongation factor G (EF‐G) in bacteria plays two distinct roles in different phases of the translation system. EF‐G catalyses the translocation of tRNAs on the ribosome in the elongation step, as well as the dissociation of the post‐termination state ribosome into two subunits in the recycling step. In contrast to this conventional view, it has very recently been demonstrated that the dual functions of bacterial EF‐G are distributed over two different EF‐G paralogues in human mitochondria. In the present study, we show that the same division of roles of EF‐G is also found in bacteria. Two EF‐G paralogues are found in the spirochaete Borrelia burgdorferi, EF‐G1 and EF‐G2. We demonstrate that EF‐G1 is a translocase, while EF‐G2 is an exclusive recycling factor. We further demonstrate that B. burgdorferi EF‐G2 does not require GTP hydrolysis for ribosome disassembly, provided that translation initiation factor 3 (IF‐3) is present in the reaction. These results indicate that two B. burgdorferi EF‐G paralogues are close relatives to mitochondrial EF‐G paralogues rather than the conventional bacterial EF‐G, in both their phylogenetic and biochemical features.