bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pirfenidone in idiopathic pulmonary fibrosis
Authors: Taniguchi H. , Ebina M. , Kondoh Y. , Ogura T. , Azuma A. , Suga M. , Taguchi Y. , Takahashi H. , Nakata K. , Sato A. , Takeuchi M. , Raghu G. , Kudoh S. , Nukiwa T. ,   the Pirfenidone Clinical Study Group in Japan
Published: December 2009

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease without proven effective therapy.A multicentre, double-blind, placebo-controlled, randomised phase III clinical trial was conducted in Japanese patients with well-defined IPF to determine the efficacy and safety of pirfenidone, a novel antifibrotic oral agent, over 52 weeks. Of 275 patients randomised (high-dose, 1,800 mg·day−1; low-dose, 1,200 mg·day−1; or placebo groups in the ratio 2:1:2), 267 patients were evaluated for the efficacy of pirfenidone. Prior to unblinding, the primary end-point was revised; the change in vital capacity (VC) was assessed at week 52. Secondary end-points included the progression-free survival (PFS) time.Significant differences were observed in VC decline (primary end-point) between the placebo group (-0.16 L) and the high-dose group (-0.09 L) (p = 0.0416); differences between the two groups (p = 0.0280) were also observed in the PFS (the secondary end-point). Although photosensitivity, a well-established side-effect of pirfenidone, was the major adverse event in this study, it was mild in severity in most of the patients.Pirfenidone was relatively well tolerated in patients with IPF. Treatment with pirfenidone may decrease the rate of decline in VC and may increase the PFS time over 52 weeks. Additional studies are needed to confirm these findings.
Strong purified protein derivative responses are associated with poor mycobacterium inhibition in latent TB
Authors: Kang J.S.L. , Cherian A. , Gan S.H. , Lee T.H. , Lee K.C. , Chee C.B.E. , Doherty T.M. , Wang Y.T. , Seah G.T. 
Published: December 2009

The tuberculin skin test (TST) using purified protein derivative (PPD) ofMycobacterium tuberculosisis traditionally used to diagnose latent tuberculosis (TB) infection (LTBI). However, LTBI diagnosis by peripheral blood mononuclear cell (PBMC) interferon (IFN)-γ responses toM. tuberculosis-specific antigens, early secreted antigenic target 6 kDa (ESAT-6) and culture filtrate protein (CFP)-10 has greater specificity. We investigated the difference in antimycobacterium cellular immunity in TB contacts who were strong TST reactors but nonresponsive to the ESAT-6/CFP-10 assay compared with those with concordant results.Healthy TB contacts were tested using the above two assays and mycobacterium survival was measured after co-culture of infected macrophages with their PBMCs.Whether PPD reactivity was tested by TST or by PBMC-specific IFN-γ responses, strongly PPD-reactive TB contacts without ESAT-6/CFP-10 responsiveness showed significantly better mycobacterium inhibition activity than ESAT-6/CFP-10-responsive TB contacts with the same PPD reactivity. In the former group, stronger PPD reactivity was associated with improved mycobacterium killing, whereas ESAT-6/CFP-10 responders showed the opposite result.PPD-reactive ESAT-6/CFP-10-nonresponsive TB contacts in our population may have had protective immunity related to prior mycobacterium exposure. ESAT-6/CFP10-responsive TB contacts are more likely to have LTBI and, in this group, strong PPD reactivity may paradoxically be associated with poor mycobactericidal activity.
Progress towards tuberculosis elimination: secular trend, immigration and transmission
Authors: Borgdorff M.W. , Van Den Hof S. , Kremer K. , Verhagen L. , Kalisvaart N. , Erkens C. , Van Soolingen D. 
Published: December 2009

This study aimed to determine to what extent tuberculosis trends in the Netherlands depend on secular trend, immigration and recent transmission.Data on patients in the Netherlands Tuberculosis Register in the period 1993–2007 were matched with restriction fragment length polymorphism (RFLP) patterns ofMycobacterium tuberculosisisolates. Index patients were defined as patients with pulmonary tuberculosis whose isolates had RFLP patterns not observed in another patient in the previous 2 yrs.Among 8,330 patients with pulmonary tuberculosis the isolates of 56% of native and 50% of foreign-born patients were clustered. Of these, 5,185 were included in detailed analysis: 1,376 native index patients, 2,822 foreign-born index patients and 987 secondary cases within 2 yrs of diagnosis of the index case. The incidence of native and foreign-born index patients declined by 6% and 2% per year, respectively. The number of secondary cases per index case was 0.24. The decline of native cases contributed most to the overall decline of tuberculosis rates and was largely explained by a declining prevalence of latent infection. Tuberculosis among immigrants was associated with immigration figures.Progress towards elimination of tuberculosis would benefit from intensifying diagnosis and treatment of latent infection among immigrants and global tuberculosis control.
Carotid body and cardiorespiratory alterations in intermittent hypoxia: the oxidative link
Authors: Del Rio R , Moya E A , Iturriaga R 
Published: December 2009

Intermittent hypoxia, a feature of obstructive sleep apnoea, potentiates ventilatory hypoxic responses, alters heart rate variability and produces hypertension, partially owing to an enhanced carotid body responsiveness to hypoxia. Since oxidative stress is a potential mediator of both chemosensory and cardiorespiratory alterations, we hypothesised that an antioxidant treatment may prevent these alterations.Accordingly, we studied the effects of ascorbic acid (1.25 g·L−1drinking water) on plasma lipid peroxidation, nitrotyrosine and inducible nitric oxide synthase (iNOS) immunoreactivity in the carotid body, ventilatory and carotid chemosensory responses to acute hypoxia, heart rate variability and arterial blood pressure in male Sprague–Dawley rats exposed to 5% O2; 12 episodes·h−1; 8 h·day−1or sham condition for 21 days.Intermittent hypoxia increased plasma lipid peroxidation, nitrotyrosine and iNOS expression in the carotid body, enhanced carotid chemosensory and ventilatory hypoxic responses, modified heart rate variability and produced hypertension. Ascorbic acid prevented the increased plasma lipid peroxidation and nitrotyrosine formation within the carotid body, and the enhanced carotid chemosensory and ventilatory responses to hypoxia, as well as heart rate variability alterations and hypertension.The present results support an essential role for oxidative stress in the generation of carotid body chemosensory potentiation and systemic cardiorespiratory alterations induced by intermittent hypoxia.
Codon usage is associated with the evolutionary age of genes in metazoan genomes
Authors: Prat Yosef , Fromer Menachem , Linial Nathan , Linial Michal 
Published: December 2009

Abstract

Background
Codon usage may vary significantly between different organisms and between genes within the same organism. Several evolutionary processes have been postulated to be the predominant determinants of codon usage: selection, mutation, and genetic drift. However, the relative contribution of each of these factors in different species remains debatable. The availability of complete genomes for tens of multicellular organisms provides an opportunity to inspect the relationship between codon usage and the evolutionary age of genes.

Results
We assign an evolutionary age to a gene based on the relative positions of its identified homologues in a standard phylogenetic tree. This yields a classification of all genes in a genome to several evolutionary age classes. The present study starts from the observation that each age class of genes has a unique codon usage and proceeds to provide a quantitative analysis of the codon usage in these classes. This observation is made for the genomes of Homo sapiens, Mus musculus, and Drosophila melanogaster. It is even more remarkable that the differences between codon usages in different age groups exhibit similar and consistent behavior in various organisms. While we find that GC content and gene length are also associated with the evolutionary age of genes, they can provide only a partial explanation for the observed codon usage.

Conclusion
While factors such as GC content, mutational bias, and selection shape the codon usage in a genome, the evolutionary history of an organism over hundreds of millions of years is an overlooked property that is strongly linked to GC content, protein length, and, even more significantly, to the codon usage of metazoan genomes.
Jellyfish mucin may have potential disease-modifying effects on osteoarthritis
Authors: Ohta Naoshi , Sato Masato , Ushida Kiminori , Kokubo Mami , Baba Takayuki , Taniguchi Kayoko , Urai Makoto , Kihira Koji , Mochida Joji 
Published: December 2009

AbstractBackgroundWe aimed to study the effects of intra-articular injection of jellyfish mucin (qniumucin) on articular cartilage degeneration in a model of osteoarthritis (OA) created in rabbit knees by resection of the anterior cruciate ligament. Qniumucin was extracted fromAurelia aurita(moon jellyfish) andStomolophus nomurai(Nomura's jellyfish) and purified by ion exchange chromatography. The OA model used 36 knees in 18 Japanese white rabbits. Purified qniumucin extracts fromS. nomuraiorA. auritawere used at 1 mg/ml. Rabbits were divided into four groups: a control (C) group injected with saline; a hyaluronic acid (HA)-only group (H group); two qniumucin-only groups (M groups); and two qniumucin + HA groups (MH groups). One milligram of each solution was injected intra-articularly once a week for 5 consecutive weeks, starting from 4 weeks after surgery. Ten weeks after surgery, the articular cartilage was evaluated macroscopically and histologically.ResultsIn the C and M groups, macroscopic cartilage defects extended to the subchondral bone medially and laterally. When the H and both MH groups were compared, only minor cartilage degeneration was observed in groups treated with qniumucin in contrast to the group without qniumucin. Histologically, densely safranin-O-stained cartilage layers were observed in the H and two MH groups, but cartilage was strongly maintained in both MH groups.ConclusionAt the concentrations of qniumucin used in this study, injection together with HA inhibited articular cartilage degeneration in this model of OA.
Comprehensive characterization of the DNA amplification at 13q34 in human breast cancer reveals TFDP1 and CUL4A as likely candidate target genes
Authors: Melchor Lorenzo , Saucedo-Cuevas Laura Paula , Muñoz-Repeto Iván , Rodríguez-Pinilla Socorro María , Honrado Emiliano , Campoverde Alfredo , Palacios Jose , Nathanson Katherine L , García María José , Benítez Javier 
Published: December 2009

Abstract
Introduction
Breast cancer subtypes exhibit different genomic aberration patterns with a tendency for high-level amplifications in distinct chromosomal regions. These genomic aberrations may drive carcinogenesis through the upregulation of proto-oncogenes. We have characterized DNA amplification at the human chromosomal region 13q34 in breast cancer.

Methods
A set of 414 familial and sporadic breast cancer cases was studied for amplification at region 13q34 by fluorescence in situ hybridization (FISH) analysis on tissue microarrays. Defining the minimal common region of amplification in those cases with amplification at 13q34 was carried out using an array-based comparative genomic hybridization platform. We performed a quantitative real-time - polymerase chain reaction (qRT-PCR) gene expression analysis of 11 candidate genes located within the minimal common region of amplification. Protein expression levels of two of these genes (TFDP1 and CUL4A) were assessed by immunohistochemical assays on the same tissue microarrays used for FISH studies, and correlated with the expression of a panel of 33 antibodies previously analyzed.

Results
We have found 13q34 amplification in 4.5% of breast cancer samples, but the frequency increased to 8.1% in BRCA1-associated tumors and to 20% in basal-like tumors. Tumors with 13q34 amplification were associated with high grade, estrogen receptor negativity, and expression of EGFR, CCNE, CK5, and P-Cadherin, among other basal cell markers. We have defined a 1.83 megabases minimal common region of genomic amplification and carried out mRNA expression analyses of candidate genes located therein, identifying CUL4A and TFDP1 as the most likely target genes. Moreover, we have confirmed that tumors with 13q34 amplification significantly overexpress CUL4A and TFDP1 proteins. Tumors overexpressing either CUL4A or TFDP1 were associated with tumor proliferation and cell cycle progression markers.

Conclusions
We conclude that 13q34 amplification may be of relevance in tumor progression of basal-like breast cancers by inducing overexpression of CUL4A and TFDP1, which are both important in cell cycle regulation. Alternatively, as these genes were also overexpressed in non-basal-like tumor samples, they could play a wider role in cancer development by inducing tumor proliferation.
Peripheral Blood Stem Cell Mobilization Tactics
Authors: Rosenbeck Lindsay L , Srivastava Shivani , Kiel Patrick J 
Published: December 2009

OBJECTIVE To evaluate the methods and collection techniques currently used in stem cell mobilization for patients undergoing autologous transplantation. DATA SOURCES Literature search was performed through PubMed (1948-August 2009) and MEDLINE (1977-August 2009). Reference citations from publications identified were also reviewed. STUDY SELECTION AND DATA EXTRACTION All literature identified was reviewed for inclusion. Original research and retrospective cohorts, along with previously published systematic reviews of stem cell mobilization and growth factors, were evaluated. Abstract data on plerixafor were also reviewed. DATA SYNTHESIS Successful mobilization of an adequate number of progenitor cells can help ensure and improve time to neutrophil and platelet engraftment. A variety of methods have been studied to find the safest and most predictable mobilization of CD34+ progenitor cells, including use of single agents or the combinations of hematopoietic growth factors, chemotherapy, and a novel chemokine receptor 4 antagonist. Currently, granulocyte colony-stimulating factor (G-CSF) 10 Mg/kg daily started 4 days prior to apheresis remains the standard of care for initial mobilization therapy. In patients who fail to mobilize or who are at high risk for mobilization failure, cyclophosphamide in conjunction with G-CSF may be used. Plerixafor, a novel chemokine receptor antagonist, in combination with G-CSF has demonstrated superiority for achieving collection goals compared to G-CSF alone in 2 Phase 3 trials. CONCLUSIONS The optimal mobilization strategy is still unknown; however, colony-stimulating factors remain the most commonly used mobilization agents. Currently, chemotherapy or plerixafor in combination with G-CSF is a reasonable option in heavily pretreated and hard-to-mobilize patients with non-Hodgkin's lymphoma and multiple myeloma.
Nonnucleoside Reverse Transcriptase Inhibitor Resistance and the Role of the Second-Generation Agents
Authors: Adams Jessica , Patel Nimish , Mankaryous Nancy , Tadros Mariam , Miller Christopher D 
Published: December 2009

OBJECTIVE To review the current state of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance, discuss the promising role of second-generation NNRTIs, and provide insight into their clinical utility. DATA SOURCES Articles were identified through searches of MEDLINE (May 2000-August 2009) and International Pharmaceutical Abstracts (May 1998-August 2009), using the key words etravirine, rilpivirine, TMC125, TMC278, diarylpyrimidine, NNRTI, and resistance. STUDY SELECTION AND DATA EXTRACTION Clinical trials, resistance studies, and pharmacokinetic data were selected for review. DATA SYNTHESIS NNRTIs are an integral class of antiretroviral agents utilized for the treatment of HIV-1 infection. These agents have become preferred therapy options for treatment-naïve individuals per treatment guideline recommendations and have gained increased popularity over protease inhibitor-based antiretroviral therapy. However, available NNRTIs possess inherent characteristics, such as low genetic barrier to resistance and high degree of cross-resistance, that limit their use in HIV therapy. Due to the growing utilization of this highly efficacious antiretroviral class and the increased capability for resistance development, many HIV-infected patients have experienced treatment failure of an NNRTI. Cross-resistance makes other first-generation NNRTI agents unavailable for future use. Etravirine and rilpivirine are second-generation NNRTIs that are not significantly hampered by cross-resistance and possess potent antiretroviral activity against current NNRTI-resistant viral strains. These agents provide new and important therapy options for many HIV-infected patients. CONCLUSIONS NNRTI resistance is an increasing problem that may impair the chances for therapeutic success in HIV-infected patients. Novel agents such as etravirine and rilpivirine provide new, sensitive options for patients and significantly improve the rate of virologic suppression when appropriately applied.
Altered Sleep Homeostasis after Restraint Stress in5-HTTKnock-Out Male Mice: A Role for Hypocretins
Authors: Rachalski Adeline , Alexandre Chloé , Bernard Jean-François , Saurini Françoise , Lesch Klaus-Peter , Hamon Michel , Adrien Joëlle , Fabre Véronique 
Published: December 2009

Restraint stress produces changes in the sleep pattern that are mainly characterized by a delayed increase in rapid eye movement sleep (REMS) amounts. Because the serotonin (5-HT) and the hypocretin (hcrt) systems that regulate REMS are interconnected, we used mutant mice deficient in the 5-HT transporter (5-HTT−/−) to examine the role of 5-HT and hcrt neurotransmissions in the sleep response to stress.In contrast to wild-type mice, restraint stress did not induce a delayed increase in REMS amounts in5-HTT−/−mice, indicating impaired sleep homeostasis in mutants. However, pharmacological blockade of the hcrt type 1 receptor (hcrt-R1) before restraint stress restored the REMS increase in5-HTT−/−mice. In line with this finding,5-HTT−/−mutants displayed after restraint stress higher long-lasting activation of hypothalamic preprohcrt neurons than wild-type mice and elevated levels of the hcrt-1 peptide and the hcrt-R1 mRNA in the anterior raphe area. Thus, hypocretinergic neurotransmission was enhanced by stress in5-HTT−/−mice. Furthermore, in5-HTT−/−but not wild-type mice, hypothalamic levels of the 5-HT metabolite 5-hydroxyindole acetic acid significantly increased after restraint stress, indicating a marked enhancement of serotonergic neurotransmission in mutants.Altogether, our data show that increased serotonergic -and in turn hypocretinergic- neurotransmissions exert an inhibitory influence on stress-induced delayed REMS. We propose that the direct interactions between hcrt neurons in the hypothalamus and 5-HT neurons in the anterior raphe nuclei account, at least in part, for the adaptive sleep–wakefulness regulations triggered by acute stress.
Diagnostic utility of the glucagon stimulation test in comparison to the insulin tolerance test in patients following pituitary surgery
Authors: Berg Christian , Meinel Timo , Lahner Harald , Yuece Ali , Mann Klaus , Petersenn Stephan 
Published: December 2009

ObjectiveThe glucagon stimulation test (GST) like the insulin tolerance test (ITT) stimulates both ACTH and GH secretion. However, there are limited data with modern assays on sensitivity and specificity for GST in comparison to ITT. The aim of this study was to evaluate the diagnostic utility of the GST for GH deficiency (GHD) and adrenal insufficiency (AI) in patients following pituitary surgery.Design and patientsITT and GST were performed within 7 days in 49 patients at least 3 months after transsphenoidal surgery. Serum GH and cortisol were measured by Immulite 2000 assay (Siemens AG). Receiver-operating characteristic (ROC) analysis was performed to identify the thresholds for GST.ResultsIn ITT, 18/49 cases were classified as AI. ROC analysis revealed a peak cortisol value >599 nmol/l in GST for adrenal sufficiency with 100% specificity and 32% sensitivity, and a peak cortisol <277 nmol/l with >95% specificity and 72% sensitivity for AI. Of the 49 subjects, 25 (51%) demonstrated levels between these cut-offs and could not be diagnosed by GST alone with sufficient accuracy. Regarding GHD, 21/49 cases were classified as insufficient by ITT. ROC analysis revealed a cut-off of 2.5 ng/ml with 95% sensitivity and 79% specificity. Of the 49 cases, seven (14%) were discordant in terms of defining GHD, with six subjects being treated for GHD according to GST although being sufficient in ITT.ConclusionIn our prospective series of patients with pituitary disease, GST is a potential alternative test for the assessment of GH reserve, but is a poor test for ACTH reserve. Test-specific cut-offs should be applied to avoid misinterpretation.
Enhancing the Effectiveness of Training through Information Feedback - The Case of Slovenia's Public Administration
Authors: Rodič Blaž , Miglič Gozdana , Vukovič Goran , Završnik Bruno , Leskovar Robert 
Published: December 2009

Enhancing the Effectiveness of Training through Information Feedback - The Case of Slovenia's Public Administration
After the fall of the Berlin wall, the public administrations in Central and Eastern European countries have had to adapt to an enormous number of changes in a relatively short time. Their civil servants are still facing a constantly changing regulatory framework which needs implementation and enforcement, as well as new demands from the growing private sector and the citizens. These challenges can only be met if the civil servants are highly qualified and constantly updating their qualifications. A sound system of in-service training is therefore crucial to keep the public servants on equal footing with the rapidly changing environment. The research presented in this paper analyzed the practices of training evaluation as an information feedback in a branch of Slovene state administration. We analyzed the attitudes of employees towards evaluation with the assumption that there probably are notable differences between the attitudes of public servants depending on their demographic qualities. The results of the research, that 414 public servants have participated in, show that the position in the hierarchy has the strongest influence on their attitude towards evaluation. Empirical data also show that most of the employees are willing to participate in a continuous and objective training evaluation, but the leading public servants are less involved in the evaluation than expected.
An Analysis of Corruption in Micro-Enterprises
Authors: Tomašič Mladen 
Published: December 2009

An Analysis of Corruption in Micro-Enterprises
The purpose of this study is to present the research work made whilst studying the presence of corruption in the operations of Slovenian micro-enterprises. Our study builds on research which we carried out in 2005 and compares the findings of both studies. We wish to present our findings to public experts for a professional assessment and provide a basis for further work. We hope that in this way we can contribute to the development of new guidelines for the preparation of further analysis, the causes and elimination or at least limitation of corruption in business operations. Notable studies, which address corporate corruption in Slovenia, are non-existent. The results have confirmed the basic research hypothesis that the presence of corruption in the micro-business environment compared to a previous study in the last five years has increased.